Details of a Researcher - Kurihara, Toshihide

Papers - Kurihara, Toshihide

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The role of sphingosine 1-phosphate receptors on retinal pigment epithelial cells barrier function and angiogenic effects.

Terao R, Honjo M, Totsuka K, Miwa Y, Kurihara T, Aihara M†

Prostaglandins Other Lipid Mediat. (Prostaglandins and Other Lipid Mediators) 145 106365 2019.12

Accepted, ISSN 10988823

© 2019 Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator, promoting angiogenesis and inflammation via interactions with its receptors (S1P1–5), but the receptors and signaling pathways responsible for the progression of choroidal neovascularization (CNV) remain unknown. We investigated the roles of S1P/S1P receptors in RPE cells. ARPE-19 cells were treated with S1P dissolved in carrier proteins of albumin or apolipoprotein M (ApoM). The mRNA expression levels of interleukin-8 (IL-8), C-C motif chemokine ligand 2 (CCL2), and vascular endothelial growth factor (VEGF) were evaluated using quantitative real-time polymerase chain reaction. The protein level of hypoxia-inducible factor (HIF)-1α was assessed via enzyme-linked immunosorbent assay. HIF transcriptional activity was evaluated with a dual-reporter luciferase assay. Cellular barrier integrity was evaluated using transepithelial electrical resistance and the FITC-dextran permeability assay. The suppressive effect of an S1P antagonist on CNV progression was investigated with a laser-induced CNV model in mice. The increase in expression of IL-8, CCL2, and VEGF due to albumin-bound S1P was significantly mitigated by an S1P2 antagonist. The expression of HIF-1α significantly decreased with inhibition of S1P2 and S1P3. In addition, albumin-bound S1P disrupted the barrier integrity of retinal pigment epithelial cells via S1P2, whereas integrity was strengthened by ApoM-bound S1P. CNV lesions were significantly reduced in the mouse model with intravitreal injection of S1P2 antagonist. This study demonstrated that S1P significantly promotes angiogenesis, inflammation, and barrier integrity, which was attenuated by inhibition of S1P2 or S1P3, suggesting that regulation of S1P2 and S1P3 is a novel therapeutic target for CNV.

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組織型プラスミノーゲンアクチベーター（tPA；モンテプラーゼ）硝子体内投与による黄斑下血腫の治療経過

園部秀樹, 篠田肇, 鴨下衛, 渡邊一弘, 栗原俊英, 永井紀博, 坪田一男, 小沢洋子

あたらしい眼科 36 ( 11 ) 104 - 108 2019.11

Current Prevalence of Myopia and Association of Myopia With Environmental Factors Among Schoolchildren in Japan.

Yotsukura E*, Torii H*, Inokuchi M, Tokumura M, Uchino M, Nakamura K, Hyodo M, Mori K, Jiang X, Ikeda SI, Kondo S, Negishi K, Kurihara T, Tsubota K

