Papers - Takizawa, Tsubasa

Functional interactions between transient receptor potential M8 and transient receptor potential V1 in the trigeminal system: Relevance to migraine pathophysiology.

Yohei Kayama, Mamoru Shibata, Tsubasa Takizawa, Keiji Ibata, Toshihiko Shimizu, Taeko Ebine, Haruki Toriumi, Michisuke Yuzaki, Norihiro Suzuki

Cephalalgia : an international journal of headache 38 ( 5 ) 833 - 845 2018.04

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Background Recent genome-wide association studies have identified transient receptor potential M8 ( TRPM8) as a migraine susceptibility gene. TRPM8 is a nonselective cation channel that mediates cool perception. However, its precise role in migraine pathophysiology is elusive. Transient receptor potential V1 (TRPV1) is a nonselective cation channel activated by noxious heat. Both TRPM8 and TRPV1 are expressed in trigeminal ganglion (TG) neurons. Methods We investigated the functional roles of TRPM8 and TRPV1 in a meningeal inflammation-based migraine model by measuring the effects of facial TRPM8 activation on thermal allodynia and assessing receptor coexpression changes in TG neurons. We performed retrograde tracer labeling to identify TG neurons innervating the face and dura. Results We found that pharmacological TRPM8 activation reversed the meningeal inflammation-induced lowering of the facial heat pain threshold, an effect abolished by genetic ablation of TRPM8. No significant changes in the heat pain threshold were seen in sham-operated animals. Meningeal inflammation caused dynamic alterations in TRPM8/TRPV1 coexpression patterns in TG neurons, and colocalization was most pronounced when the ameliorating effect of TRPM8 activation on thermal allodynia was maximal. Our tracer assay disclosed the presence of dura-innervating TG neurons sending collaterals to the face. Approximately half of them were TRPV1-positive. We also demonstrated functional inhibition of TRPV1 by TRPM8 in a cell-based assay using c-Jun N-terminal kinase phosphorylation as a surrogate marker. Conclusions Our findings provide a plausible mechanism to explain how facial TRPM8 activation can relieve migraine by suppressing TRPV1 activity. Facial TRPM8 appears to be a promising therapeutic target for migraine.

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Serial changes of corticospinal tract hyperintensity on magnetic resonance imaging from the preclinical stage in amyotrophic lateral sclerosis

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

NEUROLOGY AND CLINICAL NEUROSCIENCE (WILEY)  6 ( 1 ) 29 - 30 2018.01

Accepted,  ISSN  2049-4173

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Signaling Pathways Relevant to Nerve Growth Factor-induced Upregulation of Transient Receptor Potential M8 Expression.

Yohei Kayama, Mamoru Shibata, Tsubasa Takizawa, Keiji Ibata, Jin Nakahara, Toshihiko Shimizu, Haruki Toriumi, Michisuke Yuzaki, Norihiro Suzuki

Neuroscience 367   178 - 188 2017.12

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Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that primarily detects the innocuous cold. In pathological conditions, TRPM8 plays a role in the development of cold hyperalgesia/allodynia. Nerve growth factor (NGF) is an important mediator involved in various pain disorders. In the present study, the NGF-TrkA pathway increased TRPM8 expression by stabilizing TRPM8 mRNA through the actions of phosphatidylinositol 3-kinase and p38 MAP kinase. Moreover, c-Jun N-terminal kinase and Src tyrosine kinase were identified as a positive and negative regulator of TRPM8 expression, respectively, via post-transcriptional mechanisms independent of mRNA stabilization. PTEN activity was found to increase protein TRPM8 expression. Calcium imaging confirmed that NGF induced TRPM8 functional upregulation. Time-lapse fluorescence microscopic analysis and a cell fractionation assay revealed that NGF promoted the trafficking of TRPM8 to the plasma membrane. In the presence of NGF, lysosome-associated membrane protein-2 (LAMP-2) was localized to TRPM8-positive dot-like and linear structures, the latter of which were observed in the periphery of the cytoplasm. It was inferred that LAMP-2 was involved in the vesicular transport of TRPM8. Pharmacological blockade of the proteasome with MG132 led to a further increase in NGF-induced TRPM8 expression, indicating that the proteasome system played a pivotal role in the degradation of TRPM8. Our findings provide novel insight into the signaling pathways involved in NGF-mediated TRPM8 upregulation and its reversion to the normal state.

