Details of a Researcher - Takahashi, Shinichi

Papers - Takahashi, Shinichi

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Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery

Kato C., Ueda K., Morimoto S., Takahashi S., Nakamura S., Ozawa F., Ito D., Daté Y., Okada K., Kobayashi N., Nakahara J., Okano H.

Inflammation and Regeneration 44 ( 1 ) 2024.12

Background: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs. Methods: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment. Results: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search. Conclusions: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.

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Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS)

Harada S., Iida M., Miyagawa N., Hirata A., Kuwabara K., Matsumoto M., Okamura T., Edagawa S., Kawada Y., Miyake A., Toki R., Akiyama M., Kawai A., Sugiyama D., Sato Y., Takemura R., Fukai K., Ishibashi Y., Kato S., Kurihara A., Sata M., Shibuki T., Takeuchi A., Kohsaka S., Sawano M., Shoji S., Izawa Y., Katsumata M., Oki K., Takahashi S., Takizawa T., Maruya H., Nishiwaki Y., Kawasaki R., Hirayama A., Ishikawa T., Saito R., Sato A., Soga T., Sugimoto M., Tomita M., Komaki S., Ohmomo H., Ono K., Otsuka-Yamasaki Y., Shimizu A., Sutoh Y., Hozawa A., Kinoshita K., Koshiba S., Kumada K., Ogishima S., Sakurai-Yageta M., Tamiya G., Takebayashi T.

Journal of epidemiology 34 ( 8 ) 393 - 401 2024.08

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

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Factors influencing the early neurological deterioration in intracranial branch atheromatous diseases

Deguchi I., Fujiwara S., Arai N., Nakagami T., Kimura R., Oryu K., Watanabe K., Kato Y., Hayashi T., Takahashi S., Suda S.

Neurology and Clinical Neuroscience 12 ( 4 ) 217 - 224 2024.07

Background: Intracranial branch atheromatous disease (BAD)-type cerebral infarction is often associated with a progressive worsening of neurological symptoms in the acute phase. Aim: To investigate the factors influencing the occurrence of early neurological deterioration (END) in patients with BAD. Methods: We included and evaluated 198 consecutive patients (150 patients with lenticulostriate artery [LSA-BAD] and 48 patients with paramedian pontine artery [PPA-BAD]) with onset within 24 h and with a modified Rankin scale score of ≤1 before admission for END retrospectively out of 235 patients with BAD-type cerebral infarction admitted to our hospital from January 2019 to March 2023. Results: END was observed in 26 (17%) and 15 (31%) patients with LSA-BAD and PPA-BAD, respectively. Patients in the END group with LSA-BAD had significantly higher rates of diabetes mellitus and blood glucose (BG) levels on admission and lower rates of initial clopidogrel loading therapy than those in the non-END group. Patients in the END group with PPA-BAD had significantly higher BG levels on admission than those in the non-END group. In LSA-BAD multivariate analysis, the BG level on admission and initial clopidogrel loading were identified as factors influencing END (BG level [per 10 mg/dL], odds ratio [OR] 1.084, 95% confidence interval [CI] 1.008–1.166; initial clopidogrel loading, OR 0.302, 95% CI 0.101–0.901). Conclusions: Higher BG levels at stroke onset were associated with END in patients with LSA-BAD and PPA-BAD. Additionally, initial clopidogrel loading therapy suppressed END in patients with LSA-BAD.

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Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes

Leventoux N., Morimoto S., Ishikawa M., Nakamura S., Ozawa F., Kobayashi R., Watanabe H., Supakul S., Okamoto S., Zhou Z., Kobayashi H., Kato C., Hirokawa Y., Aiba I., Takahashi S., Shibata S., Takao M., Yoshida M., Endo F., Yamanaka K., Kokubo Y., Okano H.

Acta Neuropathologica 147 ( 1 ) 2024.06

ISSN 00016322

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson’s disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

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Cerebral Small Vessel Disease Burden for Bleeding Risk during Antithrombotic Therapy: Bleeding with Antithrombotic Therapy 2 Study

Tanaka K., Miwa K., Koga M., Yoshimura S., Kamiyama K., Yagita Y., Nagakane Y., Hoshino H., Terasaki T., Okada Y., Yakushiji Y., Takahashi S., Ueda T., Hasegawa Y., Shiozawa M., Sasaki M., Kudo K., Tanaka J., Nishihara M., Yamaguchi Y., Fujita K., Honda Y., Kawano H., Ide T., Yoshimoto T., Ihara M., Hirano T., Toyoda K.

Annals of Neurology 95 ( 4 ) 774 - 787 2024.04

ISSN 03645134

Objective: This study was undertaken to determine the excess risk of antithrombotic-related bleeding due to cerebral small vessel disease (SVD) burden. Methods: In this observational, prospective cohort study, patients with cerebrovascular or cardiovascular diseases taking oral antithrombotic agents were enrolled from 52 hospitals across Japan between 2016 and 2019. Baseline multimodal magnetic resonance imaging acquired under prespecified conditions was assessed by a central diagnostic radiology committee to calculate total SVD score. The primary outcome was major bleeding. Secondary outcomes included bleeding at each site and ischemic events. Results: Of the analyzed 5,250 patients (1,736 women; median age = 73 years, 9,933 patient-years of follow-up), antiplatelets and anticoagulants were administered at baseline in 3,948 and 1,565, respectively. Median SVD score was 2 (interquartile range = 1–3). Incidence rate of major bleeding was 0.39 (per 100 patinet-years) in score 0, 0.56 in score 1, 0.91 in score 2, 1.35 in score 3, and 2.24 in score 4 (adjusted hazard ratio [aHR] for score 4 vs 0 = 5.47, 95% confidence interval [CI] = 2.26–13.23), that of intracranial hemorrhage was 0.11, 0.33, 0.58, 0.99, and 1.06, respectively (aHR = 9.29, 95% CI = 1.99–43.35), and that of ischemic event was 1.82, 2.27, 3.04, 3.91, and 4.07, respectively (aHR = 1.76, 95% CI = 1.08–2.86). In addition, extracranial major bleeding (aHR = 3.43, 95% CI = 1.13–10.38) and gastrointestinal bleeding (aHR = 2.54, 95% CI = 1.02–6.35) significantly increased in SVD score 4 compared to score 0. Interpretation: Total SVD score was predictive for intracranial hemorrhage and probably for extracranial bleeding, suggesting the broader clinical relevance of cerebral SVD as a marker for safe implementation of antithrombotic therapy. ANN NEUROL 2024;95:774–787.

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Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial

Houkin K., Osanai T., Uchiyama S., Minematsu K., Taguchi A., Maruichi K., Niiya Y., Asaoka K., Kuga Y., Takizawa K., Haraguchi K., Yoshimura S., Kimura K., Tokunaga K., Aoyama A., Ikawa F., Inenaga C., Abe T., Tominaga A., Takahashi S., Kudo K., Fujimura M., Sugiyama T., Ito M., Kawabori M., Hess D.C., Savitz S.I., Hirano T.

JAMA Neurology 81 ( 2 ) 154 - 162 2024.02

ISSN 21686149

Importance: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke. Objective: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset. Design, Setting, and Participants: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022. Exposure: Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset. Main Outcomes and Measures: The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test. Results: This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P =.90; adjusted risk difference, 0.5% [95% CI, -7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups. Conclusions and Relevance: In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study. Trial Registration: ClinicalTrials.gov Identifier: NCT02961504.

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Recurrent Stroke with Rapid Development of Intracranial Artery Stenosis and Subsequent Successful Mechanical Thrombectomy in Essential Thrombocythemia

Kato Y., Iijima S., Kohyama S., Maeda T., Sato T., Takahashi S., Suda S.

Internal Medicine 63 ( 6 ) 847 - 852 2024

ISSN 09182918

Essential thrombocythemia is a myeloproliferative neoplasm. Ischemic stroke is frequently the first manifestation of essential thrombocythemia. We herein report a patient with JAK2V617 mutation-positive essential thrombocythemia who developed recurrent ischemic stroke with rapid development of intracranial artery stenosis and subsequently underwent successful mechanical thrombectomy. The high JAK2V617F allele burden in our patient (58.4%) may have affected the patient's condition. We discuss similar reports in the literature and the possible pathophysiologic mechanism of large artery involvement in these patients.

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Factors affecting early neurological deterioration after intravenous alteplase treatment for branch atheromatous disease

Mizuno S., Deguchi I., Takahashi S., Arai N., Nakagami T., Kimura R., Oryu K., Watanabe K., Ueda S., Fujiwara S., Kato Y., Hayashi T., Suda S.

Neurology and Clinical Neuroscience 2024

Background: Intravenous alteplase treatment is effective for acute cerebral infarction, irrespective of the stroke type. However, its value for branch atheromatous disease (BAD) remains unclear, and early neurological deterioration (END) can occur. Aim: To investigate factors affecting END after intravenous alteplase treatment in patients with acute BAD. Methods: This study included 40 consecutive patients diagnosed with cerebral infarction due to BAD in the lenticulostriate artery territory and treated with intravenous alteplase between April 2007 and March 2023. END was defined as an increase of ≥2 points in the total National Institutes of Health Stroke Scale score or ≥1 point in the motor items within 24 h post-alteplase administration compared to the score at admission. Factors affecting END were retrospectively evaluated. Results: END was observed in 17 of the 40 patients (43%). The median time from the start of alteplase administration to the worsening of neurologic symptoms was 5 h. After intravenous alteplase treatment, the END group had a significantly lower 24-h average systolic blood pressure (SBP, mean ± standard deviation mmHg) than the non-END group (142.0 ± 15.2 vs. 149.4 ± 12.0, p < 0.001). The SBP at each time point (immediately before alteplase administration and every 2 h up to 24 h after alteplase administration) was significantly lower in the END than in the non-END group at 2, 4, and 6 h after alteplase administration. Conclusions: When intravenous alteplase was administered for BAD, BP control after alteplase administration affected END. When alteplase is administered for BAD, it is important to control the blood pressure to maintain hemodynamics.

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Association between Mobility of Residual Left Atrial Thrombus and Stroke Severity in Patients with Nonvalvular Atrial Fibrillation

Kato Y., Hayashi T., Nakano S., Arai T., Fujiwara S., Watanabe K., Oryu K., Kimura R., Arai N., Nakagami T., Deguchi I., Takahashi S., Suda S.

Journal of Nippon Medical School 91 ( 3 ) 322 - 327 2024

ISSN 13454676

Background: The differences in the characteristics of ischemic stroke associated with a mobile versus nonmobile residual left atrial thrombus (LAT) are unclear. We investigated whether the mobility of an LAT detected by transthoracic echocardiography is associated with the clinical features of stroke. Methods: This study included 20 consecutive patients with nonvalvular atrial fibrillation who were ad-mitted to our hospital for treatment of acute ischemic stroke and then found to have an LAT on transthoracic echocardiography. The patients were divided into two groups: those with a mobile LAT (Group M) and those with a nonmobile LAT (Group N). The clinical, neuroradiological, and echocar-diographic variables were assessed. Results: The LAT was mobile in 11 patients (Group M) and nonmobile in nine patients (Group N). The median National Institutes of Health Stroke Scale score on admission was higher in Group M than N (17 vs. 7, respectively; p=0.196). Four patients in Group M and one in Group N developed in-hospital stroke recurrence (36% vs. 11%, respectively; p=0.319). The prevalence of large vessel occlusion (15 events in Group M and 10 events in Group N, including in-hospital recurrent events) was significantly higher in Group M than N (73% vs. 30%, respectively; p=0.049), which seemed to lead to poorer functional outcomes in Group M than N (ratio of modified Rankin scale score of 0-2 at discharge: 18% vs. 44%, respectively; p=0.336). Conclusions: The mobility of LAT may affect stroke severity in patients with nonvalvular atrial fibrillation.

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Induced pluripotent stem cells-based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis

Okano H., Morimoto S., Kato C., Nakahara J., Takahashi S.

Journal of Neurochemistry 167 ( 5 ) 603 - 614 2023.12

ISSN 00223042

It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs-based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs-based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS-specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double-blind, randomized, placebo-controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient-derived iPSCs-motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA-seq data showed that ROPI treatment suppressed the sterol regulatory element-binding protein 2-dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.

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Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery

Morimoto S., Takahashi S., Ito D., Daté Y., Okada K., Kato C., Nakamura S., Ozawa F., Chyi C.M., Nishiyama A., Suzuki N., Fujimori K., Kondo T., Takao M., Hirai M., Kabe Y., Suematsu M., Jinzaki M., Aoki M., Fujiki Y., Sato Y., Suzuki N., Nakahara J., Okano H.

Cell Stem Cell 30 ( 6 ) 766 - 780.e9 2023.06

ISSN 19345909

iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received ropinirole or placebo for 24 weeks in the double-blind period to evaluate safety, tolerability, and therapeutic effects. Adverse events were similar in both groups. During the double-blind period, muscle strength and daily activity were maintained, but a decline in the ALSFRS-R, which assesses the functional status of ALS patients, was not different from that in the placebo group. However, in the open-label extension period, the ropinirole group showed significant suppression of ALSFRS-R decline and an additional 27.9 weeks of disease-progression-free survival. iPSC-derived motor neurons from participants showed dopamine D2 receptor expression and a potential involvement of the SREBP2-cholesterol pathway in therapeutic effects. Lipid peroxide represents a clinical surrogate marker to assess disease progression and drug efficacy. Limitations include small sample sizes and high attrition rates in the open-label extension period, requiring further validation.

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Maiden voyage: induced pluripotent stem cell-based drug screening for amyotrophic lateral sclerosis

Ito D., Morimoto S., Takahashi S., Okada K., Nakahara J., Okano H.

Brain 146 ( 1 ) 13 - 19 2023.01

ISSN 00068950

Using patient-derived induced pluripotent stem cells, neurodegenerative disease phenotypes have been recapitulated and their pathogenesis analysed leading to significant progress in drug screening. In amyotrophic lateral sclerosis, high-throughput screening using induced pluripotent stem cells-derived motor neurons has identified candidate drugs. Owing to induced pluripotent stem cell-based drug evaluation/screening, three compounds, retigabine, ropinirole and bosutinib, have progressed to clinical trials. Retigabine blocks hyperexcitability and improves survival in amyotrophic lateral sclerosis patient-derived motor neurons. In a randomized clinical trial (n = 65), treatment with retigabine reduced neuronal excitability after 8 weeks. Ropinirole, identified in a high-throughput screening, attenuates pathological phenotypes in patient-derived motor neurons. In a trial limited by a small sample size (n = 20), ropinirole was tolerable and had clinical benefits on function and survival. A phase 1 study of bosutinib has reported safety and tolerability for 12 weeks. Thus, these clinical trials show safety and positive effects and confirm the reliability of stem cell-based drug discovery. This novel strategy leads to reduced costs and time when compared to animal testing and opens new avenues for therapy in intractable diseases.

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Pathophysiology and Optimal Treatment of Intracranial Branch Atheromatous Disease

Deguchi I., Takahashi S.

Journal of Atherosclerosis and Thrombosis 30 ( 7 ) 701 - 709 2023

ISSN 13403478

Intracranial branch atheromatous disease (BAD) is a pathological condition characterized by the occlusion of a relatively large perforating branch (700–800 μm) near the orifice of a parent artery due to atherosclerotic plaque-based thrombus (microatheroma). BAD is refractory to treatment and follows a course of progressive exacerbation, especially motor paralysis. Uniform treatment for common atherothrombotic cerebral infarction or lacunar infarction does not prevent the progressive exacerbation of BAD, and consequently affects functional prognosis. To date, various combinations of treatments have been investigated and proposed to attenuate the worsening symptoms of BAD. However, no therapy with established efficacy is yet available for BAD. Since it is the most difficult condition to treat in the area of cerebral infarction, the establishment of optimal treatment methods for BAD is keenly awaited. This review presents an overview of the acute treatments available for BAD and discusses the prospects for optimal treatment.

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Efficacy of Treatment with and without Initial Clopidogrel Loading in Branch Atheromatous Disease

Deguchi I., Osada T., Takahashi S.

Internal Medicine 62 ( 20 ) 2959 - 2964 2023

ISSN 09182918

Objective Despite aggressive therapeutic interventions during the acute phase of branch atheromatous disease (BAD)-type cerebral infarction, many patients, even those with a mild condition at the onset, experience neurological deterioration after hospitalization and develop serious deficits. We compared the therapeutic efficacy of multiple antithrombotic therapies for BAD between patients who received a clopidogrel loading dose (loading group; LG) and those without loading (non-loading group; NLG). Patients Between January 2019 and May 2022, patients with BAD-type cerebral infarction in the lenticulostriate artery admitted within 24 h of the onset were recruited. This study included 95 consecutive patients who received combination argatroban and dual antiplatelet therapy (aspirin and clopidogrel). Methods Patients were classified into the LG and NLG according to whether or not a loading dose of clopidogrel (300 mg) had been administered on admission. Changes in neurological severity [National Institutes of Health Stroke Scale (NIHSS) score] during the acute phase were retrospectively evaluated. Results There were 34 (36%) and 61 (64%) patients in the LG and NLG, respectively. On admission, the median NIHSS score was similar between the groups [LG: 2.5 (2-4) vs. NLG: 3 (2-4), p=0.771]. At 48 h following admission, the median NIHSS scores were 1 (0.25-4), and 2 (1-5) in the LG and NLG, respectively (p=0.045). Early neurological deterioration (END; defined as worsening of the NIHSS score by !4 points at 48 h after admission) occurred in 3% of LG and 20% of NLG patients (p=0.028). Conclusion Administration of a clopidogrel loading dose with combination antithrombotic therapy for BAD reduced END.