JAMA Ophthalmol. (JAMA Ophthalmology) 137 ( 11 ) 1233 - 1239 2019.11

Accepted, ISSN 21686165

© 2019 American Medical Association. All rights reserved. Importance: Given the estimates of increasing prevalence of myopia, especially in Asia, it is important to determine the current prevalence of myopia among populations of schoolchildren in Japan. Objective: To investigate the current prevalence rate of myopia and the association between environmental factors and myopia in Japanese schoolchildren. Design, Setting, and Participants: This cross-sectional study assessed 1478 participants, including 726 elementary school students and 752 junior high school students, at 2 schools in Tokyo, Japan, who underwent eye examinations from April 1 to May 31, 2017, that included measurement of the refractive errors by autorefractometry with noncycloplegic refraction and ocular biometric factors. After excluding those who had been treated with atropine or orthokeratology (n = 11), had a history of eye disease (n = 2), had no parental consent (n = 41), and were absent (n = 8), 1416 schoolchildren were analyzed. Main Outcomes and Measures: The primary outcome was the prevalence of myopia and high myopia. Secondary outcomes were environmental factors that were associated with myopia. Results: A total of 1416 schoolchildren (mean [SD] age, 10.8 [2.7] years; 792 [55.9%] male) were studied. The prevalence rates of myopia (spherical equivalent ≤-0.5 diopters [D]) were 76.5% (95% CI, 73.4%-79.7%) among the elementary school students and 94.9% (95% CI, 93.3%-96.5%) among the junior high school students. The prevalence rates of high myopia (spherical equivalent ≤-6.0 D) were 4.0% (95% CI, 2.5%-5.4%) among the elementary school students and 11.3% (95% CI, 8.8%-13.7%) among the junior high school students. The prevalence rates of high myopia classified based on axial length of 26.0 mm or longer were 1.2% (95% CI, 0.4%-2.0%) among elementary school students and 15.2% (95% CI, 12.5%-17.8%) among junior high school students. Multiple regression analysis showed that higher-order aberrations and dry eye disease were associated with refractive error in elementary school students (spherical aberration: β = 6.152; 95% CI, 3.161-9.143; P <.001; dry eye disease: β = -0.626; 95% CI, -1.189 to -0.063; P =.03) and with axial length in junior high school students (spherical-like aberration: β = 26.546; 95% CI, 18.708-34.385; P <.001; dry eye disease: β = 0.354; 95% CI, 0.131-0.578; P <.002). Conclusions and Relevance: Although the use of noncycloplegic autorefraction with a cutoff of -0.50 D could lead to overestimation of results, these findings suggest that the current prevalence rates of myopia among elementary and junior high school students in Asia are high, especially if the results from these 2 schools are generalizable to all schoolchildren in Japan and Asia..

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High Myopia and Its Associated Factors in JPHC-NEXT Eye Study: A Cross-Sectional Observational Study.

Mori K, Kurihara T†, Uchino M, Torii H, Kawashima M, Sasaki M, Ozawa Y, Yamagishi K†, Iso H, Sawada N, Tsugane S, Yuki K, Tsubota K

J Clin Med. (Journal of Clinical Medicine) 8 ( 11 ) 1788 2019.11

Accepted

The increasing prevalence of high myopia has been noted. We investigated the epidemiological characteristics and the related factors of high myopia in a Japanese adult population. Japan Public Health Center-Based Prospective Study for the Next Generation (JPHC-NEXT) Eye Study was performed in Chikusei-city, a rural area in mid-east Japan, between 2013 and 2015. A cross-sectional observational analysis was conducted to investigate prevalence and related factors of high myopia. A total of 6101 participants aged ≥40 years without a history of ocular surgeries was included. High myopia was defined as a spherical equivalent refraction of ≤-6.00 diopters according to the American Academy of Ophthalmology. Potential high myopia-related factors included intraocular pressure (IOP), corneal structure, corneal endothelial cell density, age, height, body mass index, heart rate, blood pressure, biochemical profile, and current history of systemic and ocular disorders. The odds ratios of high myopia were estimated using the logistic regression models adjusted for the associated factors. The prevalence of high myopia was 3.8% in males and 5.9% in females with a significant difference. Age was inversely associated, IOP was positively associated, and none of other factors were associated with high myopia in both sexes. In conclusion, only age and IOP were associated with high myopia in this community-based sample.

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Therapeutic Effect of Garcinia cambogia Extract and Hydroxycitric Acid Inhibiting Hypoxia-Inducible Factor in a Murine Model of Age-Related Macular Degeneration.

Ibuki M, Shoda C, Miwa Y, Ishida A, Tsubota K†, Kurihara T†

Int J Mol Sci. (International Journal of Molecular Sciences) 20 ( 20 ) 5049 2019.10

Accepted, ISSN 16616596

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Background: Age-related macular degeneration (AMD) is the leading cause of blindness and can be classified into two types called atrophic AMD (dry AMD) and neovascular AMD (wet AMD). Dry AMD is characterized by cellular degeneration of the retinal pigment epithelium, choriocapillaris, and photoreceptors. Wet AMD is characterized by the invasion of abnormal vessels from the choroid. Although anti-vascular endothelial growth factor (VEGF) therapy has a potent therapeutic effect against the disease, there is a possibility of chorio-retinal atrophy and adverse systemic events due to long-term robust VEGF antagonism. We focused on hypoxia-inducible factor (HIF) regulation of VEGF transcription, and report the suppressive effects of HIF inhibition against ocular phenotypes in animal models. Many of the known HIF inhibitors are categorized as anti-cancer drugs, and their systemic side effects are cause for concern in clinical use. In this study, we explored food ingredients that have HIF inhibitory effects and verified their effects in an animal model of AMD. Methods: Food ingredients were screened using a luciferase assay. C57BL6/J mice were administered the Garcinia cambogia extract (Garcinia extract) and hydroxycitric acid (HCA). Choroidal neovascularization (CNV) was induced by laser irradiation. Results: Garcinia extract and HCA showed inhibitory effects on HIF in the luciferase assay. The laser CNV model mice showed significant reduction of CNV volume by administering Garcinia extract and HCA. Conclusions: Garcinia extract and HCA showed therapeutic effects in a murine AMD model.

