Details of a Researcher - Kurihara, Toshihide

Papers - Kurihara, Toshihide

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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.

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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<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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Roles of hypoxia response in retinal development and pathophysiology

Kurihara T†

Keio J Med. (Keio Journal of Medicine) 67 ( 1 ) 1 - 9 2018

Accepted, ISSN 00229717

© 2017 by The Keio Journal of Medicine. The hypoxia response is a fundamental phenomenon mainly regulated by hypoxia-inducible factors (HIFs). For more than a decade, we have investigated and revealed the roles of the hypoxia response in the development, physiology, and pathophysiology of the retina by generating and utilizing cell-typespecific conditional knockout mice. To investigate the functions of genes related to the hypoxia response in cells composing the retina, we generated various mouse lines that lack HIFs and/or related genes specifically in retinal neurons, astrocytes, myeloid cells, or retinal pigment epithelium cells. We found that these genes in the different types of retinal cells contribute in various ways to the homeostasis of ocular vascular and visual function. We hypothesized that the activation of HIFs is likely involved in the development and progress of retinal diseases, and we subsequently confirmed the pathological roles of HIFs in animal models of neovascular and atrophic ocular diseases. Currently, anti-vascular endothelial growth factor (anti-VEGF) therapy is a first-line treatment widely used for neovascular retinal diseases. However, alternative or additional targets are now required because several recent large-scale clinical trials and animal studies, including our own research, have indicated that VEGF antagonism may induce retinal vascular and neuronal degeneration. We have identified and confirmed a microRNA as a candidate for an alternative target against neovascular retinal diseases, and we are now working to establish a novel HIF inhibitor for clinical use based on the disease mechanism that we identified.

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Progress and Control of Myopia by Light Environments.

Jiang X, Kurihara T†, Torii H, Tsubota K†

Eye Contact Lens. (Eye and Contact Lens) 44 ( 5 ) 273 - 278 2018

Accepted, ISSN 15422321

Copyright © 2018 Contact Lens Association of Ophthalmologists, Inc. Unauthorized reproduction of this article is prohibited. During the past 30 years, the prevalence rate of myopia has been increased dramatically. Myopia has become one of the leading causes of vision loss in some countries, whereas the mechanism of the main pathological change in myopia is still largely unknown. Although several studies showed genetic background influences the phenotype of myopia to some extent, the sudden increase of morbidity cannot be explained by genetics only. The change in lifestyle results in tremendous change in the light environment, which can be considered to play an important role in the onset and progression of myopia. The difference between indoor and outdoor light environments such as intensity and wavelength of modern electronic lighting equipment may be a cue for myopia control as environmental factors. In this review, we discuss the relationship between myopia and light environment focusing on the basic and clinical studies.

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Elevated Aqueous Cytokine Levels in Eyes With Ocular Surface Diseases.

Aketa N, Yamaguchi T†, Asato T, Yagi-Yaguchi Y, Suzuki T, Higa K, Kurihara T, Satake Y, Tsubota K, Shimazaki J