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Aseptic Meningitis after BNT-162b2 COVID-19 Vaccination: Case Report and Literature Review

Kato Y., Osada T., Araki N., Takahashi S.

Keio Journal of Medicine 72 ( 4 ) 102 - 105 2023

ISSN 00229717

We encountered a-27-year-old female patient who developed refractory severe headache and photo-phobia after the first dose of COVID-19 vaccine. Despite her prior history of migraine, we diagnosed COVID-19 vaccine-induced aseptic meningitis. Symptoms were significantly resolved after methylpred-nisolone therapy. On reviewing the literature, we could find only nine similar cases, with over half of them affecting women aged 20–40 years. Although uncommon, aseptic meningitis should be suspect-ed in patients with persistent or delayed onset of headache following COVID-19 vaccination.

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Status of neurological deficits after mechanical thrombectomy in elderly patients with ischemia

Deguchi I., Osada T., Kohyama S., Takahashi S.

Journal of Clinical Neuroscience 105 16 - 21 2022.11

ISSN 09675868

Background: Numerous studies report poorer outcomes after mechanical thrombectomy (MT) in elderly patients than in non-elderly patients. We aimed to investigate the changes in neurological symptoms after MT in elderly patients. Methods: We included 151 patients with acute stroke who independently performed activities of daily living before admission, underwent MT at our hospital between January 1, 2019 and December 31, 2021, and had successful recanalization (thrombolysis in cerebral infarction grade >2b). The subjects were divided into two groups according to whether they were aged ≥80 years (elderly group) or <80 years (non-elderly group), and the National Institutes of Health Stroke Scale (NIHSS) scores and deep and subcortical white matter hyperintensity (DSWMH) grades were compared between both groups. Results: There were 57 (38 %) and 94 (62 %) patients in the elderly and non-elderly groups, respectively. After propensity score matching, the median (interquartile range) NIHSS scores were significantly higher in the elderly group than in the non-elderly group at both 24 h (12 [5.5–19] vs 8; [2–14] P = 0.040) and 1 week (8 [3–12] vs 2.5 [0–13.5]; P = 0.041) after MT but not before MT (18 [13.5–22.5] vs 20 [14.5–24]; P = 0.549). DSWMH grades were significantly higher in the elderly group than in the non-elderly group (2 [1–3] vs 1 [0–2]; P = 0.018). Conclusions: MT in the elderly group was associated with poorer improvement in neurological symptoms from the early period after MT than in the non-elderly group, even when successful recanalization was achieved. White matter lesions may contribute to the poor neurological improvement after recanalization in the elderly group.

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Differences in oral anticoagulant prescriptions between specialists and non-specialists in patients with cardioembolic stroke caused by non-valvular atrial fibrillation

Deguchi I., Osada T., Arai N., Takahashi S.

Heart and Vessels 37 ( 5 ) 867 - 874 2022.05

ISSN 09108327

Atrial fibrillation (AF) is a common disease encountered in daily practice; however, few patients with AF received oral anticoagulant (OAC) therapy. This study focused on differences in OAC prescriptions and influencing factors between specialists (neurological and cardiovascular) and non-specialists. A retrospective comparative analysis was conducted on 480 patients with acute cardioembolic stroke caused by non-valvular AF who were admitted to our hospital between January 1, 2015, and December 31, 2020. All patients had visited our hospital or other hospitals for their underlying diseases. Overall, 232 (specialist group SG) and 248 patients (non-specialist group NSG) were examined by specialists and non-specialists, respectively. The NSG had a significantly lower percentage of OAC prescriptions on admission than the SG (P < 0.01), even after propensity score matching. Factors influencing OAC prescription in the SG were age, hypertension, paroxysmal AF, dementia, CHADS2 score, and antiplatelet drug use, while those in the NSG were a history of cerebral infarction, paroxysmal AF, dementia, and antiplatelet drug use [SG: age, odds ratio (OR) 0.919, 95% confidence interval (CI) 0.865–0.976; hypertension, OR 0.266, 95% CI 0.099–0.713; paroxysmal AF, OR 0.189, 95% CI 0.055–0.658; dementia, OR 0.253, 95% CI 0.085–0.758; CHADS2 score, OR 2.833, 95% CI 1.682–4.942; and antiplatelet drug use, OR 0.072, 95% CI 0.025–0.206; NSG: cerebral infarction, OR 5.940, 95% CI 1.581–22.309; paroxysmal AF, OR 0.077, 95% CI 0.010–0.623; dementia, OR 0.077, 95% CI 0.014–0.438; and antiplatelet drug use, OR 0.024, 95% CI 0.004–0.152]. In conclusion, the OAC prescription rate was higher in patients with non-valvular AF whose family physicians were specialists at the time of cerebral infarction onset. In addition, in the SG, advanced age and hypertension were associated with not prescribing OAC, whereas a higher CHADS2 score was associated with the prescription of OACs. In the NSG, a history of cerebral infarction was associated with the prescription of OACs. Further, paroxysmal AF, antiplatelet drug use, and dementia were associated with non-OAC therapy in both the groups.

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Influence of a clinical trial in the decision-making processes of patients with amyotrophic lateral sclerosis

Kato C., Morimoto S., Takahashi S., Daté Y., Okada K., Okano H., Nakahara J., Ito D.

Journal of Neurology 269 ( 5 ) 2634 - 2640 2022.05

ISSN 03405354

Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease, and patients diagnosed with ALS have a survival time of 2–5 years without life-sustaining therapy. Decision-making processes for the acceptance or decline of percutaneous endoscopic gastrostomy (PEG) and tracheostomy with invasive ventilation (TIV) therapy are complex and multifaceted. In this study, we examined whether participation or no participation in clinical trials of ALS had an influence on the decision-making processes of ALS patients. Methods: Fifty-seven consecutive ALS participants were recruited. Two participants did not wish to participate in any clinical trials, and Twenty-two participants were enrolled in clinical trials. Twenty-three participants wished to participate but could not be enrolled in any of the clinical trials because they exceeded the number of participants in these trials or they met the exclusion criteria. Result: At baseline, there was no significant difference in the preference rates for PEG and TIV between the participant and non-participant groups, but after the double-blind period/6 months, both preference rates were significantly higher in the non-participant group than in the participant group. Notably, the rate of preferred TIV in the participant group drastically decreased after the double-blind period. A single regression analysis revealed that participation in clinical trials had a strong influence on the change of TIV preference for 6 months. Conclusion: Participation in a clinical trial decreases the willingness to prolong life after the clinical trial. The present results are meaningful when designing clinical trials and discussing life-sustaining treatments with ALS patients.

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Association Between Oral Anticoagulants and Stroke Severity at Onset in Elderly Patients with Cardioembolic Stroke Due to Non-Valvular Atrial Fibrillation

Deguchi I., Osada T., Takahashi S.

Journal of Stroke and Cerebrovascular Diseases 31 ( 3 ) 2022.03

ISSN 10523057

Objectives: This study aimed to determine whether oral anticoagulant therapy affects the severity of cerebral infarction at onset in elderly patients with non-valvular atrial fibrillation. Materials and Methods: This retrospective study included 330 elderly patients (aged ≥75 years) who were hospitalized for cardioembolic stroke due to non-valvular atrial fibrillation. Patients’ medical history, stroke severity at onset (National Institutes of Health Stroke Scale score), and the prevalence of large vessel occlusion were compared between patients who received oral anticoagulant therapy (n = 109) and those who did not receive oral anticoagulant therapy (n = 221). Results: Stroke severity was significantly lower in patients who received anticoagulants than in those who did not receive anticoagulants (6 versus 12; P = 0.021). Patients who did not receive anticoagulants had a significantly higher prevalence of large vessel occlusion (52% versus 37%; P = 0.010). After resampling based on propensity score matching, both median stroke severity (7 versus 12; P = 0.046) and large vessel occlusion prevalence (36% versus 57%; P = 0.019) were significantly lower in patients who received anticoagulant therapy. Conclusions: The results of this study suggest that elderly patients with non-valvular atrial fibrillation who are administered oral anticoagulant therapy before the onset of cerebral infarction develop less severe stroke than those who are not receiving oral anticoagulant therapy. Thus, oral anticoagulant therapy should be actively considered in patients with non-valvular atrial fibrillation as it does not only prevents cerebral embolism, but also reduces the risk of severe sequelae.

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Thrombectomy for acute large vessel occlusion in posterior and anterior circulation: a single institutional retrospective observational study

Kuribara T., Iihoshi S., Tsukagoshi E., Teranishi A., Kinoshita Y., Sugasawa S., Kohyama S., Takahashi S., Kurita H.

Neuroradiology 64 ( 3 ) 565 - 574 2022.03

ISSN 00283940

Purpose: Thrombectomy has been the gold standard therapy for anterior circulation occlusion; however, studies regarding thrombectomy in posterior circulation are lacking. In this study, we compared the efficiency of thrombectomy for acute large vessel occlusion between the posterior and anterior circulation at a single institution. Methods: We retrospectively analyzed consecutive patients who underwent thrombectomy for acute large vessel occlusion at our institution between August 2014 and April 2021. Differences in the clinical background, time course, and treatment technique and outcomes were evaluated between anterior and posterior circulation occlusions. Results: Overall, 353 patients (225 men and 128 women) were included: 314 patients had anterior circulation occlusion and 39 patients had posterior circulation occlusion. Between the patients with anterior and posterior circulation occlusions, the National Institutes of Health Stroke Scale (NIHSS) score (16 [12–21] vs. 29 [19–34], respectively, p < 0.001), door-to-puncture time (65 [45–99] vs. 99 [51–121] min, respectively, p = 0.018), and mortality (22 [7%] vs. 8 [20.5%] patients, respectively, p = 0.010) were significantly different; however, favorable outcome was not significantly different. Conclusion: Higher NIHSS score, delayed treatment, and higher mortality were observed in posterior circulation occlusion than in anterior circulation occlusion; successful reperfusion and favorable outcomes were similar between them. Similar favorable outcomes and reperfusion ratio to the anterior circulation might be achieved also in the posterior circulation; however, delayed treatment and the optimal first-pass strategy might need further improvement.

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Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit

Takahashi S.

Cells 11 ( 5 ) 2022.03

The neurovascular unit (NVU) is a conceptual framework that has been proposed to bet-ter explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the brain gray matter. The major components of the NVU are the neurons, astrocytes (astroglia), microvessels, pericytes, and microglia. In addition, we believe that oligodendrocytes should also be included as an indispensable component of the NVU in the white matter. Of all these components, astrocytes in particular have attracted the interest of researchers because of their unique anatomical location; these cells are interposed between the neurons and the microvessels of the brain. Their location suggests that astrocytes might regulate the cerebral blood flow (CBF) in response to neuronal activity, so as to ensure an adequate supply of glucose and oxygen to meet the metabolic demands of the neurons. In fact, the adult human brain, which accounts for only 2% of the entire body weight, consumes approximately 20–25% of the total amount of glucose and oxygen consumed by the whole body. The brain needs a continuous supply of these essential energy sources through the CBF, because there are practically no stores of glucose or oxygen in the brain; both acute and chronic cessation of CBF can adversely affect brain functions. In addition, another important putative function of the NVU is the elimination of heat and waste materials produced by neuronal activity. Recent evidence suggests that astrocytes play pivotal roles not only in supplying glucose, but also fatty acids and amino acids to neurons. Loss of astrocytic support can be expected to lead to malfunction of the NVU as a whole, which underlies numerous neurological disorders. In this review, we shall focus on historical and recent findings with regard to the metabolic contributions of astrocytes in the NVU.

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Atrial Cardiopathy and Cryptogenic Stroke

Kato Y., Takahashi S.

Frontiers in Neurology 13 2022.02

Recent advances in pathophysiology suggest that a pathological atrial substrate can cause embolic stroke even in patients without atrial fibrillation (AF). This pathological condition is called “atrial cardiopathy”, which indicates atrial structural and functional disorders that can precede AF. The objective of this narrative review was to provide a current overview of atrial cardiopathy and cryptogenic stroke. We searched the PubMed database and summarized the recent findings of the identified studies, including the pathogenesis of atrial cardiopathy, biomarkers of atrial cardiopathy, relationship between atrial cardiopathy and cryptogenic stroke, and therapeutic interventions for atrial cardiopathy. Abnormal atrial substrate (atrial cardiopathy) that leads to AF can result in embolic stroke before developing AF, and may explain the source of cryptogenic stroke in some patients. Although there are several potential biomarkers indicative of atrial cardiopathy, P-wave terminal force in lead V1 (>5,000 μV* ms), N-terminal pro-brain natriuretic peptide (>250 pg/ml), and left atrial enlargement are currently promising biomarkers for the diagnosis of atrial cardiopathy. Because the optimal combination and thresholds of biomarkers for diagnosing atrial cardiopathy remain uncertain, atrial cardiopathy represents a spectrum disorder. The concept of atrial cardiopathy appears to be most valuable as a starting point for therapeutic intervention to prevent stroke. Validation of the diagnosis of atrial cardiopathy and whether it can be used as a new therapeutic target for direct oral anticoagulants are currently being covered in the ARCADIA trial.

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Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease

Takahashi S., Mashima K.

Antioxidants 11 ( 1 ) 2022.01

Oxidative stress and neuroinflammation are common bases for disease onset and progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of dopaminergic neurons resulting in dopamine depletion, the pathogenesis differs between hereditary and solitary disease forms and is often unclear. In addition to the pathogenicity of alpha-synuclein as a pathological disease marker, the involvement of dopamine itself and its interactions with glial cells (astrocyte or microglia) have attracted attention. Pacemaking activity, which is a hallmark of dopaminergic neurons, is essential for the homeostatic maintenance of adequate dopamine concentrations in the synaptic cleft, but it imposes a burden on mitochondrial oxidative glucose metabolism, leading to reactive oxygen species production. Astrocytes provide endogenous neuroprotection to the brain by producing and releasing antioxidants in response to oxidative stress. Additionally, the protective function of astrocytes can be modified by microglia. Some types of microglia themselves are thought to exacerbate Parkinson disease by releasing pro-inflammatory factors (M1 microglia). Although these inflammatory microglia may further trigger the inflammatory conversion of astrocytes, microglia may induce astrocytic neuroprotective effects (A2 astrocytes) simultaneously. Interestingly, both astrocytes and microglia express dopamine receptors, which are upregulated in the presence of neuroinflammation. The anti-inflammatory effects of dopamine receptor stimulation are also attracting attention because the functions of astrocytes and microglia are greatly affected by both dopamine depletion and therapeutic dopamine replacement in Parkinson disease. In this review article, we will focus on the antioxidative and anti-inflammatory effects of astrocytes and their synergism with microglia and dopamine.

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Preprocedural Prediction of Underlying Atherosclerotic Lesions in Cerebral Large-Vessel Occlusions: Clinical Backgrounds, Radiological Findings, and Treatment Outcomes

Kuribara T., Sato H., Iihoshi S., Tsukagoshi E., Teranishi A., Kinoshita Y., Sugasawa S., Kohyama S., Takahashi S., Kurita H.

Journal of Atherosclerosis and Thrombosis 29 ( 11 ) 1613 - 1624 2022

ISSN 13403478

Aims: Mechanical thrombectomy using a standard device has been effective for acute cerebral large-vessel occlusions, particularly those due to cardiogenic embolism. However, evidence for those with underlying atherosclerotic lesions is lacking. In this study, we evaluated the predictive factors, treatment details, and outcomes of acute cerebral large-vessel occlusions with underlying atherosclerotic lesions in patients who underwent mechanical thrombectomy. Methods: We retrospectively analyzed consecutive patients with acute large-vessel occlusions who underwent mechanical thrombectomy at our institution between August 2014 and May 2021. Predictive factors of underlying atherosclerotic lesions were evaluated using univariate and multivariate analyses. In addition, treatment details and outcomes were evaluated and compared with those of other etiologies. Results: Among 322 included patients, 202 (62.7%) were males and 65 (20.2%) had underlying atherosclerotic lesions. Multivariate analysis identified dyslipidemia, lack of arterial fibrillation documented on admission, smoking, internal carotid artery lesions, and stenosis ≥ 25% in non-occluded large vessels as predictive factors of underlying atherosclerotic lesions. Regarding treatment for underlying atherosclerotic lesions, the need for percutaneous transluminal angioplasty, stent placement, medical therapy, and longer procedure time were observed, while successful reperfusion rates, favorable outcomes, and mortality rates showed no significant differences with those of other etiologies. Conclusion: Coexisting diseases and radiological findings were useful for predicting underlying atherosclerotic lesions. Further understanding these characteristics may lead to the early detection of underlying atherosclerotic lesions, optimal treatment strategies, and better outcomes.

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Neuroprotective function of high glycolytic activity in astrocytes: Common roles in stroke and neurodegenerative diseases

Takahashi S.

International Journal of Molecular Sciences 22 ( 12 ) 2021.06

ISSN 16616596

Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regard-less of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from astrocytes. Although the fate of this lactate remains somewhat controversial, it is believed to fuel neurons as an energy substrate. Besides providing lactate, astrocytic glycolysis plays an important role in neuroprotection. Among the minor pathways of glucose metabolism, glucose flux to the pentose-phosphate pathway (PPP), a major shunt pathway of glycolysis, is attracting research interest. In fact, PPP activity in astrocytes is five to seven times higher than that in neurons. The astrocytic PPP plays a key role in protecting neurons against oxidative stress by providing neurons with a reduced form of glutathione, which is necessary to eliminate reactive oxygen species. Therefore, enhancing astrocytic glycolysis might promote neuronal protection during acute is-chemic stroke. Contrariwise, the dysfunction of astrocytic glycolysis and the PPP have been impli-cated in the pathogenesis of various neurodegenerative diseases such as Parkinson’s disease, Alz-heimer’s disease, and amyotrophic lateral sclerosis, since mitochondrial dysfunction and oxidative stress trigger and accelerate disease progression.