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Ultra-Widefield Retinal Imaging for Analyzing the Association Between Types of Pathological Myopia and Posterior Staphyloma.

Mimura R*, Mori K*, Torii H, Nagai N, Suzuki M, Minami S, Ozawa Y, Kurihara T†, Tsubota K†

J Clin Med. (Journal of Clinical Medicine) 8 ( 10 ) 1505 2019.10

Accepted

High myopia may develop to pathologic myopia, which brings severe visual impairment; however, the etiology is not fully understood. We, therefore, investigated the relationship between the presence of posterior staphyloma and posterior ocular disorders by assessing the patients with high myopia. A retrospective study was performed for the patients, who have more than 26 mm of the axial length and of whom fundus photography was taken with an ultra-widefield retinal imaging system. The objectives were 138 cases encompassing 229 eyes. In 138 cases, 91 were bilateral and 47 were unilateral. The averages ± SD of axial length of bilateral and unilateral were 28.8 ± 2.2 mm, 27.3 ± 1.2 mm, respectively, showing statistically significant difference. The number of eyes with and without posterior staphyloma were 107 (46.7%) and 122 (53.3%), respectively. Retinal detachment and retinal breaks are more observed in cases without posterior staphyloma (p = 0.017). Myopic choroidal neovascularization (mCNV) (p = 0.002), chorioretinal atrophy (p < 0.001), retinoschisis (p < 0.001), and optic neuropathy (p = 0.038) are more often seen in cases with posterior staphyloma. In conclusion, the prevalence rates of myopic choroidal neovascularization, retinal choroidal atrophy, and optic neuropathy were significantly higher with posterior staphyloma. The rate of periocular disorders such as retinal detachment was significantly higher without posterior staphyloma. These results indicate associations between types of pathological myopia and presence or absence of posterior staphyloma analyzed by ultra-widefield retinal imaging.

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The long dystrophin gene product Dp427 modulates retinal function and vascular morphology in response to age and retinal ischemia.

Bucher F, Friedlander MSH, Aguilar E, Kurihara T, Krohne TU, Usui Y, Friedlander M†

Neruochem Int. (Neurochemistry International) 129 104489 2019.10

Accepted, ISSN 01970186

© 2019 Elsevier Ltd Mutations in dystrophin are the major cause of muscular dystrophies. Continuous muscular degeneration and late stage complications, including cardiomyopathy and respiratory insufficiency, dominate the clinical phenotype. Gene expression and regulation of the dystrophin gene outside of muscular tissue is far more complex. Multiple tissue-specific dystrophin gene products are widely expressed throughout the body, including the central nervous system and eye, predisposing affected patients to secondary complications in non-muscular tissues. In this study, we evaluated the impact of the full-length dystrophin gene product, Dp427, on retinal homeostasis and angiogenesis. Based on the clinical case of a Duchenne muscular dystrophy (DMD) patient who developed severe fibrovascular changes in the retina in response to hypoxic stress, we hypothesized that defects in Dp427 make the retina more susceptible to stresses such as ageing and ischemia. To further study this, a mouse strain lacking Dp427 expression (Mdx) was studied during retinal development, ageing and in the oxygen-induced retinopathy (OIR) model. While retinal vascular morphology was normal during development and ageing, retinal function measured by electroretinography (ERG) was slightly reduced in young adult Mdx mice and deteriorated with age. Mdx mice also had increased retinal neovascularization in response to OIR and more pronounced long-term deterioration in retinal function following OIR. Based on these results, we suggest that DMD patients with a mutation in Dp427 may experience disturbed retinal homeostasis with increasing age and therefore be prone to develop excessive retinal neovascular changes in response to hypoxic stress. DMD patients in late disease stages should, thus, be regularly examined to detect asymptomatic retinal abnormalities and prevent visual impairment.