Am J Ophthalmol. (ELSEVIER SCIENCE INC) 184 42 - 51 2017.12

Accepted, ISSN 0002-9394

PURPOSE: To evaluate cytokine and protein levels in the aqueous humor (AqH) of eyes with ocular surface diseases.
DESIGN: Prospective consecutive case series.
METHODS: This study includes 14 patients (aged 62.4 +/- 13.7 years) with chronic-phase ocular surface diseases (4 with ocular cicatricial pemphigoid, 5 with chemical burns, 2 with a thermal burn, 2 with Stevens-Johnson syndrome, and 1 with exposure keratitis), 14 matched patients without ocular surface disease (controls with corneal scar), and 30 patients who underwent cataract surgery (healthy controls). AqH samples were collected at the beginning of surgery. AqH levels of cytokines (interleukin [IL]-1 alpha, IL-1 beta, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, monocyte chemotactic protein [MCP]-1, interferon [IFN]-alpha, IFN-gamma, macrophage inflammatory protein [MIP]-1 alpha, MIP-1 beta, P-selectin, E-selectin, soluble-intercellular adhesion molecule [s-ICAM]-1, tumor necrosis factor [TNF]-alpha, granulocyte-macrophage colony-stimulating factor [GMCSF], IFN-gamma-induced protein [IP]-10) were measured using multiplex beads immunoassays.
RESULTS: The levels of IL-6, IL-10, IL-17A, GM-CSF, E-selectin, P-selectin, and s-ICAM in AqH were significantly elevated in eyes with ocular surface diseases (in pg/mL: 1696 +/- 804, 4.0 +/- 1.0, 24.3 +/- 9.8, 26.0 +/- 18.3, 5150 +/- 1232, 13122 +/- 7219, and 7914 +/- 2813, respectively), compared to healthy controls (IL-6: 6.36 +/- 0.94, P = .001; IL-10: 1.68 +/- 0.04, P = .0006; IL-17A: 3.7 +/- 0.2, P = .008; GM-CSF: 2.7 +/- 0.3, P = .007; E-selectin: 2093 +/- 37, P = .0001; P-selectin: 3658 +/- 137, P = .0001; sICAM-1: 1397 +/- 119, P = .008). The levels of IL-6, IL-17A, E-selectin, and P-selectin in AqH were significantly higher in eyes with ocular surface diseases compared to those with corneal scar (IL-6: 44.1 +/- 15.0, P = .0077; IL-17A: 4.1 +/- 0.7, P = .034; E-selectin: 2439 +/- 302, P = .039; and P-selectin: 5673 +/- 1553, P = .017).
CONCLUSIONS: Multiple AqH cytokine levels were elevated in chronic ocular surface diseases. ((C) 2017 Elsevier Inc. All rights reserved.)

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Violet Light Transmission is Related to Myopia Progression in Adult High Myopia

Torii H, Ohnuma K, Kurihara T, Tsubota K, Negishi K†

Sci Rep. (NATURE PUBLISHING GROUP) 7 ( 1 ) 14523 2017.11

Accepted, ISSN 2045-2322

Myopia is increasing worldwide. Although the exact etiology of myopia is unknown, outdoor activity is one of the most important environmental factors for myopia control. We previously reported that violet light (VL, 360-400 nm wavelength), which is abundant in the outdoor environment, suppressed myopia progression for individuals under 20 years of age. However, whether VL is also effective for adult high myopia, which can be sight-threatening, has remained unknown. To investigate the influence of VL for adult myopia, we retrospectively compared the myopic progression and the axial length elongation over five years in adult high myopic patients over 25 years of age after two types (non-VL transmitting and VL transmitting) of phakic intraocular lens (pIOL) implantation. We found that high myopic patients with the non-VL transmitting pIOLs implanted are almost two times more myopic in the change of refraction and four times longer in the change of axial length, compared to those implanted with the VL transmitting pIOLs. This result indicated that the VL transmitting pIOL suppressed myopia progression and axial length elongation compared with the non-VL transmitting one. In conclusion, our study showed the VL possibly has an anti-myopia effect for human adults with high myopia.

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Absolute and estimated values of macular pigment optical density in young and aged Asian participants with or without age-related macular degeneration.

Ozawa Y*†, Shigeno Y*, Nagai N, Suzuki M, Kurihara T, Minami S, Hirano E, Shinoda H, Kobayashi S, Tsubota K