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Status of Acute Stroke Practice in Patients with a Cardiac Implantable Electronic Device

Kato Y., Hayashi T., Kato R., Uchino A., Takao M., Takahashi S.

Acta Medica Okayama 75 ( 6 ) 691 - 697 2021

ISSN 0386300X

Although diagnostic and therapeutic strategies for acute stroke patients in Japan depend largely on magnetic resonance imaging (MRI), patients with cardiac implantable electronic devices (CIED) must still rely on computedtomography (CT). We retrospectively analyzed clinical and neuroimaging data of ischemic strokepatients with CIED treated at our hospital. Forty-five patients were enrolled in the study. Patients were dividedinto two groups according to whether corresponding lesions were detected (group A, n=21) or not detected(group B, n=24) by the first brain CT. We also evaluated in detail the clinical courses of patients who arrived athospital within therapeutic time windows for recanalization therapy. Negative fresh infarct in the first CT wasassociated, though not significantly, with early onset-to-arrival time and subcortical white matter infarction.Five patients did not undergo recanalization therapy because their families did not agree to the procedure. Thereasons for their lack of consent included inadequate information about the safety and efficacy of recanalizationtherapy because MRI could not be performed. Our study confirmed delayed detection of the correspondinglesion and undertreatment for acute stroke in patients with CIED

Coagulation Assay and Stroke Severity upon Admission of Patients with Cardioembolic Cerebral Infarction during Direct Oral Anticoagulant Use

Deguchi I., Osada T., Takao M., Takahashi S.

Keio Journal of Medicine 70 ( 4 ) 93 - 99 2021

ISSN 00229717

Although the severity of acute cerebral infarction varies in patients receiving direct oral anticoagulants (DOACs), no practical method to predict the severity has been established. We analyzed retrospectively the relationship between cardioembolic cerebral infarction severity and coagulation indicators in patients treated with DOACs. We assessed the anticoagulation effect of DOACs using the activated partial thromboplastin time (APTT), prothrombin time (PT), and prothrombin time international standardized ratio (PT-INR) in 71 patients with cardioembolic cerebral infarction admitted to our hospital between January 2015 and December 2019. The participants were divided into a prolongation group (prolonged APTT for oral thrombin inhibitors or prolonged PT for oral factor Xa inhibitors, n =37) and a normal group (no prolongation of coagulation markers, n =34). Of the 71 patients, 21 (30%) and 50 (70%) were using oral thrombin and oral factor Xa inhibitors, respectively. PT, PT-INR, and APTT were significantly higher in the prolongation group (PT: 17.4 ± 5.1 vs. 12.8 ± 1.4 s, P < 0.001; PT-INR: 1.5 ± 0.5 vs. 1.1 ± 0.1, P < 0.001; APTT: 44.8 ± 26.4 vs. 30.4 ± 4.1 s, P = 0.003). The median National In-stitutes of Health Stroke Scale (NIHSS) score on admission and the prevalence of large vessel occlusion were significantly lower in the prolongation group (NIHSS: 2.0 vs. 9.5, P = 0.007; large vessel occlusion: 27% vs. 53%, P = 0.031). The prevalence of large vessel occlusion was low and stroke severity was mild in patients undergoing DOAC therapy with prolongation of coagulation assay markers upon onset of cardioembolic cerebral infarction.

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Diameter of fluorescent microspheres determines their distribution throughout the cortical watershed area in mice.

Naoki Tsukada, Masahiro Katsumata, Koichi Oki, Kazushi Minami, Takato Abe, Yoshiaki Itoh, Shinichi Takahashi, Norihiro Suzuki

Bain Research 1679 109 - 115 2018

Research paper (scientific journal), Joint Work, Accepted

Neuro-protective role of astroglia in Parkinson disease by reducing oxidative stress through dopamine-induced activation of pentose-phosphate pathway.

Kyoko Mahima, Shinichi Takahashi, Kazushi Minami, Yoshikane Izawa, Takato Abe, Naoki Tsukada, Takako Hishiki, Makoto Suematsu, Mayumi Kajimura, Norihiro Suzuki

ASN Neuro 10 1 - 12 2018

Research paper (scientific journal), Joint Work, Accepted

Trends of Antiplatelet Therapy for the Management of Moyamoya Disease in Japan: Results of a Nationwide Survey.

Koichi Oki, Masahiro Katsumata, Yoshikane Izawa, Shinichi Takahashi, Norihiro Susuki, Kiyohiro Houkin; Research Committee on Spontaneous Occlusion of Circle of Willis (moyamoya disease)

J Stroke Cerebrovasc Dis (in press) 2018

Research paper (scientific journal), Joint Work, Accepted

Rivaroxaban induces reduction of embolus size within intracranial arteries in a mouse model of embolic stroke.

Masahiro Katsumata, Koichi Oki, Naoki Tsukada, Takato Abe, Yoshiaki Itoh, Shinichi Takahashi, Norihiro Suzuki

Keio J Med (in press) 2018

Research paper (scientific journal), Joint Work, Accepted

De novo design of RNA-binding proteins with a prion-like domain related to ALS/FTD proteinopathies.

Kana Mitsuhashi, Daisuke Ito, Munenori Oyama, Kyoko Mashima, Shinichi Takahashi, Norihiro Suzuki

Scientific Reports Dec 4;7(1):16871. 2017.12

Research paper (scientific journal), Joint Work, Accepted

Serial changes of corticospinal tract hyperintensity on MRI from the pre-clinical stage in ALS.

Tsubasa Takizawa, Gen Shiihashi, Junki Maehara, Koichi Oki, Mayuko Osaka, David Y Chung, Hirokazu Fujiwara, Hidenori Ojima, Yuichi Ichinose, Mamoru Shibata, Shinichi Takahashi, Norihiro Suzuki

Neurology and Clinical Neuroscience 2017.10

Research paper (scientific journal), Joint Work, Accepted

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q-Space Myelin Map imaging for longitudinal analysis of demyelination and remyelination in multiple sclerosis patients treated with fingolimod: A preliminary study.

Tanikawa M, Nakahara J, Hata J, Suzuki S, Fujiyoshi K, Fujiwara H, Momoshima S, Jinzaki M, Nakamura M, Okano H, Takahashi S, Suzuki N

J Neurol Sci. 2017.01

Research paper (scientific journal), Joint Work

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Possible Involvement of Hypotension in Postprandial Headache: A Case Series.

akizawa T, Shibata M, Hiraide T, Seki M, Takahashi S, Suzuki N

Headache 2017

Research paper (scientific journal), Joint Work, Accepted

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Blood pressure reduction and noncontrast CT markers of intracerebral hemorrhage expansion.

Morotti A, Boulouis G, Romero JM, Brouwers HB, Jessel MJ, Vashkevich A, Schwab K, Afzal MR, Cassarly C, Greenberg SM, Martin RH, Qureshi AI, Rosand J, Goldstein JN; ATACH-II and NETT investigators.

Neurology 2017

Research paper (scientific journal), Joint Work, Accepted

ステロイド治療に抵抗して急速に進行し、脳生検にて診断しえた中枢神経限局性血管炎の28歳男性の1例．

'Takahashi,' Shinichi

臨床神経学 57 509 - 514 2017

Research paper (scientific journal), Joint Work, Accepted

The first report of Japanese case of seipinopathy with BSCL2 N88S mutation.

Kazushi Minami, Shinichi Takahashi*, Yoshihiro Nihei,Koichi Oki, Shigeaki Suzuki, Daisuke Ito, Hiroshi Takashima, Norihiro Suzuki

Internal Medicine 2017

Research paper (scientific journal), Joint Work, Accepted

New onset of myasthenia gravis after intravesical Bacillus Calmette-Guerin: A case report and literature review.

Tsubasa Takizawa. Marenori Kojima, Shigeaki Suzuki, Takashi Osada, Satoshi Kitagawa; Jin Nakahara, Shinichi Takahashi,Norihiro Suzuki

Medicine (Baltimore) 96 ( 46 ) e8757. 2017

Research paper (scientific journal), Joint Work

A possible role of microglia-derived nitric oxide by lipopolysaccharide in activation of astroglial pentose-phosphate pathway via the Keap1/Nrf2 system

Iizumi, Takuya, Takahashi, Shinichi, Mashima, Kyoko, Minami, Kazushi, Izawa, Yoshikane, Abe, Takato, Hishiki, Takako, Suematsu, Makoto, Kajimura, Mayumi, Suzuki, Norihiro

JOURNAL OF NEUROINFLAMMATION 13 2016.05

Research paper (scientific journal), ISSN 1742-2094

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Application of q-space diffusion MRI for the visualization of white matter

Fujiyoshi Kanehiro, Hikishima Keigo, Nakahara Jin, Tsuji Osahiko, Hata Junichi, Konomi Tsunehiko, Nagai Toshihiro, Shibata Shinsuke, Kaneko Shinjiro, Iwanami Akio, Momoshima Suketaka, Takahashi Shinichi, Jinzaki Masahiro, Suzuki Norihiro, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

Journal of Neuroscience 36 ( 9 ) 2796 - 2808 2016.03

Research paper (scientific journal), ISSN 0270-6474

<p>White matter abnormalities in the CNS have been reported recently in various neurological and psychiatric disorders. Quantitation of non-Gaussianity for water diffusion by q-space diffusional MRI (QSI) renders biological diffusion barriers such as myelin sheaths; however, the time-consuming nature of this method hinders its clinical application. In the current study, we aimed to refine QSI protocols to enable their clinical application and to visualize myelin signals in a clinical setting. For this purpose, animal studies were first performed to optimize the acquisition protocol of a non-Gaussian QSI metric. The heat map of standardized kurtosis values derived from optimal QSI (myelin map) was then created. Histological validation of the myelin map was performed in myelin-deficient mice and in a nonhuman primate by monitoring its variation during demyelination and remyelination after chemical spinal cord injury. The results demonstrated that it was sensitive enough to depict dysmyelination, demyelination, and remyelination in animal models. Finally, its utility in clinical practice was assessed by a pilot clinical study in a selected group of patients with multiple sclerosis (MS). The human myelin map could be obtained within 10 min with a 3 T MR scanner. Use of the myelin map was practical for visualizing white matter and it sensitively detected reappearance of myelin signals after demyelination, possibly reflecting remyelination inMSpatients. Our results together suggest that the myelin map, a kurtosis-related heat map obtainable with time-saving QSI, may be a novel and clinically useful means of visualizing myelin in the human CNS.</p>

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Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage.

Qureshi AI, Palesch YY, Barsan WG, Hanley DF, Hsu CY, Martin RL, Moy CS, Silbergleit R, Steiner T, Suarez JI, Toyoda K, Wang Y, Yamamoto H, Yoon BW; ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network.

N Engl J Med. 375 ( 11 ) 1033 - 1043 2016

Research paper (scientific journal), Accepted

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Ipsilateral Facial Tactile Hypesthesia in a Patient with Lateral Medullary Syndrome

Katsumata, M., Oki, K., Nakahara, J., Izawa, Y., Abe, T., Takahashi, S. and Suzuki, N.

J Stroke Cerebrovasc Dis 2015.09

Research paper (scientific journal), ISSN 1052-3057

BACKGROUND: Various sensory impairments have been reported in patients with lateral medullary syndrome, also known as Wallenberg syndrome. The typical sensory impairments experienced by patients with this condition are ipsilateral facial and contralateral trunk and limb thermal hypesthesia and hypoalgesia. Tactile (light touch) sensation is not generally diminished. Here we report the case of a 35-year-old man with lateral medullary infarction who had atypical sensory impairment. METHODS: We examined the results from the neurological examination of the patient as well as findings from computed tomography of the head and magnetic resonance imaging. RESULTS: Magnetic resonance imaging showed left lateral medullary infarction caused by left posterior inferior cerebellar artery dissection. Neurological examination revealed both tactile and thermal/pain hypesthesia on the left side of the patient's face, and thermal/pain hypesthesia on his right upper and lower limbs. CONCLUSION: There are two types of tactile sensation: epicritic and protopathic. Facial tactile sensation is usually thought to be associated with epicritic tactile sensation, which travels through principal sensory nuclei of the trigeminal nerve. The protopathic pathway travels down through the spinal tract via the trigeminal nerve and is not considered a primary pathway. However, in this case the protopathic tactile sensation pathway might be involved, and it caused facial tactile hypesthesia. Because most of previous case reports and literature reviews focused only on thermal/pain hypesthesia, we believe that this case provides critical information on the brainstem neuroanatomy, especially for the protopathic tactile sensation pathway in patients with stroke.

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Subsequent vascular events after ischemic stroke: the Japan Statin Treatment Against Recurrent Stroke-Longitudinal

Nomura, E., Suzuki, A., Inoue, I., Nakagawara, J., Takahashi, K., Takahashi, T., Manabe, Y., Yokota, C., Okada, K., Nishihara, T., Yamamoto, Y., Noda, K., Takahashi, S., Ibayashi, S., Takagi, M., Kitagawa, K., Tanahashi, N., Kuriyama, M., Hirata, K., Hosomi, N., Minematsu, K., Kobayashi, S. and Matsumoto, M.

J Stroke Cerebrovasc Dis 24 ( 2 ) 473 - 9 2015.02

Research paper (scientific journal), ISSN 1052-3057

BACKGROUND: We undertook a multicenter cohort observational study to investigate the frequency and type of subsequent vascular events after an ischemic stroke and to compare the rates of vascular events between patients with and without hyperlipidemia. METHODS: This nationwide study was conducted in 19 hospitals participating in the Japan Standard Stroke Registry Study. We enrolled ischemic stroke patients, including those with a transient ischemic attack, who had not experienced any vascular events before enrollment after their ischemic stroke events. Each subject was observed prospectively from September 1, 2003, to October 1, 2005, or until a primary end point or death. Primary end points included subsequent fatal or nonfatal vascular events: stroke, angina pectoris, acute myocardial infarction, aortic aneurysm, or arteriosclerosis obliterans. RESULTS: A total of 449 patients (mean age, 67.6 years; 64.8% men) were enrolled in this study. Of the 41 vascular events observed during follow-up, 40 were stroke. The median observation period was 568 days. We found that patients with hyperlipidemia had a significantly higher rate of vascular events compared with those without hyperlipidemia according to the Kaplan-Meier method and the log-rank test (P = .013). Hyperlipidemia significantly increased the risk of vascular events (hazard ratio, 2.169 [1.125-4.312]; P = .021) according to the Cox proportional hazard model after adjusting for confounding factors (age, sex, days from ischemic stroke until enrollment, smoking habits, and daily drinking habits). CONCLUSIONS: This study demonstrated that stroke was the most common subsequent vascular event after ischemic stroke; the study also indicated that hyperlipidemia could be a risk factor for subsequent vascular events after ischemic stroke.

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パーキンソン病のVisual View　アストロサイトとドパミンニューロン

高橋, 愼一 and 馬島, 恭子

Frontiers in Parkinson Disease 8 ( 1 ) 24 - 28 2015.02

ISSN 1883-0331

各種疾患　中毒・代謝疾患神経細胞およびグリア細胞におけるケトン体代謝の重要性

高橋, 愼一

Annual Review神経 2015 196 - 205 2015.01

ケトン体(KB),すなわちアセト酢酸(ACA)とβヒドロキシ酪酸(BHB)は,飢餓状態やインスリン抵抗性など,グルコース利用制限がある成体脳のエネルギー基質となる.KBは肝臓において脂肪酸から合成され,授乳期の脳ではKBが主要な脳のエネルギー基質となる.またACAはミエリンの構成成分であるコレステロール合成にも利用される.エネルギー基質としてのKBは,グルコースとは異なりピルビン酸を経由せずacetyl-CoAに変換されるため,ピルビン酸脱水素酵素複合体(PDHC)を必要としない.すなわちKBは,虚血障害を受けやすいPDHCに依存せずニューロンのATP産生を可能とする.脳では内因性のKB産生も可能であり,アストログリアがその役割を担う.KBの抗てんかん作用は古くから難治性てんかんに対するケトン食療法として利用されてきたが,KBの多彩なメカニズムによる神経保護作用から,脳卒中や神経変性疾患への治療応用が期待される.BHBは好中球,マクロファージ,単球,ミクログリアに発現するナイアシン受容体(HCA2)の内因性リガンドであり,プロスタグランジンD2産生を介して神経炎症反応を抑制することで,多発性硬化症に対しても治療効果をもつ可能性がある.(著者抄録)

Cellular origin and regulation of D- and L-serine in in vitro and in vivo models of cerebral ischemia

Abe, T., Suzuki, M., Sasabe, J., Takahashi, S., Unekawa, M., Mashima, K., Iizumi, T., Hamase, K., Konno, R., Aiso, S. and Suzuki, N.

J Cereb Blood Flow Metab 34 ( 12 ) 1928 - 35 2014.12

Research paper (scientific journal), ISSN 0271-678

D-Serine is known to be essential for the activation of the N-methyl-D-aspartate (NMDA) receptor in the excitation of glutamatergic neurons, which have critical roles in long-term potentiation and memory formation. D-Serine is also thought to be involved in NMDA receptor-mediated neurotoxicity. The deletion of serine racemase (SRR), which synthesizes D-serine from L-serine, was recently reported to improve ischemic damage in mouse middle cerebral artery occlusion model. However, the cell type in which this phenomenon originates and the regulatory mechanism for D-/L-serine remain elusive. The D-/L-serine content in ischemic brain increased until 20 hours after recanalization and then leveled off gradually. The results of in vitro experiments using cultured cells suggested that D-serine is derived from neurons, while L-serine seems to be released from astroglia. Immunohistochemistry studies of brain tissue after cerebral ischemia showed that SRR is expressed in neurons, and 3-phosphoglycerate dehydrogenase (3-PGDH), which synthesizes L-serine from 3-phosphoglycerate, is located in astrocytes, supporting the results of the in vitro experiments. A western blot analysis showed that neither SRR nor 3-PGDH was upregulated after cerebral ischemia. Therefore, the increase in D-/L-serine was not related to an increase in SRR or 3-PGDH, but to an increase in the substrates of SRR and 3-PGDH.