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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 96 ( 46 ) e8757 2017.11

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RATIONALE: Recently, drug-related myasthenia gravis (MG) has received attention, because the number of reported cases involving MG associated with immune checkpoint inhibitors, a new immunotherapy, is increasing. We present a case involving the new onset of MG, in which the symptoms started shortly after intravesical Bacillus Calmette-Guerin (BCG) for bladder cancer. PATIENT CONCERNS: A 69-year-old male with bladder cancer developed ptosis and diplopia 4 days after the completion of a treatment regimen with intravesical BCG weekly for 6 weeks. DIAGNOSES: Ocular MG was confirmed by a positive serum anti-acetylcholine receptor antibody test. INTERVENTIONS: Treatment with high-dose methylprednisolone pulse therapy was given, after insufficient treatment with pyridostigmine bromide and 10 mg/d prednisolone. OUTCOMES: Symptoms resolved completely 12 days after high-dose methylprednisolone pulse therapy. LESSONS: Intravesical BCG could be listed as a novel drug that may induce a new onset of MG along with drugs such as D-penicillamine and immune checkpoint inhibitors.

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

Tsubasa Takizawa, Mamoru Shibata, Takahiro Hiraide, Morinobu Seki, Shinichi Takahashi, Norihiro Suzuki

Headache 57 ( 9 ) 1443 - 1448 2017.10

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BACKGROUND: It is commonly known that headaches are induced by intake of specific food, drink, and/or additive. In addition, some patients experience postprandial headache independent of ingestion of specific items. Currently, information on the pathophysiology underlying this particular type of headache is scarce. CASE REPORTS: We report two cases in which headaches were observed after each meal. Postprandial hypotension was demonstrated in both cases. Tonometry-based continuous blood pressure measurement during head-up tilt revealed sympathetic dysfunction. In one patient, meta-iodobenzylguanidine (MIBG) myocardial scintigraphy detected cardiac sympathetic denervation, and diagnosis of pure autonomic failure was made. In both cases, treatment of postprandial hypotension was effective in relieving postprandial headache. DISCUSSION: The possibility of postprandial hypotension should be explored in patients with headache that occurs after meal. To this end, tonometry-based blood pressure measurement and MIBG myocardial scintigraphy may be useful diagnostic investigations. Treating postprandial hypotension may be effective in alleviating the symptoms.

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Facial TRPM8 stimulation ameliorates thermal hyperalgesia in a mouse migraine model

Yohei Kayama, Mamoru Shibata, Tsubasa Takizawa, Toshihiko Shimizu, Haruki Toriumi, Taeko Ebine, Norihiro Suzuki

CEPHALALGIA (SAGE PUBLICATIONS LTD)  37   294 - 294 2017.09

Accepted,  ISSN  0333-1024

High-mobility group box 1 is an important mediator of microglial activation induced by cortical spreading depression.

Tsubasa Takizawa, Mamoru Shibata, Yohei Kayama, Toshihiko Shimizu, Haruki Toriumi, Taeko Ebine, Miyuki Unekawa, Anri Koh, Akihiko Yoshimura, Norihiro Suzuki

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 37 ( 3 ) 890 - 901 2017.03

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Single episodes of cortical spreading depression (CSD) are believed to cause typical migraine aura, whereas clusters of spreading depolarizations have been observed in cerebral ischemia and subarachnoid hemorrhage. We recently demonstrated that the release of high-mobility group box 1 (HMGB1) from cortical neurons after CSD in a rodent model is dependent on the number of CSD episodes, such that only multiple CSD episodes can induce significant HMGB1 release. Here, we report that only multiple CSD inductions caused microglial hypertrophy (activation) accompanied by a greater impact on the transcription activity of the HMGB1 receptor genes, TLR2 and TLR4, while the total number of cortical microglia was not affected. Both an HMGB1-neurtalizing antibody and the HMGB1 inhibitor glycyrrhizin abrogated multiple CSD-induced microglial hypertrophy. Moreover, multiple CSD inductions failed to induce microglial hypertrophy in TLR2/4 double knockout mice. These results strongly implicate the HMGB1-TLR2/4 axis in the activation of microglia following multiple CSD inductions. Increased expression of the lysosomal acid hydrolase cathepsin D was detected in activated microglia by immunostaining, suggesting that lysosomal phagocytic activity may be enhanced in multiple CSD-activated microglia.

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Alterations in the threshold of the potassium concentration to evoke cortical spreading depression during the natural estrous cycle in mice.