BMC Ophthalmol. (BIOMED CENTRAL LTD) 17 ( 1 ) 161 2017.08

Accepted, ISSN 1471-2415

Background: Lutein and zeaxanthin are suggested micronutrient supplements to prevent the progression of age-related macular degeneration (AMD), a leading cause of blindness worldwide. To monitor the levels of lutein/zeaxanthin in the macula, macular pigment optical density (MPOD) is measured. A commercially available device (MPSII (R), Elektron Technology, Switzerland), using technology based on heterochromatic flicker photometry, can measure both absolute and estimated values of MPOD. However, whether the estimated value is applicable to Asian individuals and/or AMD patients remains to be determined.
Methods: The absolute and estimated values of MPOD were measured using the MPSII (R) device in 77 participants with a best-corrected visual acuity (BCVA) > 0.099 (logMAR score).
Results: The studied eyes included 17 young (20-29 years) healthy, 26 aged (> 50 years) healthy, 18 aged and AMD-fellow, and 16 aged AMD eyes. The mean BCVA among the groups were not significantly different. Both absolute and estimated values were measurable in all eyes of young healthy group. However, absolute values were measurable in only 57.7%, 66.7%, and 43.8%, of the aged healthy, AMD-fellow, and AMD groups, respectively, and 56.7% of the eyes included in the 3 aged groups. In contrast, the estimated value was measurable in 84.6%, 88.9% and 93.8% of the groups, respectively, and 88.3% of eyes in the pooled aged group. The estimated value was correlated with absolute value in individuals from all groups by Spearman's correlation coefficient analyses (young healthy: R-2 = 0.885, P = 0. 0001; aged healthy: R-2 = 0.765, P = 0.001; AMD-fellow: R-2 = 0.851, P = 0.0001; and AMD: R-2 = 0.860, P = 0.013). Using the estimated value, significantly lower MPOD values were found in aged AMD-related eyes, which included both AMD-fellow and AMD eyes, compared with aged healthy eyes by Student's t-test (P = 0.02).
Conclusions: Absolute, in contrast to estimated, value was measurable in a limited number of aged participants; however, it was correlated with estimated value both in young and aged Asian populations with or without AMD. These results may inform future clinical studies investigating the measurement of MPOD in understanding the role of macular pigments in the pathogenesis of AMD.

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Predictive factors of better outcomes by monotherapy of an antivascular endothelial growth factor drug, ranibizumab, for diabetic macular edema in clinical practice.

Sato S, Shinoda H, Nagai N, Suzuki M, Uchida A, Kurihara T, Kamoshita M, Tomita Y, Iyama C, Minami S, Yuki K, Tsubota K, Ozawa Y†

Medicine. (LIPPINCOTT WILLIAMS & WILKINS) 96 ( 16 ) e6459 2017.04

Accepted, ISSN 0025-7974

Intravitreal ranibizumab (IVR) has been approved for treating diabetic macular edema (DME), and is used in daily clinical practice. However, the treatment efficacies of IVR monotherapy in real-world clinical settings are not well known.
The medical records of 56 eyes from 38 patients who received their first IVR for DME between April 2014 and March 2015, and were retreated with IVR monotherapy as needed with no rescue treatment, such as laser photocoagulation, were retrospectively reviewed. The clinical course, best-corrected visual acuity (BCVA), and fundus findings at baseline, before the initial IVR injection, and at 12 months, were evaluated.
Twenty-five eyes from 25 patients (16 men; mean age 68.7+/-9.8 years) who received IVR in the first eye, or unilaterally, without any other treatments during follow-up were included. After 12 months, mean central retinal thickness (CRT), which includes edema, was reduced (P=.003), although mean BCVA remained unchanged. There was a negative correlation between individual changes in BCVA (r=-.57; P=.003) and CRT (r=-.60; P=.002) at 12 months compared with baseline values. BCVA changes were greater in individuals with a history of pan-retinal photocoagulation at baseline (P=.026). After adjusting for age and sex, CRT improvement >100 mu m at 12 months was associated with a greater CRT at baseline (OR 0.87 per 10 mu m [95% CI 0.72-0.97]; P=.018) according to logistic regression analyses; however, better BCVA and CRT at 12 months were associated with a better BCVA (r= 0.77; P<.001) and lower CRT (r=0.41; P=.039) at baseline, respectively, according to linear regression analyses.
IVR monotherapy suppressed DME, and the effects varied according to baseline conditions. Eyes that had poorer BCVA or greater CRT, or a history of pan-retinal photocoagulation at baseline, demonstrated greater improvement with IVR monotherapy. In contrast, to achieve better outcome values, DME eyes should be treated before the BCVA and CRT deteriorate. These findings advance our understanding of the optimal use of IVR for DME in daily clinical practice, although further study is warranted.

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Violet Light Exposure Can Be a Preventive Strategy Against Myopia Progression.