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パーキンソン病の病態とドパミンによるアストロサイトの抗酸化ストレス作用の制御機構

馬島, 恭子, 高橋, 愼一, 飯泉, 琢矢, 安部, 貴人 and 鈴木, 則宏

臨床神経学 54 ( Suppl. ) S67 2014.12

ISSN 0009-918X

ドパミンとグルタミン酸に対するアストログリアの酸化ストレス応答の差異

馬島, 恭子, 高橋, 愼一, 飯泉, 琢矢, 安部, 貴人 and 鈴木, 則宏

脳循環代謝 26 ( 1 ) 222 2014.11

ISSN 0915-9401

脳梗塞病態と新規治療開発アストログリアをターゲットとした脳梗塞治療戦略の構築

高橋, 愼一

脳循環代謝 26 ( 1 ) 67 2014.11

ISSN 0915-9401

【多発性硬化症のパラダイムシフト-病態から治療まで】治療　フマル酸ジメチル(BG-12)

高橋, 愼一, 中原, 仁 and 鈴木, 則宏

Clinical Neuroscience 32 ( 11 ) 1287 - 1290 2014.11

ISSN 0289-0585

Microsphere注入脳塞栓モデルにおける塞栓子径と分布の検討

塚田, 直己, 勝又, 雅裕, 大木, 宏一, 安部, 貴人, 高橋, 愼一, 伊藤, 義彰 and 鈴木, 則宏

脳循環代謝 26 ( 1 ) 226 2014.11

ISSN 0915-9401

高橋, 愼一

日本臨床 72 ( 増刊7 最新臨床脳卒中学(下) ) 155 - 158 2014.10

ISSN 0047-1852

非典型的髄液所見を呈した硬膜下膿瘍の成人発症例

馬島, 恭子, 玉井, 直敬, 土屋, 光正, 大木, 宏一, 鈴木, 重明, 柴田, 護, 高橋, 愼一 and 鈴木, 則宏

神経免疫学 19 ( 1 ) 148 2014.09

ISSN 0918-936X

非典型的髄液所見を呈した硬膜下膿瘍の成人発症例

馬島, 恭子, 玉井, 直敬, 土屋, 光正, 大木, 宏一, 鈴木, 重明, 柴田, 護, 高橋, 愼一 and 鈴木, 則宏

NEUROINFECTION 19 ( 2 ) 212 2014.08

ISSN 1348-2718

脳出血にて来院し剖検で急性白血病(Cup-like AML)の診断が確定された41歳男性

勝又, 雅裕, 中原, 仁, 安部, 貴人, 内田, 理瑛, 真杉, 洋平, 高橋, 愼一 and 鈴木, 則宏

臨床神経学 54 ( 8 ) 688 2014.08

ISSN 0009-918X

【神経診察-そのポイントと次の一手】内科医が行う神経診察　"苦手"を攻略するコツと考え方

山脇, 正永, 高橋, 愼一, 塩尻, 俊明 and 川越, 正平

Medicina 51 ( 7 ) 1182 - 1188 2014.07

ISSN 0025-7699

高橋, 愼一

日本臨床 72 ( 増刊5 最新臨床脳卒中学(上) ) 86 - 90 2014.07

ISSN 0047-1852

【神経診察-そのポイントと次の一手】全身診察法

高橋, 愼一

Medicina 51 ( 7 ) 1202 - 1204 2014.07

ISSN 0025-7699

＜ポイント＞神経診察は,系統的に行う診察全体がスクリーニングであり,項目のどれかを抜粋することは病巣診断の見落としを生じる.神経診察によって得られた病巣診断が,患者の訴えや症状にどう寄与するかを考えることが疾患診断となる.神経診察によるスクリーニングが,画像,電気生理,ラボデータなどの検査の要否と緊急性を決定する指針となる.(著者抄録)

MRIを用いた中枢神経系髄鞘の可視化と多発性硬化症への応用

中原, 仁, 藤吉, 兼浩, 疋島, 啓吾, 中村, 雅也, 高橋, 慎一 and 鈴木, 則宏

日本内科学会雑誌 103 ( Suppl. ) 264 2014.02

ISSN 0021-5384

Roles and regulation of ketogenesis in cultured astroglia and neurons under hypoxia and hypoglycemia

Takahashi, S., Iizumi, T., Mashima, K., Abe, T. and Suzuki, N.

ASN Neuro 6 ( 5 ) 2014

Research paper (scientific journal)

Exogenous ketone bodies (KBs), acetoacetate (AA), and beta-hydroxybutyrate (BHB) act as alternative energy substrates in neural cells under starvation. The present study examined the endogenous ketogenic capacity of astroglia under hypoxia with/without glucose and the possible roles of KBs in neuronal energy metabolism. Cultured neurons and astroglia were prepared from Sprague-Dawley rats. Palmitic acid (PAL) and l-carnitine (LC) were added to the assay medium. The 4- to 24-hr production of AA and BHB was measured using the cyclic thio-NADH method. (14)C-labeled acid-soluble products (KBs) and (14)CO2 produced from [1-(14)C]PAL were also measured. l-[U-(14)C]lactic acid ([(14)C]LAC), [1-(14)C]pyruvic acid ([(14)C]PYR), or beta-[1-(14)C]hydroxybutyric acid ([(14)C]BHB) was used to compare the oxidative metabolism of the glycolysis end products with that of the KBs. Some cells were placed in a hypoxic chamber (1% O2). PAL and LC induced a higher production of KBs in astroglia than in neurons, while the CO2 production from PAL was less than 5% of the KB production in both astroglia and neurons. KB production in astroglia was augmented by the AMP-activated protein kinase activators, AICAR and metformin, as well as hypoxia with/without glucose. Neuronal KB production increased under hypoxia in the absence of PAL and LC. In neurons, [(14)C]LAC and [(14)C]PYR oxidation decreased after 24 hr of hypoxia, while [(14)C]BHB oxidation was preserved. Astroglia responds to ischemia in vitro by enhancing KB production, and astroglia-produced KBs derived from fatty acid might serve as a neuronal energy substrate for the tricarboxylic acid cycle instead of lactate, as pyruvate dehydrogenase is susceptible to ischemia.

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[Roles of metabolic compartmentalization by astrocytes and neurons in the pathophysiology and treatment of Parkinson's disease]

Takahashi, S., Seki, M. and Suzuki, N.

Brain Nerve 65 ( 12 ) 1497 - 508 2013.12

ISSN 1881-6096

Mitochondrial dysfunction has been implicated in the pathogenesis of both idiopathic and familial Parkinson's disease (PD). Dopamine neurons in the substantia nigra exhibit autonomous pacemaking activity to maintain an optimal dopamine concentration in the striatum, resulting in the activation of energy metabolism. ATP production in neuronal cells is dependent on mitochondrial glucose oxidation, and reactive oxygen species (ROS) production associated with neuronal activation might be a major cause of mitochondrial damage in dopamine neurons. Alpha-synuclein, a major component of Lewy bodies, induces mitochondrial damage, and several genes responsible for familial PD encode molecules necessary for normal mitochondrial function. In addition, the auto-oxidation of dopamine produces dopamine quoinone and ROS. Astroglia provide neurons with lactate produced from glucose via glycolysis in response to neuronal activation. The co-activation of the pentose-phosphate pathway (PPP), a shunt pathway of glycolysis, in astroglia plays a pivotal role in protecting neurons against ROS with glutathione peroxidase and the reduced form of glutathione (GSH). In addition to the allosteric regulation of the PPP, which is associated with the activation of glycolysis, the PPP in astroglia can also be activated by ROS through the Kelch-like enoyl-CoA hydratase-associated protein 1 (Keap1)/nuclear factor-erythroid 2 p45 subunit-related factor 2 (Nrf2) system. A rate-limiting enzyme of the PPP, glucose-6-phosphate dehydrogenase (G6PDH), is transcriptionally regulated by the Keap1/Nrf2 system, which is a master regulator of phase 2 detoxifying enzymes. ROS is thought to modify the thiol residue of Keap1 and to facilitate Nrf2 dissociation from Keap1. Thereafter, Nrf2 translocates into the nucleus where it induces the transcription of G6PDH. The pharmacological activation of the Keap1/Nrf2 PPP in astroglia may provide a novel strategy for preventing the onset and progression of PD.

アストロサイトとニューロンの代謝コンパートメントからみたパーキンソン病の病態と治療

高橋, 愼一, 関, 守信 and 鈴木, 則宏

BRAIN and NERVE: 神経研究の進歩 65 ( 12 ) 1497 - 1508 2013.12

ISSN 1881-6096

パーキンソン病(PD)は黒質緻密層のドパミンニューロンの変性・脱落に伴って生じる、線状体ドパミン量低下に伴う運動症状を中核とする変性疾患である。ニューロンにおけるグルコース代謝のサポートと酸化ストレスへの保護機構の中核をなすアストロサイトの生理機能に注目し、PDのミトコンドリア機能障害仮説と治療戦略をニューロンとアストロサイトからなる代謝コンパートメントから、以下の項目について述べた。1)脳のグルコース代謝とミトコンドリア、2)Default mode networkとpacemaking activity、3)αシヌクレインとミトコンドリア障害、4)家族性PDとミトコンドリア障害、5)アストロサイトとパーキンソン病におけるグルコース代謝、6)アストロサイトの解糖系による抗酸化ストレス作用、7)Keap1/Nrf2システム、8)糖尿病とパーキンソン病、9)Nrf2活性化とパーキンソン病治療。

Roles and regulation of ketogenesis in astroglia and neurons under hypoxia

飯泉, 琢矢, 高橋, 愼一, 安部, 貴人 and 鈴木, 則宏

臨床神経学 53 ( 12 ) 1547 2013.12

ISSN 0009-918X

マウス脳虚血巣におけるD-/L-セリン動態の検討

安部, 貴人, 高橋, 愼一, 笹部, 潤平, 畝川, 美悠紀, 鈴木, 将貴, 飯泉, 琢矢, 相磯, 貞和 and 鈴木, 則宏

脳循環代謝 25 ( 1 ) 178 2013.11

ISSN 0915-9401

脳血管障害の基礎知識　脳卒中専門医に知っておいてほしいキーワード　内科系(第4回)　神経血管ユニット(neurovascular unit:NVU)

高橋, 愼一

分子脳血管病 12 ( 4 ) 387 - 392 2013.10

ISSN 1346-8995

Neurovascular unit(NVU)とは、ニューロンと血管(内皮細胞、周皮細胞、平滑筋細胞、非細胞性要素として細胞外マトリックスを構成する蛋白とその調節酵素)、両者の橋渡しをするアストロサイトからなる機能的統合体を示す。NVUは脳血管障害急性期の病態をこれらの機能ユニットとして捉えることで、新たな急性期治療戦略を模索するために提唱された。近年NVUは、脳血管障害急性期のみならず、広く中枢神経疾患を理解するためのツールとしても用いられている。(著者抄録)

上喉頭神経麻痺を呈したシェーグレン症候群の61歳女性例

二瓶, 義廣, 伊東, 大介, 高橋, 愼一, 野川, 茂 and 鈴木, 則宏

臨床神経学 53 ( 10 ) 883 2013.10

ISSN 0009-918X

【Neurovascular Unit〜神経-血管-グリアのユニットが脳と体を支配する】血液脳関門および脳循環・代謝調節とアストロサイト

高橋, 愼一

実験医学 31 ( 14 ) 2195 - 2203 2013.09

ISSN 0288-5514

NVU(Neurovascular Unit)とは脳卒中の病態から治療戦略を構築するための概念的枠組み(conceptual framework)である。NVUには微小血管(毛細血管と細動脈)とニューロン、これらを橋渡しするアストロサイトが含まれる。その血管側では内皮細胞、細胞外マトリクス、アストロサイトの足突起が血液脳関門を形成する。脳血流はニューロンの活動によって増減し、代謝基質としてのグルコース、脂肪酸、アミノ酸はアストロサイトで中間代謝を受け効率よくニューロンに運搬される。NVUの生理的メカニズムの研究は、脳卒中のみならず、神経変性疾患、神経免疫疾患など広く中枢神経疾患を理解するツールとなる。(著者抄録)

重症筋無力症に合併する甲状腺眼症の臨床像

逢坂, 麻由子, 鈴木, 重明, 清水, 利彦, 高橋, 愼一 and 鈴木, 則宏

神経治療学 30 ( 5 ) 651 2013.09

ISSN 0916-8443

MRIからみた骨関節疾患の病態脊髄損傷におけるq-space imaging(QSI)とmyelin mapの開発

藤吉, 兼浩, 岩波, 明生, 許斐, 恒彦, 安田, 明正, 金子, 慎二郎, 辻, 収彦, 疋島, 啓吾, 中原, 仁, 高橋, 愼一, 鈴木, 則宏, 百島, 祐貴, 岡野, 栄之, 戸山, 芳昭, 松本, 守雄 and 中村, 雅也

日本整形外科学会雑誌 87 ( 8 ) S1278 2013.08

ISSN 0021-5325

【アストロサイトをめぐる最近の話題】脳血管とアストロサイト　neurovascular unitの概念について

高橋, 愼一, 安部, 貴人 and 鈴木, 則宏

神経内科 79 ( 2 ) 247 - 256 2013.08

ISSN 0386-9709

血液脳関門 NVUにおけるBBBの役割とcellular metabolic compartment

高橋, 愼一, 安部, 貴人, 伊澤, 良兼, 飯泉, 琢矢 and 鈴木, 則宏

脳循環代謝 24 ( 2 ) 75 - 82 2013.07

ISSN 0915-9401

Neurovascular unit(NVU)とは、ニューロンと脳微小循環を基盤として脳機能を統合的に捉え、脳虚血病態を理解するためのconceptual frameworkである。主要な構造要素としてニューロン、脳微小血管のほか、両者を橋渡しするアストロサイトが含まれる。血液脳関門(BBB)はNVUの血管側の解剖学的構造に由来するバリア機能であり、脳微小循環から脳実質内への物質移動の制御機構を担う。BBBという透過性の制限を設けることは、脳の保護機構として重要な生体戦略であるが、BBBには必須物質に対する特異的輸送系のほか、safety systemとしてエネルギー代替物質となるモノカルボン酸(乳酸、ケトン体)トランスポーターが存在し、さらに脳実質内には細胞(種)間の合成系と消費系が存在する。NVU構成要素のうちニューロンとアストロサイトに注目し、cellular metabolic compartmentを介したNVU維持機構を論じる。(著者抄録)

脳梗塞急性期治療　tissue clockとreperfusion

高橋, 愼一

麻酔 61 ( 増刊 ) S11 - S22 2012.11

ISSN 0021-4892

血液脳関門 NVUにおけるBBBの役割とcellular metabolic compartment

高橋, 愼一, 安部, 貴人, 伊澤, 良兼, 飯泉, 琢矢 and 鈴木, 則宏

脳循環代謝 24 ( 1 ) 114 2012.11

ISSN 0915-9401

治療ターゲットとしての脳虚血後の炎症アストロサイトからみた脳虚血後の炎症

高橋, 愼一, 伊澤, 良兼, 飯泉, 琢矢, 安部, 貴人 and 鈴木, 則宏

脳循環代謝 23 ( 2 ) 66 - 74 2012.09

ISSN 0915-9401

脳梗塞後の炎症による神経障害のメディエータとして活性酸素種(ROS)と活性窒素種(RNS)は重要であるが、その上流因子であるToll様受容体4(TLR4)の有する神経保護シグナルに注目した。脳梗塞急性期において、TLR4の内因性リガンド刺激は下流シグナルであるNFκB、JAK/STAT、MAPKなどを介してNADPH oxidase、iNOS、炎症性サイトカインを誘導し神経障害を増悪させる。ROS消去にはペントースリン酸経路(PPP)活性の維持が必須であり、アストロサイトは高いPPP活性を有す。PPPの律速酵素G6PDHの転写調節は、グルタチオン合成、グルタチオンペルオキシダーゼなどの酵素を含めて転写因子Nrf2による制御下にある。TLR4リガンドであるリポ多糖(LPS)刺激は、Nrf2依存性にアストロサイトのPPPを活性化し、虚血性神経細胞障害に対する保護作用をもたらす可能性が示された。(著者抄録)

【脳を救え!-急性期脳梗塞の最新治療事情-】脳を救え　脳保護療法と再生医療

高橋, 愼一

循環器内科 72 ( 3 ) 295 - 301 2012.09

ISSN 1884-2909

A case of spinal and bulbar muscular atrophy with high-stage and high-Gleason Score prostate cancer responded to maximal androgen blockade therapy

Kosaka, T., Miyajima, A., Kikuchi, E., Takahashi, S., Suzuki, N. and Oya, M.

J Androl 33 ( 4 ) 563 - 5 2012.07

ISSN 0196-3635

Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of CAG triplets in the androgen receptor. Because the length of CAG repeat is inversely related with androgen receptor function, patients with a longer CAG repeat are expected to have a lower incidence of prostate cancer. Here, we report an extremely rare case of high-stage prostate cancer in a patient with spinal and bulbar muscular atrophy, which responded to maximal androgen blockade therapy.