Taeko Ebine, Haruki Toriumi, Toshihiko Shimizu, Miyuki Unekawa, Tsubasa Takizawa, Yohei Kayama, Mamoru Shibata, Norihiro Suzuki

Neuroscience research 112   57 - 62 2016.11

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Cortical spreading depression (CSD) has been implicated in a variety of neurological disorders. However, the relationship between serum sex hormones and susceptibility to the development of CSD in naturally estrous cycling female animals is largely unknown. The natural estrous cycle of mice consists of four stages, namely, proestrus, estrus, metestrus and diestrus. We measured the serum concentration of estradiol and progesterone in estrus and diestrus and compared the minimum potassium concentrations necessary to evoke CSD in each stage and in males. In diestrus, the minimum potassium concentration required to evoke CSD was significantly lower compared to the other three phases and male animals. The serum level of estradiol is significantly higher and serum level of progesterone is significantly lower in diestrus compared to estrus. Furthermore, when we administered an estrogen receptor antagonist, the susceptibility to the development of CSD was decreased. Conversely, the administration of a progesterone receptor antagonist increased the susceptibility to CSD. Our results demonstrated that neuronal excitability related to CSD induction differs among the natural estrous phases in mice.

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Repetitive trigeminal nociceptive stimulation in rats increases their susceptibility to cortical spreading depression.

Haruki Toriumi, Toshihiko Shimizu, Taeko Ebine, Tsubasa Takizawa, Yohei Kayama, Anri Koh, Mamoru Shibata, Norihiro Suzuki

Neuroscience research 106   74 - 8 2016.05

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We examined the ability of trigeminal nerve activation to induce cortical spreading depression in rats. Capsaicin was injected into the bilateral plantar or whisker pad for either 4 or 6 days in rats. The number and duration of cortical spreading depressions induced by potassium were significantly increased in animals injected with capsaicin in the bilateral whisker pad compared with animals injected in the bilateral plantar or in controls, while administration of a GABAA receptor agonist decreased these effects. Repetitive nociceptive stimulation of the trigeminal nerve lowers the threshold for the induction of cortical spreading depression by altering GABAergic neuronal activity.

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Adult-onset recurrent painful ophthalmoplegic neuropathy displaying atypical oculomotor nerve gadolinium-enhancement pattern in the orbit and cavernous sinus.

Tsubasa Takizawa, Mamoru Shibata, Hirokazu Fujiwara, Toshihiko Shimizu, Suketaka Momoshima, Norihiro Suzuki

Cephalalgia : an international journal of headache 36 ( 2 ) 199 - 200 2016.02

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Temporal profiles of high-mobility group box 1 expression levels after cortical spreading depression in mice.

Tsubasa Takizawa, Mamoru Shibata, Yohei Kayama, Haruki Toriumi, Taeko Ebine, Anri Koh, Toshihiko Shimizu, Norihiro Suzuki

Cephalalgia : an international journal of headache 36 ( 1 ) 44 - 52 2016.01

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INTRODUCTION: Cortical spreading depression (CSD) has recently been shown to induce the release of the nuclear protein termed high-mobility group box 1 from neurons, causing activation of the trigeminovascular system. Here, we explored the effects of single and multiple cortical spreading depression inductions on high-mobility group box 1 (HMGB1) transcriptional activity relative to high-mobility group box 1 protein expression levels and intracellular localization in cortical neurons and astrocytes. METHODS: Single or multiple cortical spreading depression inductions were achieved by KCl application to the mouse cerebral cortex. The animals were sacrificed at 30 minutes, 3 hours and 24 hours after cortical spreading depression induction. High-mobility group box 1 expression levels were explored with in situ hybridization, Western blotting and immunostaining. RESULTS: Cortical spreading depression up-regulated high-mobility group box 1 transcriptional activity in neurons at 3 hours in a manner that was dependent on the number of cortical spreading depression inductions. At 24 hours, the high-mobility group box 1 transcriptional activity had returned to basal levels. Cortical spreading depression induced a reduction in high-mobility group box 1 protein expression at 3 hours, which was also dependent on the number of cortical spreading depression inductions. Following cortical spreading depression, the release of high-mobility group box 1 from the nucleus was observed in a small proportion of neurons, but not in astrocytes. CONCLUSION: Cortical spreading depression induced translocation of high-mobility group box 1 from neuronal nuclei, driving transcriptional up-regulation of high-mobility group box 1 to maintain protein levels.

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When do we judge IVIg for myasthenia gravis ineffective?

Tsubasa Takizawa, Shigeaki Suzuki, Norihiro Suzuki

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 36 ( 7 ) 1295 - 7 2015.07

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Lowering barometric pressure induces c-Fos expression in neurons of rat vestibular nucleus

Megumi Funakubo, Toshihiko Shimizu, Mamoru Shibata, Tatsuo Iwashita, Haruki Toriumi, Taeko Ebine, Youhei Kayama, Tsubasa Takizawa, Jun Sato, Norihiro Suzuki

JOURNAL OF PHYSIOLOGICAL SCIENCES (SPRINGER JAPAN KK)  63   S155 - S155 2013

ISSN  1880-6546