Torii H, Kurihara T, Seko Y, Negishi K, Ohnuma K, Inaba T, Kawashima M, Jiang X, Kondo S, Miyauchi M, Miwa Y, Katada Y, Mori K, Kato K, Tsubota K, Goto H, Oda M, Hatori M, Tsubota K†

EBioMedicine. (ELSEVIER SCIENCE BV) 15 210 - 219 2017.02

Accepted, ISSN 2352-3964

Prevalence of myopia is increasing worldwide. Outdoor activity is one of the most important environmental factors for myopia control. Here we show that violet light (VL, 360-400 nm wavelength) suppresses myopia progression. First, we confirmed that VL suppressed the axial length (AL) elongation in the chick myopia model. Expression microarray analyses revealed that myopia suppressive gene EGR1 was upregulated by VL exposure. VL exposure induced significantly higher upregulation of EGR1 in chick chorioretinal tissues than blue light under the same conditions. Next, we conducted clinical research retrospectively to compare the AL elongation among myopic children who wore eyeglasses (VL blocked) and two types of contact lenses (partially VL blocked and VL transmitting). The data showed the VL transmitting contact lenses suppressed myopia progression most. These results suggest that VL is one of the important outdoor environmental factors for myopia control. Since VL is apt to be excluded from our modern society due to the excessive UV protection, VL exposure can be a preventive strategy against myopia progression. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Non-responsiveness to intravitreal aflibercept treatment in neovascular age-related macular degeneration: implications of serous pigment epithelial detachment

Nagai, Norihiro, Suzuki, Misa, Uchida, Atsuro, Kurihara, Toshihide, Kamoshita, Mamoru, Minami, Sakiko, Shinoda, Hajime, Tsubota, Kazuo, Ozawa, Yoko

SCIENTIFIC REPORTS (NATURE PUBLISHING GROUP) 6 52 - 59 2016.07

Research paper (scientific journal), Accepted, ISSN 2045-2322

The prognosis of neovascular age-related macular degeneration (AMD) has been improved by anti-vascular endothelial growth factor treatments, including intravitreal aflibercept (IVA) treatment. However, many patients remain incurable. In this study, we retrospectively evaluated non-responsiveness to IVA monotherapy at 12 months in 133 eyes of 133 AMD patients. Sixty-two patients were initially treatment-naive, and 71 had received other treatments before IVA (the treatment-switched group). Mean best-corrected visual acuity (BCVA) was improved in the treatment-naive group but not in the treatment-switched group, although mean central retinal thickness (CRT) decreased in both groups. The respective percentages of non-responders as determined by worsened BCVA in the treatment-naive and treatment-switched groups were 8.1% and 15.5%, and via fundus findings, they were 12.9% and 8.5%. Multivariate analyses adjusted for age, gender, CRT, and greatest linear dimension showed that serous pigment epithelial detachment (PED) at baseline was associated with non-responsiveness in both groups as determined by BCVA and by fundus findings, and fibrovascular PED measurements indicated no response as determined by fundus findings in the treatment-switched group. The results reported herein may assist the formulation of appropriate treatment protocols for AMD patients.

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Distinct Responsiveness to Intravitreal Ranibizumab Therapy in Polypoidal Choroidal Vasculopathy With Single or Multiple Polyps

Suzuki, Misa, Nagai, Norihiro, Shinoda, Hajime, Uchida, Atsuro, Kurihara, Toshihide, Tomita, Yohei, Kamoshita, Mamoru, Iyama, Chigusa, Tsubota, Kazuo, Ozawa, Yoko

AMERICAN JOURNAL OF OPHTHALMOLOGY (ELSEVIER SCIENCE INC) 166 52 - 59 2016.06

Research paper (scientific journal), Accepted, ISSN 0002-9394

PURPOSE: To understand the prognosis of polypoidal choroidal vasculopathy (PCV) by evaluating the responsiveness to intravitreal ranibizumab (IVR) monotherapy according to the presence of a single or multiple polyps.
DESIGN: Retrospective case series.
METHODS: We included 48 treatment-naive eyes of 48 patients who received IVR monotherapy at the Medical Retina Division Clinic, Keio University Hospital between March 2009 and January 2013 and attended the clinic for at least 12 months. All patients received 3 monthly IVR injections followed by pro re nata injections and were divided into single polyp and multiple polyps groups according to indocyanine green angiography and optical coherence tomography (OCT) findings. The outcome measures included changes in best corrected visual acuity (BCVA) and OCT findings over 2 years after initial IVR.
RESULTS: At baseline, the multiple polyps group exhibited a poorer BCVA, larger greatest linear dimension, and higher prevalence of fibrovascular pigment epithelial detachment compared with the single polyp group. Over 2 years, the multiple polyps group showed no improvement in BCVA, although the central retinal thickness (CRT) decreased in both groups. The multiple polyps group exhibited a significantly greater CRT at 1 year and required more injections in the first year compared with the single polyp group; furthermore, it included a higher number of nonresponders judged either by BCVA or fundus findings at 1 year and fundus findings at 2 years.
CONCLUSIONS: We propose that the stratification of PCV lesions according to the presence of single or multiple polyps may be valuable to understand the prognosis. (C) 2016 The Authors. Published by Elsevier Inc.