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Clinical and Genetic Characteristics of East Asian Patients with Occult Macular Dystrophy (Miyake Disease): East Asia Occult Macular Dystrophy Studies Report Number 1.

Fujinami K*†, Yang L*, Joo K*, Tsunoda K, , Kameya S, Hanazono G, Fujinami-Yokokawa Y, Arno G, Kondo M, Nakamura N, Kurihara T, , Tsubota K, , Zou X, Li H, Park KH, Iwata T, Miyake Y, Woo SJ†, Sui R†

Ophthalmology. (Ophthalmology) 126 ( 10 ) 1432 - 1444 2019.10

Accepted, ISSN 01616420

PURPOSE: To describe the clinical and genetic characteristics of the cohort enrolled in the East Asian studies of occult macular dystrophy (OMD). DESIGN: International, multicenter, retrospective cohort studies. PARTICIPANTS: A total of 36 participants from 21 families with a clinical diagnosis of OMD and harboring pathogenic RP1L1 variants (i.e., Miyake disease) were enrolled from 3 centers in Japan, China, and South Korea. METHODS: A detailed history was obtained, and comprehensive ophthalmological examinations including spectral-domain OCT were performed. All detected sequence variants in the RP1L1 gene were reviewed, and in silico analysis was performed, including allele frequency analyses and pathogenicity predictions. MAIN OUTCOME MEASURES: Onset of disease, visual acuity (VA) converted to the logarithm of the minimum angle of resolution (logMAR), OCT findings, and effect of detected variants. RESULTS: Eleven families from Japan, 6 from South Korea, and 4 from China were recruited. There were 12 female and 24 male participants. The median age of onset was 25.5 years (range, 2-73), and the median age at the latest examination was 46.0 years (range, 11-86). The median VA (logMAR) was 0.65 (range, -0.08-1.22) in the right eye and 0.65 (-0.08-1.10) in the left eye. A significant correlation between onset of disease and VA was revealed. The Classical morphologic phenotype showing both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors was demonstrated in 30 patients (83.3%), and subtle photoreceptor architectural changes were demonstrated in 6 patients (16.6%). Eight pathogenic RP1L1 variants were identified, including 6 reported variants and 1 novel variant: p.R45W, p.T1194M/p.T1196I (complex), p.S1199C, p.G1200A, p.G1200D, p.V1201G, and p.S1198F, respectively. Two variants were recurrent: p.R45W (11 families, 52.4%) and p.S1199C (5 families, 23.8%). The pathogenic missense variants in 10 families (47.6%) were located within the previously reported unique motif, including 6 amino acids (1196-1201). CONCLUSIONS: There is a large spectrum of clinical findings in Miyake disease, including various onset of disease and VA, whereas the characteristic photoreceptor microstructures were shared in most cases. Two hot spots including amino acid numbers 45 and 1196-1201 in the RP1L1 gene were confirmed in the East Asian population.

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Pharmacological HIF inhibition prevents retinal neovascularization with improved visual function in a murine oxygen-induced retinopathy model

Miwa Y, Hoshino Y, Shoda C, Jiang X, Tsubota K†, Kurihara T†

Neurochem Int. (Neurochemistry International) 128 21 - 31 2019.09

Accepted, ISSN 01970186

© 2019 Elsevier Ltd Neovascular retinal diseases are the leading causes of blindness in advanced countries. To date, anti-VEGF (vascular endothelial growth factor) drugs are clinically effective and widely used for these diseases. However, recent animal and clinical studies reported that potent and long-term VEGF antagonism may induce chorioretinal atrophy. Thus, physiological amount of VEGF is required for the homeostasis in the retina. Hypoxia-inducible factors (HIFs) are transcription factors located upstream of VEGF. We hypothesized that ectopically stabilized HIFs induce pathological amount of VEGF involved with retinal neovascularization. Therefore, HIF inhibition could be an alternative therapeutic candidate targeting the pathological amount of VEGF while holding a physiological amount of VEGF. To test this hypothesis, topotecan and doxorubicin, HIF inhibitors with different mechanisms were administered to the murine oxygen-induced retinopathy (OIR) model. We found that both topotecan and doxorubicin significantly prevented pathological but not physiological neovascularization in OIR. Furthermore, impaired visual function observed in OIR can also be suppressed by administering topotecan. These data suggested that HIF inhibition may be effective for pathological angiogenesis and neurodegeneration of the retina.