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動眼神経に沿って進展を認めたIgG4 related inflammatory pseudotumorの一例

冨尾, 亮介, 大平, 貴之, 杜, ぶん林, 高橋, 愼一, 柴尾, 俊輔 and 吉田, 一成

Brain Tumor Pathology 29 ( Suppl. ) 195 2012.05

ISSN 1433-7398

【類似する神経症候・徴候を正しく理解する-神経診断のピットフォール】純粋失読と失書を伴う失読

高橋, 愼一

Clinical Neuroscience 30 ( 5 ) 498 - 500 2012.05

ISSN 0289-0585

Differential diagnosis between intracranial dissemination of spinal cord astrocytoma and paraneoplastic limbic encephalitis

Seki, M., Suzuki, S., Ishii, K., Izawa, Y., Takahashi, S., Toyama, Y., Nakamura, M. and Suzuki, N.

Intern Med 51 ( 3 ) 321 - 4 2012

ISSN 0918-2918

We describe the clinical features of limbic encephalitis that developed after palliative spinal cordotomy in 2 patients with malignant thoracic astrocytoma. Both patients showed short-term memory loss, hallucinations of smells and psychiatric symptoms. Brain MRI on T2-weighted and fluid-attenuated inversion recovery sequences revealed high intensity lesions in bilateral temporal lobe areas. We considered that both patients had paraneoplastic limbic encephalitis associated with astrocytoma because of various clinical and radiological features. But the possibility of intracranial dissemination of astrocytoma could not be fully excluded. The differential diagnosis between intracranial dissemination of spinal cord astrocytoma and paraneoplastic limbic encephalitis may be sometimes difficult.

Astrogliopathy as a loss of astroglial protective function against glycoxidative stress under hyperglycemia

Takahashi, S., Izawa, Y. and Suzuki, N.

Rinsho Shinkeigaku 52 ( 1 ) 41 - 51 2012

ISSN 0009-918

Reactive oxygen species (ROS) derived from mitochondria play an essential role in stroke as well as in neurodegenerative disorders. Although hyperglycemia associated with diabetes mellitus is well known to enhance ROS production in vascular endothelial cells, the effects of either acute or chronic high glucose environments on neurons and glial cells remain unclear. Astroglia play a pivotal role in glucose metabolism. Thus, the astroglial metabolic response to high glucose environments is an interesting subject. In particular, the glutathione/pentose phosphate pathway (PPP) system, which is a major defense mechanism against ROS in the brain, contributes to glucose metabolism and is more active in astroglia. We propose that high glucose environments activate PPP through an increased flux to the hexosamine biosynthetic pathway (HBP). HBP is known to induce endoplasmic reticulum (ER) stress under hyperglycemia, resulting in the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2), a master regulator of phase 2 detoxifying enzymes including glucose-6-phosphate dehydrogenase that regulates PPP activity, as Nrf2 is reported to be a direct substrate of protein kinase RNA (PKR)-like ER kinase (PERK), a transducer of ER stress. Therefore, the phosphorylation of Nrf2 by hyperglycemia-induced ER stress facilitates Nrf2 translocation through PERK, thus activating the PPP. If acute or chronic hyperglycemia induces PPP activation in astroglia to reduce ROS, reducing the glucose concentration may be accompanied by a risk, which may explain the lack of evidence that strict glycemic control during the acute phase of stroke conveys no beneficial effect.

Astroglial pentose phosphate pathway rates in response to high-glucose environments

Takahashi, S., Izawa, Y. and Suzuki, N.

ASN Neuro 4 ( 2 ) 2012

ROS (reactive oxygen species) play an essential role in the pathophysiology of diabetes, stroke and neurodegenerative disorders. Hyperglycaemia associated with diabetes enhances ROS production and causes oxidative stress in vascular endothelial cells, but adverse effects of either acute or chronic high-glucose environments on brain parenchymal cells remain unclear. The PPP (pentose phosphate pathway) and GSH participate in a major defence mechanism against ROS in brain, and we explored the role and regulation of the astroglial PPP in response to acute and chronic high-glucose environments. PPP activity was measured in cultured neurons and astroglia by determining the difference in rate of (14)CO(2) production from [1-(14)C]glucose and [6-(14)C]glucose. ROS production, mainly H(2)O(2), and GSH were also assessed. Acutely elevated glucose concentrations in the culture media increased PPP activity and GSH level in astroglia, decreasing ROS production. Chronically elevated glucose environments also induced PPP activation. Immunohistochemical analyses revealed that chronic high-glucose environments induced ER (endoplasmic reticulum) stress (presumably through increased hexosamine biosynthetic pathway flux). Nuclear translocation of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), which regulates G6PDH (glyceraldehyde-6-phosphate dehydrogenase) by enhancing transcription, was also observed in association with BiP (immunoglobulin heavy-chain-binding protein) expression. Acute and chronic high-glucose environments activated the PPP in astroglia, preventing ROS elevation. Therefore a rapid decrease in glucose level seems to enhance ROS toxicity, perhaps contributing to neural damage when insulin levels given to diabetic patients are not properly calibrated and plasma glucose levels are not adequately maintained. These findings may also explain the lack of evidence for clinical benefits from strict glycaemic control during the acute phase of stroke.

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神経内科学　Neurovascular unit　その10年

高橋, 愼一

医学のあゆみ 239 ( 11 ) 1132 - 1133 2011.12

ISSN 0039-2359

高グルコース環境とアストログリアのglycoxidative stress応答

高橋, 慎一, 伊澤, 良兼 and 鈴木, 則宏

臨床神経学 51 ( 12 ) 1309 2011.12

ISSN 0009-918X

[Cerebral infarction: tissue clock and reperfusion, brief overview]

Takahashi, S.

Rinsho Shinkeigaku 51 ( 11 ) 1173 2011.11

ISSN 0009-918

脳梗塞　Tissue clockとReperfusion Tissue clockとReperfusion:Brief overview

高橋, 愼一

臨床神経学 51 ( 11 ) 1173 2011.11

ISSN 0009-918X

グリア細胞と神経疾患脳虚血とアストロサイト

高橋, 愼一

臨床神経学 51 ( 11 ) 1032 - 1035 2011.11

ISSN 0009-918X

【アストロサイト-その驚くべき多彩な機能】アストロサイトと糖代謝

高橋, 愼一

Clinical Neuroscience 29 ( 11 ) 1262 - 1267 2011.11

ISSN 0289-0585

治療ターゲットとしての脳虚血後の炎症アストロサイトからみた脳虚血後の炎症

高橋, 愼一, 伊澤, 良兼, 飯泉, 琢矢, 安部, 貴人 and 鈴木, 則宏

脳循環代謝 23 ( 1 ) 86 2011.11

ISSN 0915-9401

脳梗塞急性期患者の病態把握における血管内皮機能検査の有用性

小泉, 健三, 山田, 哲, 伊澤, 良兼, 伊藤, 義彰, 高橋, 愼一 and 鈴木, 則宏

脳循環代謝 23 ( 1 ) 171 2011.11

ISSN 0915-9401

[Astroglial protective mechanisms against ROS under brain ischemia]

Takahashi, S.

Rinsho Shinkeigaku 51 ( 11 ) 1032 - 5 2011.11

ISSN 0009-918

Reactive oxygen species (ROS) derived from mitochondria in neural cells play an essential role in the pathophysiology of stroke. Hyperglycemia is also known to enhance ROS production, resulting in oxidative stress. We reported that both acute and chronic high glucose environments enhance the pentose phosphate pathway (PPP) in astroglia, reducing ROS production and thereby providing a neuroprotective role. In particular, chronic hyperglycemia elicits PPP activation through the Keap1/Nrf2 system, which is induced by endoplasmic (ER) stress via an increase in hexosamine biosynthetic pathway flux. We examined the effects of hypoxia with or without glucoprivation on PPP in cultured neurons and astroglia. Hypoxia without glucoprivation for 12 or 24 hours induced PPP activation in astroglia (126% and 177%, respectively) but not in neurons. PPP activation by hypoxia was accompanied by Nrf2 translocation to the nucleus but not by Bip expression in the ER. Re-oxygenation supplemented with glucose after 12 hours of hypoxia with or without glucoprivation markedly enhanced PPP in astroglia (231% and 178%, respectively). Hypoxia induced PPP activation in astroglia, exerting a neuroprotective role. While the Keap1/Nrf2 system seems to be involved, ER stress is not necessarily required.

脳虚血・基礎・メカニズム慢性高グルコース環境がアストログリアのグルコース依存性ROS消去反応に及ぼす影響

伊澤, 良兼, 高橋, 愼一 and 鈴木, 則宏

脳循環代謝 22 ( 2 ) 35 - 39 2011.08

ISSN 0915-9401

糖尿病は脳梗塞を含む大血管症のリスクとなり、長期にわたる厳格な血糖管理はその発症リスクを減じる可能性があるが、急速な血糖降下や血糖変動は、逆にリスクを増加させる可能性も指摘されている。また、アストログリアは細胞外グルコース濃度変化に対して鋭敏な代謝応答を示し、急性高グルコース環境ではペントースリン酸経路pentose phosphate pathway(PPP)への流れが増加し、NADPH産生を介して還元型グルタチオンを供給することで活性酸素種reactive oxygen species(ROS)に対する神経保護機能をもたらす。今回、慢性高グルコース環境下(23mM)および低グルコース環境下(5mM)で培養されたアストログリアにおいて、細胞外グルコースを2mMおよび20mMに変化させた際のPPP活性を評価した。結果、慢性高グルコース環境は、アストログリアのPPP活性を亢進させ神経保護作用を示す反面、この状態からグルコース濃度を急性に低下させた際にはPPP活性は低下し、酸化ストレスを一時的に増大させる可能性が示唆された。(著者抄録)

高橋, 愼一

分子脳血管病 10 ( 3 ) 352 - 355 2011.07

ISSN 1346-8995

スタチンによる血中LDL-Cの低下が、主要血管イベントのリスクを減じることはすでにエビデンスとして確立している。今回Cholesterol Treatment Trialists'(CTT)Collaborationによって26のランダム化比較試験に参加した170,000人の個別データのメタ解析から、さらに強力にLDL-Cを低下させた場合にも1年あたりLDL-C値1.0mmol/L低下で、閾値なく、安全に5分の1強のリスク低減をもたらすことが明らかとなった。このことはLDL-Cを2〜3mmol/L低下させることで、リスクを40〜50%減じる可能性を示す。(著者抄録)

専門医に求められる最新の知識　脳血管障害　Neurovascular unit

高橋, 愼一

脳神経外科速報 21 ( 5 ) 531 - 541 2011.05

ISSN 0917-1495

Neurovascular unit(NVU)とは、ニューロンと血管内皮細胞、細胞外マトリックス、アストロサイトの機能的統合体を示す。NVUは、脳血管障害急性期の治療方策としてニューロンの救済のみならず、ニューロンの機能を支える血管、そして構造的に血管とニューロンを橋渡しするアストロサイトを機能ユニットとしてとらえることによって、新たな急性期脳梗塞治療戦略を模索するためのconceptual frameworkとして提唱された。しかし近年、NVUは脳血管障害急性期のみならず慢性虚血や、さらに神経変性疾患においてもその発症と病態進展に循環障害が重要な役割を担うという観点から、広く中枢神経疾患を理解するためのツールとして用いられている。(著者抄録)

【脳卒中診療の新しい展開　治療ガイドライン新改訂に基づく実地診療】実地医家が取り組む脳卒中診療の新展開

矢崎, 義雄, 阿部, 康二, 神谷, 達司 and 高橋, 愼一

Medical Practice 28 ( 4 ) 611 - 630 2011.04

ISSN 0910-1551

各種疾患　中毒・代謝疾患糖尿病の血糖管理と脳卒中

高橋, 愼一

Annual Review神経 2011 278 - 292 2011.01

糖尿病は脳卒中(脳梗塞)の独立した危険因子であり,その新規発症と再発予防のためには適切な血糖管理が重要となる.また脳卒中急性期の治療においても血糖管理は重要であるが,管理目標と予後改善効果に関する十分なエビデンスは乏しい.脳卒中を含めた心血管イベントは大血管症(macroangiopathy)として総括される糖尿病の合併症でありながら,網膜症,腎症といった細小血管症(microangiopathy)に比較して,血糖管理による発症予防効果の検証が困難であった.2008〜2010年にかけて,長期にわたる安定した血糖管理が大血管症の発症予防効果を示す大規模臨床試験の結果が相次いで報告されたが,脳卒中に関しての明らかな抑制効果は証明されていない.今後さらに脳卒中の病型別(ラクナ,アテローム血栓性,あるいは分枝粥腫型梗塞)の研究,各々の管理目標,さらに急性期治療における血糖管理に関するエビデンスの構築が望まれる.(著者抄録)

PPARγ作動薬がラット培養アストログリアとニューロンの糖代謝に及ぼす影響

伊澤, 良兼, 高橋, 愼一 and 鈴木, 則宏

臨床神経学 50 ( 12 ) 1090 2010.12

ISSN 0009-918X

[Aiming for a breakthrough in therapy for cerebrovascular disorders]

Takahashi, S. and del Zoppo, G. J.

Rinsho Shinkeigaku 50 ( 11 ) 875 2010.11

ISSN 0009-918

脳虚血・基礎・メカニズム慢性高グルコース環境がアストログリアのグルコース依存性ROS消去反応に及ぼす影響

伊澤, 良兼, 高橋, 愼一 and 鈴木, 則宏

脳循環代謝 22 ( 1 ) 68 2010.11

ISSN 0915-9401

高グルコース環境とERストレス　アストログリアにおけるグルコース代謝のminor pathways

高橋, 愼一, 伊澤, 良兼 and 鈴木, 則宏

脳循環代謝 22 ( 1 ) 99 2010.11

ISSN 0915-9401

【血液脳関門　分子機序から病態まで】 Neurovascular unitにおける血液脳関門の役割

高橋, 愼一

分子脳血管病 9 ( 3 ) 275 - 281 2010.07

ISSN 1346-8995

血液脳関門(BBB)は、古典的には隣接する脳血管内皮細胞間の接着に由来する物質透過性の制御機構である。近年、脳血管障害の病態を考察するツールとして提唱され広く用いられるようになったNeurovascular unit(NVU)は、ニューロンと血管内皮細胞、細胞外マトリックス、アストロサイトの機能的統合体を示す。NVUでは、BBBを内皮細胞間接着に加え、アストロサイトの足突起と血管内皮細胞、その間の基底膜細胞外マトリックスの接着を第2次バリアと考えることによって、虚血性脳損傷の更なる病態理解を進め、新しい治療法の開発につながることが期待される。(著者抄録)

脳エネルギー代謝研究の最前線ニューロンとアストロサイトのエネルギー代謝

高橋, 愼一

脳循環代謝 21 ( 2 ) 18 - 27 2010.07

ISSN 0915-9401

ヒトの脳は生理的条件下ではD-グルコースのみをエネルギー基質とし、その酸化的代謝から得られるATPで機能活動を維持している。脳のエネルギー代謝をグルコース代謝として検討すると、CMRO2とCMRglcの実測比(CMRO2/CMRglc)は約5であり、グルコースが完全な酸化的代謝でCO2に分解された際の理論値6に近く、脳のグルコース代謝は、ほとんどがエネルギー産生のための酸化的消費である。ヒト大脳皮質ではアストロサイトの数はニューロンの約1.4倍とされる。アストロサイトはニューロンと微小血管を橋渡しするように位置し、エネルギー代謝からみてもニューロンと機能的に連動し、脳血流調節にも関与する。グルコース代謝から見たニューロンとアストロサイトのエネルギー代謝において、1)エネルギー基質としてのグルコースと乳酸の選択性(preference)、2)ニューロンの活動亢進に伴って起こるエネルギー基質の供給、3)エネルギー産生を伴わないグルコース代謝、の3点を中心に現在の脳のエネルギー代謝の知見をまとめる。(著者抄録)

Risk factor profiles of stroke, myocardial infarction, and atrial fibrillation: a Japanese Multicenter Cooperative Registry

Uchiyama, S., Shibata, Y., Hirabayashi, T., Mihara, B., Hamashige, N., Kitagawa, K., Goto, S., Origasa, H., Shimada, K., Kobayashi, H., Isozaki, M. and Ikeda, Y.

J Stroke Cerebrovasc Dis 19 ( 3 ) 190 - 7 2010.05

ISSN 1052-3057

OBJECTIVE: We sought to clarify risk factor profiles and current treatment of Japanese patients with stroke, myocardial infarction (MI), and nonvalvular atrial fibrillation (NVAF) using the database of the Japan Thrombosis Registry for Atrial Fibrillation, Coronary, or Cerebrovascular Events (J-TRACE). METHODS: J-TRACE is a nationwide multicenter cooperative cohort of Japanese patients with MI, stroke, and NVAF. Baseline characteristics of 8087 Japanese patients (5804 male, average age 68.7 years) with history of stroke (n=3554), MI (n=2291), or NVAF (n=2242) were analyzed. RESULTS: History of stroke (14.7%) was more frequent than history of MI (2.6%) in patients with stroke, whereas history of stroke (6.6%) was less frequent than history of MI (7.6%) in patients with MI. In patients with NVAF, history of stroke (14.3%) was far more frequent than history of MI (3.4%). Hypertension was more frequent in stroke (74.4%) than MI (62.0%) or NVAF (57.7%), whereas hypercholesterolemia, diabetes mellitus, and cigarette smoking were more prevalent in patients with MI (56.1%, 35.1%, and 33.3%, respectively) than in those with stroke (35.7%, 22.4%, and 19.7%, respectively) or NVAF (26.9%, 17.2%, and 16.1%, respectively). Alcohol consumption (34.9%) and obesity (body mass index>25) (32.8%) were most common in patients with NVAF. In all patients, nonmedication rates were higher in patients with hypercholesterolemia (29.8%) or diabetes (36.9%) than in those with hypertension (9.5%). Warfarin was used in 58.9% of patients with low-risk and 75.4% with high-risk NVAF. CONCLUSION: Risk factor profiles and their modification were not similar among patients in Japan with MI, stroke, and NVAF, although they share a high risk of thrombotic events.