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Development and pathological changes of neurovascular unit regulated by hypoxia response in the retina.

Kurihara T†

Prog Brain Res. (ELSEVIER SCIENCE BV) 225 201 - 211 2016.04

Lead author, Last author, Corresponding author, Accepted, ISSN 0079-6123

Retina is a highly vascularized tissue with a high oxygen and metabolic demand receiving light located in the back of the eye. The development and the maintenance of the retinal vasculature are important to regulate the homeostasis in the tissue. a Subunits of hypoxia-inducible factor (HIF) are key molecules in hypoxia response inducing genes required for cell survival such as vascular endothelial growth factor under hypoxia. Neurons, glia, and vascular endothelium cells interdependently form neurovascular unit in the retina tightly regulated by hypoxia response via HIF expression. A corruption of the precise hypoxia response in the developmental or matured retinal tissue may lead congenital vascular anomalies or adult neovascular ocular diseases. To regulate hypoxia response through HIF activity would be an ideal therapeutic target for these vision-threatening eye diseases.

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Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration

Kurihara, Toshihide, Westenskow, Peter D., Gantner, Marin L., Usui, Yoshihiko, Schultz, Andrew, Bravo, Stephen, Aguilar, Edith, Wittgrove, Carli, Friedlander, Mollie S. H., Paris, Liliana P., Chew, Emily, Siuzdak, Gary, Friedlander, Martin

ELIFE (ELIFE SCIENCES PUBLICATIONS LTD) 5 52 - 59 2016.03

Research paper (scientific journal), Accepted, ISSN 2050-084X

Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies.

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iPSC-Derived Retinal Pigment Epithelium Allografts Do Not Elicit Detrimental Effects in Rats: A Follow-Up Study.

Westenskow PD, Bucher F, Bravo S, Kurihara T, Feitelberg D, Paris LP, Aguilar E, Lin JH, Friedlander M†

Stem Cells Int. (HINDAWI LTD) 2016 Article ID 8470263 2016.01

Accepted, ISSN 1687-966X

Phototransduction is accomplished in the retina by photoreceptor neurons and retinal pigment epithelium (RPE) cells. Photoreceptors rely heavily on the RPE, and death or dysfunction of RPE is characteristic of age-related macular degeneration (AMD), a very common neurodegenerative disease for which no cure exists. RPE replacement is a promising therapeutic intervention for AMD, and large numbers of RPE cells can be generated from pluripotent stem cells. However, questions persist regarding iPSC-derived RPE (iPS-RPE) viability, immunogenicity, and tumorigenesis potential. We showed previously that iPS-RPE prevent photoreceptor atrophy in dystrophic rats up until 24 weeks after implantation. In this follow-up study, we longitudinally monitored the same implanted iPS-RPE, in the same animals. We observed no gross abnormalities in the eyes, livers, spleens, brains, and blood in aging rats with iPSC-RPE grafts. iPS-RPE cells that integrated into the subretinal space outlived the photoreceptors and survived for as long as 21/2 years while nonintegrating RPE cells were ingested by host macrophages. Both populations could be distinguished using immunohistochemistry and electron microscopy. iPSC-RPE could be isolated from the grafts and maintained in culture; these cells also phagocytosed isolated photoreceptor outer segments. We conclude that iPS-RPE grafts remain viable and do not induce any obvious associated pathological changes.