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Ocular-Component-Specific miRNA Expression in a Murine Model of Lens-Induced Myopia.

Tanaka Y, Kurihara T†, Hagiwara Y, Ikeda SI, Mori K, Jiang X, Torii H, Tsubota K†

Int J Mol Sci. (International Journal of Molecular Sciences) 20 ( 15 ) 3629 2019.08

Accepted, ISSN 16616596

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. To identify tissues and molecules involved in refractive myopic shift and axial length elongation in a murine lens-induced myopia model, we performed a comprehensive analysis of microRNA (miRNA) expression. Three weeks after negative 30 diopter lens fixation on three-week-old C57BL/6J mice, total RNA was extracted from individual ocular components including cornea, iris, lens, retina, retinal pigment epithelium (RPE)/choroid, and sclera tissue. The miRNA expression analysis was pooled from three samples and carried out using Agilent Mouse miRNA Microarray (8 × 60 K) miRBase21.0. The expression ratio was calculated, and differentially expressed miRNAs were extracted, using GeneSpring GX 14.5. Myopic induction showed a significant myopic refractive change, axial elongation, and choroidal thinning. Through the comprehensive miRNA analysis, several upregulated miRNAs (56 in cornea tissue, 13 in iris tissue, 6 in lens tissue, 0 in retina tissue, 29 in RPE/choroid tissue, and 30 in sclera tissue) and downregulated miRNAs (7 in cornea tissue, 28 in iris tissue, 17 in lens tissue, 9 in retina tissue, 7 in RPE/choroid tissue, and 40 in sclera tissue) were observed. Overlapping expression changes in miRNAs were also found in different ocular components. Some of this miRNA dysregulation may be functionally involved in refractive myopia shift and axial length elongation.

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The Effect of Dietary Supplementation of Crocetin for Myopia Control in Children: A Randomized Clinical Trial

Mori K*, Torii H*, Fujimoto S*, Jiang X, Ikeda SI, Yotsukura E, Koh S, Kurihara T†, Nishida K†, Tsubota K†

J Clin Med. (Journal of Clinical Medicine) 8 ( 8 ) 1179 2019.08

Accepted

The prevalence of myopia has been increasing in recent years. The natural carotenoid crocetin has been reported to suppress experimental myopia in mice. We evaluated the effects of crocetin on myopia suppression in children. A multicenter randomized double-blind placebo-controlled clinical trial was performed with 69 participants aged 6 to 12 years, whose cycloplegic spherical equivalent refractions (SER) were between −1.5 and −4.5 diopter (D). The participants were randomized to receive either a placebo or crocetin and followed up for 24 weeks. Axial length (AL) elongation and changes in SER were evaluated for 24 weeks. Both written informed assent from the participants and written informed consent from legal guardians were obtained in this study because the selection criteria of this trial included children aged between 6 and 12 years old. This trial was approved by the institutional review boards. A mixed-effects model was used for analysis, using both eyes. Two participants dropped out and 67 children completed this trial. The change in SER in the placebo group, −0.41 ± 0.05 D (mean ± standard deviation), was significantly more myopic compared to that in the crocetin group, −0.33 ± 0.05 D (p = 0.049). The AL elongation in the placebo group, 0.21 ± 0.02 mm, was significantly bigger than that in the crocetin group, 0.18 ± 0.02 mm (p = 0.046). In conclusion, dietary crocetin may have a suppressive effect on myopia progression in children, but large-scale studies are required in order to confirm this effect.

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A Novel HIF Inhibitor Halofuginone Prevents Neurodegeneration in a Murine Model of Retinal Ischemia-Reperfusion

Kunimi H, Miwa Y, Inoue H, Tsubota K†, Kurihara T†

Int J Mol Sci. (International Journal of Molecular Sciences) 20 ( 13 ) 3171 2019.07

Accepted, ISSN 16616596

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Neurodegeneration caused with retinal ischemia or high intraocular pressure is irreversible in general. We have focused on the role of hypoxia-inducible factor (HIF) in retinal homeostasis and revealed that HIF inhibition may be effective against retinal neovascular and neurodegeneration. In this study, we performed in vitro screening of natural products and found halofuginone, which is a derivative of febrifugine extracted from hydrangea, as a novel HIF inhibitor. Administration of halofuginone showed a significant neuroprotective effect by inhibiting HIF-1α expression in a murine retinal ischemia-reperfusion model histologically and functionally. These results indicate that halofuginone can be a neuroprotective agent in ischemic retinal degenerative diseases.