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【神経内科の病気のすべて】神経内科の病気を理解するための基礎知識　神経機能解剖　大脳、小脳、脳幹　脊髄、末梢神経、筋、脳脊髄血管

高橋, 愼一

からだの科学 ( 265 ) 6 - 16 2010.05

ISSN 0453-3038

Sex-related differences in the risk factor profile and medications of patients with atrial fibrillation recruited in J-TRACE

Inoue, H., Nozawa, T., Hirai, T., Goto, S., Origasa, H., Shimada, K., Uchiyama, S., Hirabayashi, T., Koretsune, Y., Ono, S., Hasegawa, T., Sasagawa, Y., Kaneko, Y. and Ikeda, Y.

Circ J 74 ( 4 ) 650 - 4 2010.04

ISSN 1346-9843

BACKGROUND: Clinical characteristics, including risk factors for thromboembolism, and medications differ between men and women with atrial fibrillation (AF) in Western countries. Whether such a difference exists for Japanese patients with AF is unclear, so data from J-TRACE were used to investigate this issue. METHODS AND RESULTS: A total of 2,892 patients (2,028 men, 864 women; 70.3 years old) with AF were analyzed for the respective prevalences of risk factors and medications. CHADS2 score was calculated to determine thromboembolic risk level. Women were older (P<0.001), and more frequently had heart failure (P<0.001), and hypertension (P=0.051) than men. The proportion of subjects aged 75 years or older was higher among women than among men (P<0.001). CHADS2 score was therefore significantly higher in women than in men (2.05+/-1.29 vs 1.88+/-1.33, P<0.001). Sex-related differences were not observed for the prevalence of diabetes mellitus, myocardial infarction or ischemic stroke, nor did warfarin usage differ between men and women. CONCLUSIONS: Sex-related differences were observed in the risk factor profile and medications of Japanese patients with AF. CHADS2 score was higher in women than in men.

Pioglitazone enhances pyruvate and lactate oxidation in cultured neurons but not in cultured astroglia

Izawa, Y., Takahashi, S. and Suzuki, N.

Brain Res 1305 64 - 73 2009.12

ISSN 0006-8993

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists play important roles in the regulation of energy metabolism and are widely used for patients with type 2 diabetes. PPARgamma agonists reportedly reduce plasma glucose levels by recruiting glucose transporters to the cellular membrane, resulting in the enhanced uptake of glucose. However, only a limited number of studies have examined the effect of PPARgamma on cerebral glucose metabolism. In the present study, we examined the effects of a PPARgamma agonist, pioglitazone, on glucose metabolism in cultured rat neurons and astroglia. Cultures of neurons or astroglia were prepared from Sprague-Dawley rats. The cells were treated with pioglitazone (0-50 muM) for 48 hours prior to assay. Lactate released into the culture medium (an index of glycolytic glucose metabolism) and [U-(14)C]lactate or [1-(14)C]pyruvate oxidation (an index of oxidative glucose metabolism) were measured. In addition, the production of cellular reactive oxygen species (ROS) was determined utilizing an H(2)DCFDA assay. Forty-eight hours of exposure to pioglitazone (0.5 and 5 muM) resulted in dose-dependent increases in lactate release into the astroglial culture medium but not into the neuronal culture medium. [U-(14)C]lactate oxidation and [1-(14)C]pyruvate oxidation were enhanced in the neurons, but not in the astroglia. These actions of pioglitazone were not inhibited by 2-chloro-5-nitrobenzanilide (GW9662), a potent antagonist of PPARgamma, and were not mimicked by N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine (GW1929), a non-thiazolidinedione PPARgamma agonist. Pioglitazone enhanced aerobic glycolysis and lactate release in astroglia, while the oxidative metabolism of glucose, but not glycolysis, was augmented in neurons without increasing ROS production. These results indicate that pioglitazone may enhance the efficiency of glucose metabolism in the brain.

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ニューロン活動時のアストロサイトのグルコース代謝応答と血流カップリングへの影響

高橋, 愼一, 伊澤, 良兼 and 鈴木, 則宏

脳循環代謝 21 ( 1 ) 107 2009.11

ISSN 0915-9401

OLETFラットを用いたメタボリックシンドロームの脳梗塞予後に及ぼす影響の検討

関, 守信, 鈴木, 重明, 高橋, 愼一, 伊澤, 良兼, 河野, 一弥 and 鈴木, 則宏

脳循環代謝 21 ( 1 ) 121 2009.11

ISSN 0915-9401

脳エネルギー代謝研究の最前線ニューロンとアストロサイトのエネルギー代謝

高橋, 愼一

脳循環代謝 21 ( 1 ) 78 2009.11

ISSN 0915-9401

【脳卒中の征圧をめざして】　明日の脳卒中　7つの課題と展望無症候性脳血管障害への対応

高橋, 愼一

Medicina 46 ( 11 ) 1841 - 1846 2009.11

ISSN 0025-7699

＜ポイント＞●無症候性脳梗塞は将来の脳卒中のリスクファクターである.その進展には高血圧の関与が大きく,厳格な血圧コントロールが必要である.降圧薬として,Caチャネル遮断薬,ACE阻害薬,ARBなどが推奨される.抗血小板薬の必要性は個別に判断する.●無症候性白質病変の多くは高血圧を背景とした虚血性病変である.脳卒中,認知症への進展予防のための血圧コントロールが重要である.●無症候性脳出血はMRIのT2*強調画像で認められるmicrobleedsによって診断する.将来の脳出血のリスクが高く,抗血小板薬の投与は慎重に行う.●無症候性頸部頸動脈狭窄または閉塞に対しては,抗血小板薬やスタチンの内服に加えて,高度狭窄の場合には頸動脈内膜剥離術(CEA),ステント留置術(CAS)の適応を判断する.●無症候性頭蓋内主幹動脈狭窄または閉塞の治療についての十分なエビデンスはないが,アスピリンとシロスタゾールの併用療法により血管狭窄の改善効果が報告されている.さらに,適切な降圧は病変血管支配領域の将来の虚血性イベントを抑制する可能性が高い.(著者抄録)

【糖尿病とBrain Attack】脳虚血病態と糖代謝障害

高橋, 愼一 and 鈴木, 則宏

Diabetes Frontier 20 ( 5 ) 572 - 576 2009.10

ISSN 0915-6593

高橋, 愼一

医学のあゆみ 231 ( 5 ) 339 - 346 2009.10

ISSN 0039-2359

ニューロン(neuron)の生存に不可欠な脳循環の途絶は、ただちに脳の機能障害を起こし、時間経過とともに不可逆的損傷を起こす。脳梗塞急性期治療には、脳循環の改善という最大の治療方針に加え、可能なかぎりニューロンを救済するための併用治療が望まれる。しかし、新規治療法の確立には、ニューロンのみを対象にした虚血性細胞障害のメカニズムの基礎研究と薬剤の開発だけでは不十分である。生理的状態において、ニューロンの機能と脳循環はつねに連動しており、血管を構成する内皮細胞(endothelium)、基底膜(basal lamina)の細胞外マトリックス(extracellular matrix)とその中に存在する周皮細胞(pericyte)、さらに血管平滑筋、血管外にあってニューロンとの間に介在するアストロサイト(astrocyte)という機能ユニットの理解が必須である。これをneurovascular unit(NVU)と命名し、その包括的な研究を推進することで、脳血管障害のメカニズム解明と治療法開発のさらなる進展が期待できる。(著者抄録)

孤発性筋萎縮性側索硬化症患者からのiPS細胞樹立

二瓶, 義廣, 八木, 拓也, 伊東, 大介, 小堺, 有史, 吉崎, 崇仁, 赤松, 和土, 岡田, 洋平, 川村, 雅文, 高橋, 愼一, 岡野, 栄之 and 鈴木, 則宏

Dementia Japan 23 ( 2 ) 186 2009.08

ISSN 1342-646X

脊髄アストロサイトーマに合併した辺縁系脳炎の41歳女性の一例

伊澤, 良兼, 鈴木, 重明, 高橋, 愼一, 二瓶, 義廣, 中村, 雅也 and 鈴木, 則宏

神経免疫学 17 ( 1 ) 63 2009.03

ISSN 0918-936X

XeCT-CBFからみた特発性正常圧水頭症の病態と髄液タップテストのメカニズム

高橋, 愼一, 大木, 宏一, 傳法, 倫久, 木村, 浩晃, 加藤, 元一郎, 大平, 貴之 and 鈴木, 則宏

臨床神経学 48 ( 12 ) 1090 2008.12

ISSN 0009-918X

高グルコース環境におけるラット培養アストログリアとニューロンの酸化ストレス応答

伊澤, 良兼, 高橋, 愼一 and 鈴木, 則宏

脳循環代謝 20 ( 1 ) 97 2008.11

ISSN 0915-9401

MR imaging can predict the development of nonalcoholic Wernicke encephalopathy

Ohira, M., Suzuki, S., Takahashi, S., Takahashi, K. and Suzuki, N.

AJNR Am J Neuroradiol 29 ( 9 ) E81 - 2; author reply E83 2008.10

ISSN 0195-6108

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意識消失発作で発症した内頸動脈閉塞症の38歳男性例

二瓶, 義廣, 佐々木, 貴浩, 後藤, 京子, 大木, 宏一, 高橋, 愼一, 星野, 晴彦 and 鈴木, 則宏

分子脳血管病 7 ( 4 ) 489 - 491 2008.10

ISSN 1346-8995

The Japan Thrombosis Registry for Atrial Fibrillation, Coronary or Cerebrovascular Events (J-TRACE): a nation-wide, prospective large cohort study; the study design

Origasa, H., Goto, S., Uchiyama, S., Shimada, K. and Ikeda, Y.

Circ J 72 ( 6 ) 991 - 7 2008.06

ISSN 1346-9843

BACKGROUND: A previous history of myocardial infarction (MI), stroke, and the presence of atrial fibrillation (AF) are known risk factors for the onset of arterial thromboembolic events such as MI and ischemic stroke. To clarify the rate of incidence of such events for these high-risk patients in Japan, a nation-wide cohort study was conducted that was named the 'Japan Thrombosis Registry of Atrial Fibrillation, Coronary and Cerebrovascular Events' (ie, J-TRACE) [UMIN Registered ID C000000189]. METHODS AND RESULTS: In the J-TRACE registry, a total of 8,093 Japanese patients with either a history of stroke and/or MI or patients with non-valvular AF were registered. This registry was developed by specialists in cardiology and neurology, physicians working at general hospitals, as well as general practice physicians, from whole regions of Japan, possibly reflecting the real-world medical practice. Recruited patients will be followed up for 2-3 years. Medical history, accompanying risk factors, demographic characteristics, and information regarding the use of medications were collected for these patients at baseline. Cardiovascular ischemic events and serious adverse experiences, including cerebral bleedings, which occur during the follow-up period will be recorded over a maximum of 3 years. CONCLUSION: The J-TRACE offers an opportunity to provide fundamental information regarding the incidence of cardiovascular ischemic events by a stratum of the risk factor profile and current medical treatment for Japanese patients at high risk for thromboembolic diseases.

Basic Neuroscience アストロサイトと脳循環調節

高橋, 愼一

Annual Review神経 2008 25 - 34 2008.01

脳実質内細動脈の血管口径がアストロサイトを介して調節されていることを示す証左が集積しつつある.興奮性ニューロンの機能活動亢進に伴って放出されるグルタミン酸が,シナプスを包むアストロサイトに発現する代謝型グルタミン酸受容体に作用し,IP3を介して細胞内Ca2+濃度上昇を惹起する.続いて起こるアストロサイトの細胞内アラキドン酸代謝経路の活性化は,PGE2,EET等の産生を介してアストロサイトの足突起に接した脳動脈平滑筋の弛緩を起こす.またアストロサイトを通じてシナプスから血管壁近傍に運搬されるK+も動脈拡張反応に関与する可能性がある.総じてアストロサイトの介在するメカニズムはfunctional hyperemiaとして生じるCBF増加の約50%を担うと推定される.一方,ノルアドレナリン作動性ニューロンの神経終末はアストロサイトに存在し,その興奮がアストロサイトから搬送されたアラキドン酸を直接血管平滑筋内で20-HETEに変換することで血管収縮作用を惹起している可能性もある.(著者抄録)

シロスタゾールがラット培養アストログリアとニューロンの酸化的グルコース代謝に与える影響

高橋, 愼一 and 鈴木, 則宏

脳循環代謝 19 ( 2 ) 101 2007.10

ISSN 0915-9401

悪性腫瘍を伴って発症した抗SRP抗体陽性多発筋炎の82歳男性例

佐藤, 秀樹, 長田, 高志, 伊東, 大介, 高橋, 慎一 and 鈴木, 則宏

臨床神経学 47 ( 7 ) 447 2007.07

ISSN 0009-918X

Neurogenesisと神経再生医療 Neurogenesisとニューロン-アストロサイトのエネルギー代謝連関

高橋, 愼一, 安部, 貴人 and 鈴木, 則宏

脳循環代謝 18 ( 4 ) 180 - 183 2006.12

ISSN 0915-9401

脳の機能再生には、ニューロンによる神経回路網の再構築のみならず、ニューロン(シナプス)-アストロサイト-微小循環の3者間ネットワークの再構築が必要である。エネルギー需要と連動する脳循環調節と、ニューロンのエネルギー代謝を円滑に行うためのエネルギー基質の受け渡しの2点において、アストロサイト(アストログリア)の役割が注目されている。神経再生医療においても、移植や内在性神経幹細胞性の賦活化による「機能的ニューロン」への再生とともに、「機能的アストロサイト」への再生が必須と考えられるが、これまで後者について機能評価は十分に行われていない。本研究結果は、ラット胎児脳由来neurosphereから分化させた培養アストログリアのin vitroグルコース代謝機能は、対照アストログリアと差異を認めず、再生脳におけるニューロン-アストロサイトのエネルギー代謝連関の再構築に十分寄与し得る可能性を示した。(著者抄録)

ラット培養アストロサイトの酸化的リン酸化に対するD-アスパラギン酸刺激の影響

安部, 貴人, 高橋, 慎一 and 鈴木, 則宏

脳循環代謝 18 ( 4 ) 192 2006.12

ISSN 0915-9401

ラット胎仔由来neurosphereから分化誘導したアストログリアのグルコース代謝機能解析

高橋, 愼一, 安部, 貴人 and 鈴木, 則宏

脳循環代謝 18 ( 4 ) 193 2006.12

ISSN 0915-9401

高グルコース24時間曝露がラット培養アストログリアのグルコース代謝に及ぼす影響

高橋, 愼一, 安部, 貴人 and 鈴木, 則宏

脳循環代謝 18 ( 3 ) 112 2006.11

ISSN 0915-9401

【脳室とその病変　水頭症をめぐって】正常圧水頭症　臨床症状　正常圧水頭症の三徴以外の症状

高橋, 愼一

Clinical Neuroscience 24 ( 11 ) 1251 - 1254 2006.11

ISSN 0289-0585

[Stroke presenting dementia as its cardinal symptom]

Takahashi, S.

Nihon Rinsho 64 Suppl 7 469 - 72 2006.10

ISSN 0047-1852

脳卒中専門医のためのミクロ解剖学　アストロサイト　その機能と虚血時の反応

高橋, 愼一

分子脳血管病 5 ( 4 ) 478 - 487 2006.10

ISSN 1346-8995

正常脳においてアストロサイトは、ニューロンのための細胞外環境の維持、エネルギー代謝の補助、脳血流調節と多面的に作用している。虚血脳において、その作用は急性期、亜急性期、慢性期のいずれにおいても、ニューロンに対して時に保護的、時に傷害性に作用するため一元的に論じることは難しい。またアストロサイトは成体脳における神経幹細胞の一部である可能性があり、回復期の再生医療を考えるうえでも重要な細胞である。(著者抄録)

【インターベンション時代の脳卒中学　超急性期から再発予防まで】脳血管障害総論　脳卒中の直後と脳卒中後の諸症状とその管理　痴呆を主症状とする脳卒中

高橋, 愼一

日本臨床 64 ( 増刊7 インターベンション時代の脳卒中学(上) ) 469 - 472 2006.10

ISSN 0047-1852

【脳虚血基礎研究Up to Date】脳虚血病態におけるグリアの役割　グリア機能の制御は脳梗塞治療にどこまで貢献するか

安部, 貴人, 高橋, 愼一 and 鈴木, 則宏

脳循環代謝 18 ( 2 ) 93 - 97 2006.08

ISSN 0915-9401

Metabolic properties of astrocytes differentiated from rat neurospheres

Abe, T., Takahashi, S. and Suzuki, N.

Brain Res 1101 ( 1 ) 5 - 11 2006.07

ISSN 0006-8993

The metabolic properties of astroglia differentiated from neurospheres have not been fully assessed. In this study, the glycolytic and oxidative metabolism of glucose in astroglia differentiated from rat tertiary neurospheres (astroglia(NS)) was compared with that in astroglia prepared from the striata of embryonic day 16 rats (astroglia(ST)). In addition to the basal condition, we also investigated energy metabolism under Na+,K+-ATPase activation. Furthermore, the effects of glucose concentration in the culture medium were assessed. No significant differences in 2-deoxy-D-[1-(14)C]glucose phosphorylation were observed between astroglia(NS) and astrogliaST. The rates of L-[U-14C]lactate ([14C]lactate) and D-[U-14C]glucose ([14C]glucose) oxidation were 5.74+/-0.82 and 2.83+/-0.4 pmol/60 min/microg protein, respectively, in astrogliaNS grown in low glucose (2 mM) and 3.01+/-1.03 and 1.77+/-0.23 pmol/60 min/microg protein, respectively, in astrogliaNS grown in high glucose (22 mM). Neither the [14C]lactate nor the [14C]glucose oxidation rates in astrogliaNS were significantly different from those in astrogliaST. D-aspartate (500 microM) significantly increased the [14C]lactate and [14C]glucose oxidation rates by 127% and 62%, respectively, in astrogliaNS grown in low glucose and by 217% and 115%, respectively, in astroglia(NS) grown in high glucose. D-aspartate also increased the oxidation of [14C]lactate and [14C]glucose to 236% and 147% of the control values, respectively, in astrogliaST grown in low glucose and to 174% and 144%, respectively, in astrogliaST grown in high glucose. Rat astroglia differentiated from neurospheres might possess an equivalent capacity for utilizing energy substrates under both basal and activated conditions to that of astroglia prepared from striatum.