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Global metabolomics reveals metabolic dysregulation in ischemic retinopathy

Paris, Liliana P., Johnson, Caroline H., Aguilar, Edith, Usui, Yoshihiko, Cho, Kevin, Hoang, Lihn T., Feitelberg, Daniel, Benton, H. Paul, Westenskow, Peter D., Kurihara, Toshihide, Trombley, Jennifer, Tsubota, Kinya, Ueda, Shunichiro, Wakabayashi, Yoshihiro, Patti, Gary J., Ivanisevic, Julijana, Siuzdak, Gary, Friedlander, Martin

METABOLOMICS (SPRINGER) 12 ( 1 ) 52 - 59 2016.01

Research paper (scientific journal), Accepted, ISSN 1573-3882

Proliferative diabetic retinopathy (PDR) is the most severe form of diabetic retinopathy and, along with diabetic macular edema, is responsible for the majority of blindness in adults below the age of 65. Therapeutic strategies for PDR are ineffective at curtailing disease progression in all cases; however a deeper understanding of the ocular metabolic landscape in PDR through metabolomic analysis may offer new therapeutic targets. Here, global and targeted mass spectrometry-based metabolomics were used to investigate metabolism. Initial analyses on vitreous humor from patients with PDR (n = 9) and non-diabetic controls (n = 11) revealed an increase of arginine and acylcarnitine metabolism in PDR. The oxygen-induced-retinopathy (OIR) mouse model, which exhibits comparable pathological manifestations to human PDR, revealed similar increases of arginine and other metabolites in the urea cycle, as well as downregulation of purine metabolism. We validated our findings by targeted multiple reaction monitoring and through the analysis of a second set of patient samples [PDR (n = 11) and non-diabetic controls (n = 20)]. These results confirmed a predominant and consistent increase in proline in both the OIR mouse model and vitreous samples from patients with PDR, suggesting that over activity in the arginine-to-proline pathway could be used as a therapeutic target in diabetic retinopathy.

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The Neuroprotective Effect of Rapamycin as a Modulator of the mTOR-NF-kappa B Axis during Retinal Inflammation

Okamoto, Tomohiro, Ozawa, Yoko, Kamoshita, Mamoru, Osada, Hideto, Toda, Eriko, Kurihara, Toshihide, Nagai, Norihiro, Umezawa, Kazuo, Tsubota, Kazuo

PLOS ONE (PUBLIC LIBRARY SCIENCE) 11 ( 1 ) 52 - 59 2016.01

Research paper (scientific journal), Accepted, ISSN 1932-6203

Purpose
The determination of the molecular mechanism underlying retinal pathogenesis and visual dysfunction during innate inflammation, and the treatment effect of rapamycin thereon.
Methods
The endotoxin-induced uveitis and retinitis mouse model was established by injecting lipopolysaccharide. The mice were subsequently treated with rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. The rhodopsin mRNA and protein expression level in the retina and the photoreceptor outer segment (OS) length in immunohistochemical stainings were measured, and visual function was recorded by electroretinography. Inflammatory cytokines, their related molecules, mTOR, and LC3 levels were measured by real-time PCR and/or immunoblotting. Leukocyte adhesion during inflammation was analyzed using concanavalin A lectin.
Results
The post-transcriptional reduction in the visual pigment of rod photoreceptor cells, rhodopsin, OS shortening, and rod photoreceptor cell dysfunction during inflammation were suppressed by rapamycin. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and induction of inflammatory cytokines, such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and the activation of the downstream signaling protein, signal transducer and activator of transcription 3 (STAT3), which reduces rhodopsin in the retina during inflammation, were attenuated by rapamycin. Increased leukocyte adhesion was also attenuated by rapamycin. Interestingly, although mTOR activation was observed after NF-kappa B activation, mTOR inhibition suppressed NF-kappa B activation at the early phase, indicating that the basal level of activated mTOR was sufficient to activate NF-kappa B in the retina. In addition, the inhibition of NF-kappa B suppressed mTOR activation, suggesting a positive feedback loop of mTOR and NF-kappa B during inflammation. The ratio of LC3II to LC3I, which reflects autophagy induction, was not changed by inflammation but was increased by rapamycin.
Conclusions
Our results propose the potential use of rapamycin as a neuroprotective therapy to suppress local activated mTOR levels, related inflammatory molecules, and the subsequent visual dysfunction during retinal inflammation.

Access to Document (DOI)

Effects of Constant Intake of Lutein-rich Spinach on Macular Pigment Optical Density: a Pilot Study

Ozawa Y†, Nagai N, Suzuki M, Kurihara T, Shinoda H, Watanabe M, Tsubota K

Nippon Ganka Gakkai zasshi 120 ( 1 ) 41 - 48 2016.01

Accepted, ISSN 0029-0203

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