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Three Cases of Developing Myopia in Newly Developed Dry Eye Disease after Hematopoietic Stem Cell Transplantation

伊藤賀一, 小川葉子, 清水映輔, 鈴木孝典, 西條裕美子, 内野美樹, 栗原俊英, 坪田一男

あたらしい眼科 ((株)メディカル葵出版) 36 ( 5 ) 684 - 688 2019.05

ISSN 0910-1810

移植片対宿主病(GVHD)によるドライアイ(DE)発症に伴い近視化を伴う3症例を経験したので報告する。症例1は32歳、男性。Fanconi貧血(先天性再生不良性貧血)に対し非血縁者骨髄移植を行った。移植前の自覚的視力検査による等価球面度数(SE)は右眼-2.75Dと左眼-3.00Dであった。移植後4ヵ月時GVHDによるDEを発症し、同時期のSEは右眼-2.75Dと左眼-4.50Dで左眼の近視化を認めた。移植後7ヵ月時のSEは右眼-3.00Dと左眼-4.625Dで時期の差があるが両眼の近視化を認めた。症例2は34歳、女性。急性リンパ性白血病に対し非血縁骨髄移植を行った。移植前の自覚的視力検査によるSEは右眼+3.375Dと左眼+0.50D、移植後13ヵ月時にGVHDによるDEを発症し、同時期のSEは右眼+2.50Dと左眼0.00Dと両眼の近視化を認めた。症例3は40歳、女性。急性骨髄性白血病に対し血縁末梢血幹細胞移植を行った。移植前の自覚的視力検査のSEは右眼-1.50Dと左眼0.00D。移植後9ヵ月時にDEを発症し、同時期のSEは右眼-1.50Dと左眼-0.625Dで左眼の近視化を認めた。他覚的検査では移植前後のSEの差が右眼1.125D、左眼1.75Dと両眼の近視化を認めた。3症例ともに白内障は認めず、眼底に異常は認められなかった。炎症性疾患であるGVHDによるDE発症時期に、近視化する3症例を認めた。GVHDと近視化との関連に関する因子について今後さらなる検討が必要である。(著者抄録)

Inducement and Evaluation of a Murine Model of Experimental Myopia.

Jiang X, Kurihara T†, Ikeda SI, Kunimi H, Mori K, Torii H, Tsubota K†

J Vis Exp. (Journal of Visualized Experiments) 2019 ( 143 ) e58822 2019.01

Accepted, ISSN 1940087X

© 2019 Journal of Visualized Experiments. Murine model of myopia can be a powerful tool for myopia research because of the comparatively easy genetic manipulation. One way to induce myopia in animals is to put clear minus lenses in front of eyes for weeks (lens-induced myopia, LIM). However, extant protocols for inducement and evaluation vary from laboratory to laboratory. Here, we described a highly practical and reproducible method to induce LIM in mice using newly designed eyeglasses. The method fixes the lens stably in front of the mouse eye while allows the lens to be taken off for cleaning or topical drug administration. The phenotype is robust and efficient, and the variance is small. The method described here can be applied to mice right after weaning which extends the possible duration for experiments. We also gave technical advises for achieving reproducible results in refraction and axial length measurements. We hope the step-by-step protocol described here and the detailed article can help researchers perform myopia experiments with myopia more smoothly and make the data comparable across laboratories.

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HIF inhibitor topotecan has a neuroprotective effect in a murine retinal ischemia-reperfusion model.