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【メタボリックシンドローム】　メタボリックシンドロームに合併する疾患　脳血管障害

高橋, 愼一 and 鈴木, 則宏

最新医学 61 ( 6月増刊 ) 1340 - 1354 2006.06

ISSN 0370-8241

メタボリックシンドロームは虚血性脳血管障害の発症リスクを約2倍に増大させる.人種,民族の差異に基づいた適正なカットオフ値による診断をもとに,生活習慣によって生じる軽微なリスクの集積に早期から対処することで脳梗塞や一過性脳虚血発作(TIA)の発症を有効に予防できる可能性が高い.治療には運動と体重減少とともにアンジオテンシンII受容体拮抗薬(ARB)やペルオキシソーム増殖剤応答性受容体(PPAR)α,γアゴニストの適正な選択が必要で,時に複数の薬剤の使用が有効である(著者抄録)

Oxidative metabolism in cultured rat astroglia: effects of reducing the glucose concentration in the culture medium and of D-aspartate or potassium stimulation

Abe, T., Takahashi, S. and Suzuki, N.

J Cereb Blood Flow Metab 26 ( 2 ) 153 - 60 2006.02

ISSN 0271-678X

The glucose concentration in the culture medium may affect the energy metabolism of cultured cells. The oxidative metabolism of glucose in astrocytes might also be affected because the glucose concentration (25 mmol/L) of many culture media is higher than the physiological levels (approximately 3 mmol/L). In the present study, we assessed the effects of reducing the glucose concentration in the culture medium on the oxidative metabolism of glucose in cultured rat astroglia by measuring the oxidation rates of L-[U-14C]lactate or D-[U-14C]glucose to 14CO2. The effects of D-aspartate and elevated extracellular K+ levels on oxidative and glycolytic metabolism in astroglia were also investigated. The rates of [14C]lactate and [14C]glucose oxidation in astroglia cultured in a medium containing 2 mmol/L of glucose (astroglia2) were approximately twofold of those in astroglia cultured in a medium containing 22 mmol/L of glucose (astroglia22). D-Aspartate (500 micromol/L) significantly increased [14C]lactate oxidation by 156% in astroglia22 and by 83% in astroglia2. D-[U-14C]glucose oxidation in astroglia22 and astroglia2 was also increased by 94% and 76%, respectively. In contrast, an elevated extracellular K+ concentration (7.4 mmol/L) did not affect glucose and lactate oxidation, although it increased 2-deoxy-D-[1-14C]glucose phosphorylation. Astroglia grown in the physiological glucose concentration are more dependent on the oxidative metabolism of glucose than that in high-glucose concentration. Glucose concentration in culture medium has a strong influence on astrocytic oxidative capacity in vitro.

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アスペルギルス感染をともなった肥厚性硬膜炎の1剖検例

安富, 大祐, 奥井, 俊一, 淺葉, 義明, 赤塚, 誠哉 and 高橋, 慎一

臨床神経学 45 ( 9 ) 692 2005.09

ISSN 0009-918X

脳循環代謝に関する最近の知見　ニューロン-アストロサイト-微小循環のネットワーク

高橋, 愼一

慶應医学 82 ( 3 ) 119 - 127 2005.09

ISSN 0368-5179

びまん性脳浮腫をきたしたCNSループスの一例

安富, 大祐, 川越, 光博 and 高橋, 慎一

臨床神経学 45 ( 7 ) 545 2005.07

ISSN 0009-918X

アストロサイトのエネルギー代謝とイオン動態から見た脳循環調節機構

高橋, 慎一 and 安部, 貴人

脳循環代謝 17 ( 2 ) 150 - 155 2005.06

ISSN 0915-9401

機能活動亢進に伴うエネルギー消費の亢進はニューロンのみならず近傍のアストロサイトでも起こっている事が確認された.同時に局所脳血流代謝カップリングにアストロサイトを介した細動脈拡張メカニズムが関与する可能性も指摘されている.そこで,ラット培養細胞を用いたin vitroのデータを交えて,エネルギー代謝とイオン動態からレビュー検討した.アストロサイトは神経活動亢進に伴い増大するシナプス部のエネルギー消費とカップルした脳血流増加に重要な役割を果たす可能性があり,神経活動亢進は,シナプス間へのK+とグルタミン酸放出をもたらした.K+はアストロサイトに取り込まれ,細胞外K+濃度増加が血管拡張を来たす可能性があった.また,グルタミン酸はグルコース消費増大,TCAサイクルの活性化とCO2産生増加を惹起した.また同時にアストロサイトの代謝型グルタミン酸受容体を介して血管反応物質の産生を惹起し,エネルギー消費に影響せず細動脈拡張をきたす可能性もあった

てんかん発作で発症し,脳梗塞と鑑別が困難であった脳膿瘍の1例

安富, 大祐, 片山, 隆晴, 奥井, 俊一 and 高橋, 慎一

日本内科学会関東地方会 526回 30 2005.05

ラクナ梗塞の危険因子　慶応義塾大学脳卒中データベースより

田中, 耕太郎, 棚橋, 紀夫, 濱田, 潤一, 野川, 茂, 武田, 英孝, 高橋, 慎一 and 鈴木, 則宏

脳卒中 27 ( 1 ) 133 2005.04

ISSN 0912-0726

ラット中大脳動脈閉塞再灌流後のmonocarboxylate transporters発現の経時的変化

安部, 貴人, 鈴木, 重明, 高橋, 慎一 and 鈴木, 則宏

脳卒中 27 ( 1 ) 166 2005.04

ISSN 0912-0726

細胞外K+濃度上昇がラット培養アストログリアのエネルギー基質利用率に与える影響

安部, 貴人, 高橋, 慎一 and 鈴木, 則宏

脳循環代謝 17 ( 1 ) 83 - 84 2005.03

ISSN 0915-9401

生理的範囲での[K+]oの変化がアストロサイトのエネルギー基質利用率に与える影響を検討した.更に高グルコース(22mM)DMEMと低グルコース(2mM)DMEMで培養したアストログリアの反応の差異についても検討した.尚,アストログリアは新生仔Sprague-Dawleyラット大脳皮質より組織を採取し培養を行った.1)グルコース2mM下で培養した細胞では,22mMに比べ[14C]lactate酸化率の上昇を認めた.[14C]deoxyglucoseリン酸化率は変化しなかった.2)細胞外K+濃度の上昇により,培養アストログリアの[14C]deoxyglucoseリン酸化率は増加し,[14C]lactate 酸化率は変化しなかった.3)神経活動亢進時に放出されるK+を介し,アストロサイトの解糖系エネルギー消費のみが亢進する可能性が示唆された

化膿性髄膜炎として発症した脳塞栓症,上肢動脈塞栓症を合併した感染性心内膜炎の1救命例

安富, 大祐, 高橋, 慎一, 石川, 美江, 石川, 士郎, 村山, 晃 and 朝見, 淳規

日本内科学会関東地方会 525回 24 2005.03

成長ホルモン分泌不全性低身長症としてホルモン補充療法をうけていたMELASの一例

安富, 大祐 and 高橋, 慎一

臨床神経学 45 ( 2 ) 152 2005.02

ISSN 0009-918X

【内科医が診るしびれと痛み】　しびれと痛みに対する対症療法　その他の薬物治療

高橋, 慎一

Medicina 41 ( 8 ) 1369 - 1371 2004.08

ISSN 0025-7699

救急医療における二次医療機関の役割

芳賀, 佳之, 高橋, 慎一, 奥井, 俊一, 鈴木, 暁, 山藤, 和夫, 藤田, 亨介, 村山, 晃, 川越, 光博, 遠藤, 昌夫 and 戸倉, 康之

埼玉県医学会雑誌 38 ( 3 ) 304 - 307 2003.12

ISSN 0389-0899

細胞内グリコーゲン量の変化がアストログリアのエネルギー代謝に与える影響:Alamar Blue還元法による検討

安部, 貴人, 高橋, 慎一 and 福内, 靖男

脳卒中 25 ( 1 ) 159 2003.03

ISSN 0912-0726

頸部整体中に延髄内側症候群(Dejerine症候群)を発症した椎骨動脈解離の1例

横田, 淳一, 天草, 弥生, 冨田, 裕 and 高橋, 慎一

脳と神経 55 ( 2 ) 121 - 125 2003.02

ISSN 0006-8969

38歳男.頸部整体治療中に突然,右片麻痺,深部感覚障害および左舌下神経麻痺を発症した.脳血管撮影およびMR angiographyにて左椎骨動脈の狭窄,不整拡張などが認められた.MRI上,延髄左内側部に梗塞巣が確認され,延髄内側梗塞と診断された.発症機序としては,頸部整体術による頸部回旋運動で椎骨動脈に過度に伸展,圧排が加わることにより血管内膜損傷を生じ,動脈解離を引き起こすことにより虚血に陥り,延髄梗塞を発症したと考えられた.臨床経過は全般的に改善傾向がみられ約2ヵ月半後退院となったが,右上肢麻痺の改善は認められなかった.本症の発症を少しでも未然に防ぐには,整体術を受ける前に頭頸部を静かに回旋,過伸展させた状態でいったん経過観察し,何らかの異常を訴える場合は即時中止すべきである

Reduction of Alamar Blue, a novel redox indicator, is dependent on both the glycolytic and oxidative metabolism of glucose in rat cultured neurons

Abe, T., Takahashi, S. and Fukuuchi, Y.

Neurosci Lett 326 ( 3 ) 179 - 82 2002.07

ISSN 0304-3940

Recently, it has been hypothesized that neurons mainly utilize lactate produced by astrocytes to generate energy (i.e. ATP). Regardless of numerous studies, whether lactate rather than glucose fuels neurons in vivo remains a matter of controversy. In the present study we have examined the substrate-preference of the reduction of Alamar Blue, a novel redox indicator, by cultured rat astroglia and neurons. Alamar Blue reduction is dependent on cellular reducing equivalents. Therefore, the substrate-preference of Alamar Blue reduction could reflect that for cellular energy production. Rates of Alamar Blue reduction by 2 mM glucose were two-fold higher in astroglia than those in neurons. Alamar Blue reduction induced by 2 mM lactate was 78% of that by 2 mM glucose in neurons while only 20% in astroglia. Nevertheless, glucose elicited larger Alamar Blue reduction than lactate both in astroglia and neurons. These results indicate that neuronal energy production in vivo depends on both the glycolytic and oxidative metabolism of glucose even though astroglia rely on glycolysis as has been reported.

Substrate-dependence of reduction of MTT: a tetrazolium dye differs in cultured astroglia and neurons

Takahashi, S., Abe, T., Gotoh, J. and Fukuuchi, Y.

Neurochem Int 40 ( 5 ) 441 - 8 2002.04

ISSN 0197-0186

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction is widely used to evaluate cell proliferation and viability. MTT reduction is interpreted to be indicative of cellular metabolic activity, and the site of reduction includes both mitochondrial and cytosolic redox reactions. Astrocytes are believed to rely mainly on glycolysis for ATP generation, whereas neurons are considered to depend more on oxidative metabolism. The present study, therefore, tested the substrate-preference of glucose and its metabolites for MTT reduction in cultures of rat type 1 astroglia and neurons.MTT specific activity of astroglia was much higher than that of neurons. Astroglial MTT reducing activity in glucose-free medium or 2mM glucose with iodoacetate (5mM) was completely blocked. In glucose-depleted medium, 2mM lactate, pyruvate, malate, or acetate elicited minimal increases in MTT reduction by astroglia. In contrast, MTT reducing activity in neurons was enhanced two-fold by pyruvate and the reducing activity of lactate was equivalent to that of glucose, while malate had a small and acetate had no effect on MTT reduction. These results indicate that these two cell types differ markedly in their substrate-preferences for MTT reduction. In astroglia, MTT reduction reflects mainly cytosolic redox activity and is dependent on glyceraldehyde-3-phosphate dehydrogenase. In neurons, pyruvate dehydrogenase supports MTT reduction more effectively than glucose or lactate, even though both of these substrates can produce NADH and pyruvate.

Becker型筋ジストロフィーの症候性保因者の一例

岸林, 潤, 谷田部, 可奈, 川村, 潤, 石原, 傳幸 and 高橋, 慎一

臨床神経学 41 ( 6 ) 341 2001.06

ISSN 0009-918X

Astroglial cell death induced by excessive influx of sodium ions

Takahashi, S., Shibata, M., Gotoh, J. and Fukuuchi, Y.

Eur J Pharmacol 408 ( 2 ) 127 - 35 2000.11

ISSN 0014-2999

Na(+) influx has been implicated to play an important role in the mechanisms of neuronal cell damage under ischemia as well as in neurodegenerative disorders. Thus far, however, the effects of Na(+) influx on astrocytic damage have not been studied extensively. In the present study, we have examined the effects of Na(+) influx induced by veratridine (Na(+) channel opener), monensin (Na(+) ionophore), and glutamate (co-transportation with Na(+)) on rat cultured astroglial damage. Cells were incubated with bicarbonate buffer with 25 mM glucose containing either 100 microM veratridine, 10 microM monensin, or 1 mM glutamate with or without 1 mM ouabain for 20 h. Cellular damage was evaluated quantitatively by lactate dehydrogenase (LDH) release or 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) reduction. Veratridine, monensin, or glutamate alone did not induce significant astroglial damage. Veratridine and monensin co-incubated with ouabain, which inhibits active extrusion of Na(+) by Na(+),K(+)-ATPase, thereby enhances intracellular Na(+) accumulation, caused significant cell death (P<0. 001, approximately 50% cell damage), whereas glutamate did not. Na(+)-free solution substituted by choline (impermeable cation) attenuated cell damage induced by veratridine and monensin markedly, while Li(+) substitution (permeable cation) rather exacerbated. Nifedipine (100 microM), a blocker of L-type Ca(2+) channel, reduced veratridine-induced glial damage by 50%. Neither bepridil nor benzamil, a blocker of Na(+)-Ca(2+) exchanger, had any protection. Cyclosporin A (1 or 10 microM), an inhibitor of mitochondrial permeability transition or 10 microM N-benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)fluoromethyl ketone (zVAD-fmk), which inhibits a broad range of caspases, did not show protective effects.

【眼で見る神経内科】　粟粒結核症に随伴した多発性中枢神経結核腫

高橋, 慎一 and 植松, 大輔

神経内科 53 ( Suppl.2 ) 60 - 61 2000.09

ISSN 0386-9709

【浮腫の病態と治療】　浮腫の病態と治療　脳循環異常にみる浮腫

高橋, 慎一 and 福内, 靖男

医学と薬学 43 ( 5 ) 927 - 933 2000.05

ISSN 0389-3898

MTT還元反応から見たラット培養アストログリアとニューロンのエネルギー代謝

高橋, 慎一, 後藤, 淳 and 福内, 靖男

脳循環代謝 12 ( 1 ) 93 - 94 2000.04

ISSN 0915-9401

Role of sodium ion influx in depolarization-induced neuronal cell death by high KCI or veratridine

Takahashi, S., Shibata, M. and Fukuuchi, Y.

Eur J Pharmacol 372 ( 3 ) 297 - 304 1999.05

ISSN 0014-2999

Intracellular Na+ concentration plays an important role in the regulation of cellular energy metabolism; i.e., increased intracellular Na+ concentration stimulates glucose utilization both in cultured neurons and astrocytes. Both high KCI and veratridine, which have been known to cause neuronal damage, elicit increased glucose utilization, presumably via increased intracellular Na+ concentration. In the present study, we examined the role of intracellular Na+ influx in the mechanisms of neuronal cell damage induced by high KCl or veratridine assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric method. Rat primary cultures of striatal neurons were incubated with high KCl (final concentrations: 25, 50 mM) or veratridine (0.1-100 microM) with or without various inhibitors. High KCl depolarizes cell membrane, thus, leading to Na+ influx through an activation of voltage-sensitive Na+ channels, while veratridine elicits Na+ influx by directly opening these channels. After 24-h incubation with elevated [K+]o or veratridine, glucose contents in the medium decreased significantly (approximately by 7 mM), but remained higher than 18 mM. High [K+]o reduced percent cell viability significantly (approximately 50% at 25 mM, approximately 40% at 50 mM [K+]o, P<0.01), but tetrodotoxin (100 nM) had no protective effect, indicating that Na+ influx was not essential to high K+ -induced cell death. DL-2-Amino-5-phosponovaleric acid (APV) (1 mM) completely blocked cell death induced by elevated [K+]o, while 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 microM) did not. In contrast, veratridine (>10 microM) caused cell damage in a dose-dependent and tetrodotoxin-sensitive manner, but none of APV, CNQX, or bepridil (Na+ -Ca2+ exchanger blocker) had any protective effect. Nifedipine (50 approximately 100 microM), however, reduced percent cell damage induced by veratridine.