Kunimi H, Miwa Y, Katada Y, Tsubota K†, Kurihara T†

PeerJ. (PeerJ) 2019 ( 10 ) e7849 2019

Accepted

Copyright 2019 Kunimi et al. Purpose. The therapeutic approach for retinal ganglion cell (RGC) degeneration has not been fully established. Recently, it has been reported that hypoxia-inducible factor (HIF) may be involved with retinal neurodegeneration. In this study, we investigated neuroprotective effects of a HIF inhibitor against RGC degeneration induced in a murine model of retinal ischemia-reperfusion (I/R). Methods. Eight-weeks-old male C57/BL6J mice were treated with intraperitoneal injection of a HIF inhibitor topotecan (1.25 mg/kg) for 14 days followed by a retinal I/R procedure. Seven days after the I/R injury, the therapeutic effect was evaluated histologically and electrophysiologically. Results. The increase of HIF-1α expression and the decrease of retinal thickness and RGC number in I/R were significantly suppressed by administration of topotecan. Impaired visual function in I/R was improved by topotecan evaluated with elec-troretinogram and visual evoked potentials. Conclusions. Topotecan administration suppressed HIF-1a expression and improved RGC survival resulting in a functional protection against retinal I/R. These data indicated that the HIF inhibitor topotecan may have therapeutic potentials for RGC degeneration induced with retinal ischemia or high intraocular pressure.

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Evaluation of AAV-DJ vector for retinal gene therapy

Katada Y, Kobayashi K, Tsubota K†, Kurihara T†

PeerJ. (PeerJ) 2019 ( 1 ) e6317 2019

Accepted

Copyright 2019 Katada et al. Purpose. The most common virus vector used in gene therapy research for ophthalmologic diseases is the adeno-associated virus (AAV) vector, which has been used successfully in a number of preclinical and clinical studies. It is important to evaluate novel AAV vectors in animal models for application of clinical gene therapy. The AAV-DJ (type 2/type 8/type 9 chimera) was engineered from shuffling eight different wild-type native viruses. In this study, we investigated the efficiency of gene transfer by AAV-DJ injections into the retina. Methods. One microliter of AAV-2-CAGGS-EGFP or AAV-DJ-CAGGS-EGFP vector at a titer of 1.4 x 10e12 vg/ml was injected intravitreally or subretinally in each eye of C57BL/6 mice. We evaluated the transduction characteristics of AAV-2 and -DJ vectors using fluorescence microscopy and electroretinography. Results. The results confirmed that AAV-DJ could deeply transfer gene to photoreceptor layer with intravitreal injection and has an efficient gene transfer to various cell types especially the Mueller cells in the retina. Retinal function was not affected by AAV-DJ infection or ectopic EGFP expression. Conclusions. The AAV-DJ vector efficiently induces the reporter gene in both the inner and outer murine retina without functional toxicity. These data indicated that the AAV-DJ vector is a useful tool for the gene therapy research targeting retinal disorders.

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Effect of midazolam, medetomidine, and butorphanol tartrate combination anesthetic on electroretinograms of mice.

Miwa Y, Tsubota K†, Kurihara T†

Mol Vis. (Molecular Vision) 25 645 - 653 2019

Accepted

© 2019 Molecular Vision. Purpose: To evaluate electroretinogram (ERG) responses under anesthesia with midazolam, medetomidine, and butorphanol tartrate (MMB) combination compared with pentobarbital sodium and ketamine/xylazine (KX). Methods: Six-week-old male C57BL/6J mice were divided into MMB-, pentobarbital sodium-, and KX-administered groups. Following overnight dark adaptation, an ERG was performed. The parameters sensitivity (S), log maximum amplitude (Rmax), Rmax, and time delay to the onset (Td) of the ERG a-waves were computed based on the Lamb and Pugh model. The parameters light intensity at half maximum amplitude (K), Rmax, and n of the ERG b-waves were computed based on the Naka-Rushton equation. The amplitude and the implicit time of oscillatory potentials (OPs) were quantified. Results: The Td of the dark-adapted a-waves was statistically significantly larger under anesthesia with the MMB combination and pentobarbital sodium compared to KX. The K of the dark-adapted b-waves was statistically significantly larger under anesthesia with pentobarbital sodium compared to the MMB combination. The amplitude of the dark-adapted OPs was statistically significantly larger under anesthesia with the MMB combination compared to pentobarbital sodium. The implicit time of the dark-adapted OPs was statistically significantly smaller under anesthesia with the KX combination compared to pentobarbital sodium. Conclusions: The results suggested that ERG responses, especially in OPs, are greatly affected by the type of anesthetic. It is important to consider the sensitive responses influenced by the selection of anesthetics when ERG is performed.

<i>Lactobacillus paracasei</i> KW3110 Prevents Blue Light-Induced Inflammation and Degeneration in the Retina.

Morita Y*†, Miwa Y*, Jounai K, Fujiwara D, Kurihara T, Kanauchi O

Nutrients. (Nutrients) 10 ( 12 ) pii: E1991 2018.12

Accepted

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Age-related macular degeneration and retinitis pigmentosa are leading causes of blindness and share a pathological feature, which is photoreceptor degeneration. To date, the lack of a potential treatment to prevent such diseases has raised great concern. Photoreceptor degeneration can be accelerated by excessive light exposure via an inflammatory response; therefore, anti-inflammatory agents would be candidates to prevent the progress of photoreceptor degeneration. We previously reported that a lactic acid bacterium, Lactobacillus paracasei KW3110 (L. paracasei KW3110), activated macrophages suppressing inflammation in mice and humans. Recently, we also showed that intake of L. paracasei KW3110 could mitigate visual display terminal (VDT) load-induced ocular disorders in humans. However, the biological mechanism of L. paracasei KW3110 to retain visual function remains unclear. In this study, we found that L. paracasei KW3110 activated M2 macrophages inducing anti-inflammatory cytokine interleukin-10 (IL-10) production in vitro using bone marrow-derived M2 macrophages. We also show that IL-10 gene expression was significantly increased in the intestinal immune tissues 6 h after oral administration of L. paracasei KW3110 in vivo. Furthermore, we demonstrated that intake of L. paracasei KW3110 suppressed inflammation and photoreceptor degeneration in a murine model of light-induced retinopathy. These results suggest that L. paracasei KW3110 may have a preventive effect against degrative retinal diseases.

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A highly efficient murine model of experimental myopia.

Jiang X, Kurihara T†, Kunimi H, Miyauchi M, Ikeda SI, Mori K, Tsubota K, Torii H, Tsubota K†

Sci Rep. (Scientific Reports) 8 ( 1 ) 2026 2018.12

Accepted

© 2018 The Author(s). Despite the global pandemic of myopia, the precise molecular mechanism of the onset of myopia remains largely unknown. This is partially because of the lack of efficient murine myopic models that allow genetic manipulation at low cost. Here we report a highly practical and reproducible lens-induced myopia model by specially designed frames and lenses for mice. A lens power dependent myopic induction in mice was shown until minus 30 diopter lenses. The phenotype was significantly stronger than form-deprivation myopia. We presented the protocol for precise evaluations of the state of myopia, including refraction, corneal curvature and axial length using up-to-date devices. We also found that myopic mouse eyes showed decreased visual acuity on optokinetic response examination. Finally, we confirmed the anti-myopic effect of 1% atropine using this model, which showed its potential in drug screening. The strong phenotype, stable evaluation and the potential for gene manipulation utilizing the presented method in mice will accelerate the translational research of myopia.

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Benefits of aflibercept treatment for age-related macular degeneration patients with good best-corrected visual acuity at baseline.

Minami S, Nagai N, Suzuki M, Kurihara T, Sonobe H, Kamoshita M, Uchida A, Shinoda H, Takagi H, Sonoda S, Sakamoto T, Tsubota K, Ozawa Y†

Sci Rep. (Scientific Reports) 8 ( 1 ) 58 2018.12

Accepted

© 2017 The Author(s). Currently, age-related macular degeneration (AMD) is treated while patients exhibit good best-corrected visual acuity (BCVA). However, previous clinical trials only include patients with poor BCVA. We prospectively analyzed the benefits of intravitreal aflibercept (IVA) treatment for AMD patients exhibiting good BCVA at baseline. Twenty-nine treatment-naive AMD patients (29 eyes) with BCVA better than 0.6 (74 letters in ETDRS chart) were treated with IVA once a month for 3 months and every 2 months thereafter with no additional treatments. Improvement in mean BCVA, measured using the conventional Landolt C chart, contrast VA chart, and functional VA (FVA) system, and reductions in mean central retinal thickness (CRT), central choroidal thickness, macular volume (MV), and choroidal area on optical coherence tomography images were observed at 6 and 12 months. Improvements in contrast VA and FVA scores, in contrast to conventional BCVA, correlated with MV reduction; no VA scores correlated with a reduced CRT. The MV correlated with choroidal area after IVA. No severe adverse events occurred. IVA improved visual function, retinal condition, and quality of life evaluated by Visual Function Questionnaire, and was beneficial in these patients. The contrast VA and FVA scores and MVs, which detect subtle changes, helped demonstrate the benefits.

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