肺炎球菌による髄膜炎を契機に発症した急性散在性脳脊髄炎の1例

菊池, 敬, 高橋, 慎一, 植松, 大輔, 藤田, 功 and 竹内, 東太郎

埼玉県医学会雑誌 33 ( 6 ) 886 - 889 1999.03

ISSN 0389-0899

ラット初代培養線条体ニューロンの脱分極性細胞死とそのメカニズム

高橋, 慎一 and 他

脳卒中 20 ( 1 ) 114 1998.02

ISSN 0912-0726

Effects of increased extracellular potassium on influx of sodium ions in cultured rat astroglia and neurons

Takahashi, S., Shibata, M. and Fukuuchi, Y.

Brain Res Dev Brain Res 104 ( 1-2 ) 111 - 7 1997.12

ISSN 0165-3806

Membrane depolarization by elevated extracellular K+ concentration ([K+]o) causes rapid Na+ influx through voltage-sensitive Na+ channels into excitable cells. The consequent increases in intracellular Na+ concentration ([Na+]i) and/or [K+]o stimulate Na+,K+-ATPase activity, which in turn stimulates energy metabolism and rates of glucose utilization (CMR[glc]) in neurons. We previously reported that in cultured cells elevated [K+]o stimulated CMR(glc) in neurons but not astroglia; but increasing [Na+]i by opening voltage-sensitive Na+ channels with veratridine stimulated CMR(glc) in both. These results indicated that Na+ influx plays a key role in the regulation of energy metabolism in neurons and astroglia, but that depolarization of astroglial membranes by elevated [K+]o does not open voltage-sensitive Na+ channels as it does in neurons. To examine this possibility directly we have measured the effects of increased [K+]o and of veratridine on Na+ influx into cultured rat astroglia and neurons. Cells were incubated in bicarbonate buffer containing ouabain (1 mM), tracer amounts of 22NaCl, and various concentrations (5.4, 28, 56 mM) of K+ or 75 microM veratridine for 0-60 min. Cells were digested and assayed for intracellular 22Na+ content. Elevated extracellular K+ stimulated tetrodotoxin-sensitive 22Na+ accumulation in cultured neurons but inhibited 22Na+ influx in astroglia. Veratridine-stimulated Na+ influx in both astroglia and neurons (144% and 133%, respectively), and these effects were completely blocked by 10 microM tetrodotoxin. These results indicate that increased [K+]o does not open voltage-sensitive Na+ channels and may inhibit Na+ influx in astroglia.

Examination of potential mechanisms in the enhancement of cerebral blood flow by hypoglycemia and pharmacological doses of deoxyglucose

Horinaka, N., Artz, N., Jehle, J., Takahashi, S., Kennedy, C. and Sokoloff, L.

J Cereb Blood Flow Metab 17 ( 1 ) 54 - 63 1997.01

ISSN 0271-678X

Cerebral blood flow (CBF) rises when the glucose supply to the brain is limited by hypoglycemia or glucose metabolism is inhibited by pharmacological doses of 2-deoxyglucose (DG). The present studies in unanesthetized rats with insulin-induced hypoglycemia show that the increases in CBF, measured with the [14C]iodoantipyrine method, are relatively small until arterial plasma glucose levels fall to 2.5 to 3.0 mM, at which point CBF rises sharply. A direct effect of insulin on CBF was excluded; insulin administered under euglycemic conditions maintained by glucose injections had no effects on CBF. Insulin administration raised plasma lactate levels and decreased plasma K+ and HCO3- concentrations and arterial pH. These could not, however, be related to the increased CBF because insulin under euglycemic conditions had similar effects without affecting CBF; furthermore, the inhibition of brain glucose metabolism with pharmacological doses (200 mg/kg intravenously) of DG increased CBF, just like insulin hypoglycemia, without altering plasma lactate and K+ levels and arterial blood gas tensions and pH. Nitric oxide also does not appear to mediate the increases in CBF. Chronic blockade of nitric oxide synthase activity by twice daily i.p. injections of NG-nitro-L-arginine methyl ester for 4 days or acutely by a single i.v. injection raised arterial blood pressure and lowered CBF in normoglycemic, hypoglycemic, and DG-treated rats but did not significantly reduce the increases in CBF due to insulin-induced hypoglycemia (arterial plasma glucose levels, 2.5-3 mM) or pharmacological doses of deoxyglucose.

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糖尿病と神経系　脳の糖代謝と脳循環

高橋, 慎一 and 福内, 靖男

Clinical Neuroscience 14 ( 12 ) 1353 - 1356 1996.12

ISSN 0289-0585

Contribution of astroglia to functionally activated energy metabolism

Sokoloff, L., Takahashi, S., Gotoh, J., Driscoll, B. F. and Law, M. J.

Dev Neurosci 18 ( 5-6 ) 344 - 52 1996

ISSN 0378-5866

Studies of local glucose utilization in neural tissues in vivo with the autoradiographic [14C]deoxyglucose method have demonstrated that energy metabolism increases almost linearly with the degree of functional activation, i.e. spike frequency, in the terminal projection zones of activated pathways. The increased metabolism is found in neuropil and is minimal or undetectable in neuronal cell bodies. Electrical stimulation, increased extracellular [K+] ([K+]o), or opening of Na+ channels with veratridine stimulates metabolism in neutral tissues, and this increase is blocked by ouabain, a specific inhibitor of Na+,K(+)-ATPase. Activation of this enzyme to restore ionic gradients across cellular membranes appears to mediate the function-related increase in energy metabolism. The metabolic activation is, therefore, not directly related to the functional activity itself but to processes operating to recover from that activity. The limited spatial resolution of the [14C]DG method precludes identification of cellular elements in neuropil participating in the metabolic activation, e.g. axonal terminals, dendrites, or astrocytic processes enveloping the synapses. We have, therefore, attempted to stimulate in vitro conditions to be expected from functional activation and increased spike activity in vivo, e.g. increased extracellular [K+], intracellular [Na+], or extracellular neurotransmitter levels, and examined their effects on glucose metabolism in neurons and astroglia in culture. Increased [K+]o stimulated [14C]DG phosphorylation in neuronal and mixed neuronal-astroglial cultures, but not in astroglial cultures assayed in bicarbonate buffer; it did occasionally stimulate metabolism in astroglia when assayed in HEPES or phosphate buffers, but these effects were variable and inconsistent. Veratridine (75 microM) stimulated [14C]DG phosphorylation in neurons and astroglia; these stimulations were blocked by 1 mM ouabain or 10 microM tetrodotoxin (TTX), which blocks voltage-dependent Na+ channels. The Na+ ionophore monensin (10 microM) doubled the rate of metabolism, a stimulation that was only partially blocked by ouabain and unaffected by TTX. L-Glutamate (500 microM) stimulated [14C]DG phosphorylation in astroglia, but this stimulation was probably secondary to Na+ uptake into the cells via a sodium/glutamate co-transporter because it was not blocked by inhibitors of NMDA or non-NMDA receptors but was absent in Na(+)-free medium. These results indicate that astroglia contribute to the increased energy metabolism in neuropil during functional activation by mechanisms that promote Na+ entry into the cells.

Lack of effects of inhibition of nitric oxide synthesis on local glucose utilization in the rat brain

Takahashi, S., Cook, M., Jehle, J., Kennedy, C. and Sokoloff, L.

J Neurochem 65 ( 1 ) 414 - 9 1995.07

ISSN 0022-3042

The effects of chronic treatment with NG-nitro-L-arginine methyl ester, a potent inhibitor of nitric oxide synthase activity, on local cerebral glucose utilization were examined in conscious rats. Intraperitoneal injections of 50 mg/kg of the nitroarginine twice daily for 4 days have been found to result in almost complete inhibition of nitric oxide synthase activity in brain. Local cerebral glucose utilization was determined by means of the quantitative autoradiographic [14C]deoxyglucose method in an experimental group (n = 7) of rats that were treated with the nitroarginine according to this schedule and in a normal control group (n = 7) treated similarly with saline. The rats were conscious but partially restrained during the determinations of local cerebral glucose utilization. The nitroarginine treatment raised mean arterial blood pressure statistically significantly to 147 +/- 3 mm Hg (mean +/- SEM) from a level of 120 +/- 5 mm Hg in the saline controls (p < 0.001 by grouped t test), but there were no statistically significant effects on glucose utilization in any of 39 brain structures examined. It is concluded that nitric oxide normally exerts no significant influence on energy metabolism in the rat brain.

Role of sodium and potassium ions in regulation of glucose metabolism in cultured astroglia

Takahashi, S., Driscoll, B. F., Law, M. J. and Sokoloff, L.

Proc Natl Acad Sci U S A 92 ( 10 ) 4616 - 20 1995.05

ISSN 0027-8424

Effects of increasing extracellular K+ or intracellular Na+ concentrations on glucose metabolism in cultures of rat astroglia and neurons were examined. Cells were incubated in bicarbonate buffer, pH 7.2, containing 2 mM glucose, tracer amounts of [14C]deoxyglucose ([14C]dGlc), and 5.4, 28, or 56 mM KCl for 10, 15, or 30 min, and then for 5 min in [14C]dGlc-free buffer to allow efflux of unmetabolized [14C]dGlc. Cells were then digested and assayed for labeled products, which were shown to consist of 96-98% [14C]deoxyglucose 6-phosphate. Increased K+ concentrations significantly raised [14C]deoxyglucose 6-phosphate accumulation in both neuronal and mixed neuronal-astroglial cultures at 15 and 30 min but did not raise it in astroglial cultures. Veratridine (75 microM), which opens voltage-dependent Na+ channels, significantly raised rates of [14C]dGlc phosphorylation in astroglial cultures (+20%), and these elevations were blocked by either 1 mM ouabain, a specific inhibitor of Na+,K(+)-ATPase (EC 3.6.1.37), or 10 microM tetrodotoxin, which blocks Na+ channels. The carboxylic sodium ionophore, monensin (10 microM), more than doubled [14C]dGlc phosphorylation; this effect was only partially blocked by ouabain and unaffected by tetrodotoxin. L-Glutamate (500 microM) also stimulated [14C]dGlc phosphorylation in astroglia--not through N-methyl-D-aspartate or non-N-methyl-D-aspartate receptor mechanisms but via a Na(+)-dependent glutamate-uptake system. These results indicate that increased uptake of Na+ can stimulate energy metabolism in astroglial cells.

Preservation of autoregulatory cerebral vasodilator responses to hypotension after inhibition of nitric oxide synthesis

Takahashi, S., Cook, M., Jehle, J., Kennedy, C. and Sokoloff, L.

Brain Res 678 ( 1-2 ) 21 - 8 1995.04

ISSN 0006-8993

Effects of inhibition of nitric oxide (NO) synthesis on the cerebrovascular autoregulatory vasodilator response to hypotension were studied in conscious rats. Cerebral blood flow (CBF) was determined with [14C]iodoantipyrine in a saline-treated control group and in three groups following inhibition of NO synthase activity by twice daily intraperitoneal injections of 50 mg/kg of NG-nitro-L-arginine methyl ester (L-NAME) for four days. In the saline-control group (n = 8) and in the L-NAME-treated Group (a) (n = 8) CBF was determined while systemic mean arterial blood pressure (MABP) remained at its resting level (means +/- S.D., 128 +/- 6 and 151 +/- 11 mmHg, respectively). In the other groups CBF was determined after MABP was reduced by blood withdrawal to 118 +/- 9 and 88 +/- 8 mmHg in Groups (b) (n = 8) and (c) (n = 8), respectively. Despite the elevated MABP, global CBF was significantly lower in L-NAME-treated Group (a) than in the saline-controls (P < 0.005), indicating cerebral vasoconstriction resulting from inhibition of NO synthesis. Global CBF was not significantly reduced further in the two groups with hypotension. Local CBF in the hypotensive rats showed no significant reductions below values in L-NAME-treated control rats (Group (a)) in 31 of 32 brain structures; the only exception was in the auditory cortex of the severely hypotensive rats (Group (c)). The autoregulatory mechanism for cerebral vasodilatation to compensate for reduced arterial blood pressure is maintained following inhibition of NO synthesis.

Role of the cerebellar fastigial nucleus in the physiological regulation of cerebral blood flow

Takahashi, S., Crane, A. M., Jehle, J., Cook, M., Kennedy, C. and Sokoloff, L.

J Cereb Blood Flow Metab 15 ( 1 ) 128 - 42 1995.01

ISSN 0271-678X

Local cerebral blood flow (ICBF) was measured with [14C]iodoantipyrine in conscious, unrestrained rats during electrical stimulation of the fastigial nucleus (FN). Electrode position in the FN was determined by blood pressure (MABP) responses to stimulation under anesthesia. In nine rats in which MABP responses had been variable under anesthesia, bipolar stimulation (50 Hz, 0.5 ms, 1 s on/1 s off) with currents of 30-100 microA after recovery from anesthesia produced stereotypic behavior but little effect on MABP and ICBF. In seven other conscious rats currents could be raised to 75-200 microA without inducing seizures, resulting in sustained MABP elevations during the ICBF measurement and significantly increased ICBF in the sensory-motor (+45%), parietal (+31%), and frontal cortices (+56%) and the caudate-putamen (+27%) above control values (n = 9). Glucose utilization, measured with [14C]deoxyglucose, in rats similarly stimulated was significantly increased in six structures, including some of the above, indicating increases in ICBF due to metabolic activation. Unilateral or bilateral electrolytic lesions of the FN, placed 6-7 days before ICBF measurement, had negligible effects on resting ICBF and on autoregulation in conscious rats. These results fail to support a specific role for the FN in physiological regulation of cerebral blood flow in unanesthetized rats.

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Increases in local cerebral blood flow associated with somatosensory activation are not mediated by NO

Adachi, K., Takahashi, S., Melzer, P., Campos, K. L., Nelson, T., Kennedy, C. and Sokoloff, L.

Am J Physiol 267 ( 6 Pt 2 ) H2155 - 62 1994.12

ISSN 0002-9513

Effects of inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester (L-NAME) on the increases in local cerebral blood flow (LCBF) produced in the whisker-to-barrel sensory pathway by vibrissal stimulation were studied in conscious rats with the autoradiographic iodo[14C]antipyrine method. Unilateral whisker stroking increased LCBF in the ipsilateral trigeminal spinal and principal sensory nuclei, contralateral ventral posteromedial thalamic nucleus, and contralateral somatosensory barrel cortex. Intravenous L-NAME (30 mg/kg) lowered baseline LCBF without altering the percent increases due to stimulation. Intracisternal infusions of L-NAME in doses about 10 times the molar content of free arginine in brain inhibited brain NO synthesis activity by 88%, but the percent augmentations of LCBF by stimulation remained unchanged. Chronic treatment with L-NAME (50 mg/kg ip twice daily for 4 days) inhibited NO synthase activity in brain by 84% but also failed to reduce the percent increases in LCBF due to stimulation. These results indicate that NO does not mediate the increases in LCBF associated with functional activation.

Locus coeruleus stimulation exerts different influences on the dynamic changes of cerebral pial and intraparenchymal vessels

Ohta, K., Gotoh, F., Shimazu, K., Amano, T., Komatsumoto, S., Hamada, J. and Takahashi, S.

Neurol Res 13 ( 3 ) 164 - 7 1991.09

ISSN 0161-6412

The present experimental study was undertaken to investigate the effects of locus coeruleus stimulation on the dynamic changes of intraparenchymal vessels and pial vessels. Twelve cats were anaesthetized with alpha-chloralose and urethane. For stimulation of the locus coeruleus, a concentric stainless-steel needle electrode was inserted stereotaxically. During the stimulation, volumetric changes of the intraparenchymal vessels were monitored by a photoelectric method for estimating the cerebral blood volume (CBV) (6 cats), and the diameters of pial arteries were measured continuously using a video camera system (6 cats). The CBV followed a decreasing course during the stimulation of the locus coeruleus. The decrease in CBV from the control value (6.3 vol%) was 0.14 +/- 0.04 vol% at 80 s (p less than 0.05), 0.15 +/- 0.05 vol% at 100 s (p less than 0.05), and 0.15 +/- 0.03 vol% at 120 s (p less than 0.01). After cessation of the stimulation, CBV showed a gradual recovery. On the other hand, the diameters of the pial arteries did not change during or after the stimulation of the locus coeruleus. The above results suggest that the locus coeruleus has a vasoconstrictive effect on the intraparenchymal vessels, although it exerts no apparent influence on the pial arteries.

クモ膜下出血(SAH)における上頸部交感神経節節前線維の電気活動

高橋, 慎一

自律神経 27 ( 3 ) 338 - 345 1990.06

ISSN 0288-9250

SAH後の脳血管攣縮に対するノルアドレナリン(NA)作動性神経系の関与を明らかにするため,実験的SAHにおける上頸部交感神経節(SCG)節前線維の電気活動を検討した.成猫13匹を用い,SCG近傍で節前線維を切断後,中枢側から活動電位を導出し,pulse density variation法を用いて連続的に解析した.実験的SAHは大槽内に自家血0.3 mlを注入し作製した(SAH群8例),対照群(5例)では生理食塩水0.3 mlを注入をした.SAH群では節前線維の放電頻度はSAH作製後,前値に比し有意に増加した(10分後:186.9±48.1%,mean±SEM, 30分後:328.4±88.5%,90分後:296.3±132.0%,各々p<0.05),対照群の放電頻度は有意な変化を示さなかった.なお,経過中両群とも全身血圧に有意な変動を認めなかった.SAH急性期において,脳軟膜血管壁に分布するNA作動性神経系の電気活動亢進が示唆された

青斑核が脳実質内血管に及ぼす収縮作用に関する研究

高橋, 慎一, 後藤, 文男, 島津, 邦男 and 他

自律神経 26 ( 4 ) 394 - 400 1989.08

ISSN 0288-9250

青斑核の脳実質内血管に対する作用について

高橋, 慎一 and 他

自律神経 26 ( 2 ) 200 1989.04

ISSN 0288-9250

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