Details of a Researcher - Kurihara, Toshihide

Papers - Kurihara, Toshihide

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Pemafibrate prevents choroidal neovascularization in a mouse model of neovascular age-related macular degeneration

Lee D, Nakai A, Miwa Y, Negishi K, Tomita Y, Kurihara T†

PeerJ. (PeerJ) 11 e14611 2023.01

Last author, Corresponding author, Accepted

Background. Pathological choroidal neovascularization (CNV) is one of the major causes of visual impairment in neovascular age-related macular degeneration (AMD). CNV has been suppressed by using anti-vascular endothelial growth factor (VEGF) antibodies. However, some clinical cases have demonstrated the failure of anti-VEGF therapies. Furthermore, anti-VEGF agents might induce the development of ocular atrophy. Recently, peroxisome proliferator-activated receptor alpha (PPARα) activation using pemafibrate treatment was suggested as one of the promising therapeutic targets in the prevention of ocular ischemia. However, the preventive role of pemafibrate remains unclear in CNV. We aimed to examine the preventive role of pemafibrate on laser-induced pathological CNV. Methods. Adult male C57BL/6 mice were orally supplied pemafibrate (0.5 mg/kg) for four days, followed by laser irradiation. Then, pemafibrate was consecutively given to mice with the same condition. CNV was visualized with isolectin-IB4. The eye (retina and/or retinal pigment epithelium [RPE]-choroid), liver, and serum were used for biomolecular analyses. Results. We found that pemafibrate administration suppressed CNV volumes. Pemafibrate administration activated PPARα downstream genes in the liver and eye (especially, RPE-choroid). Furthermore, pemafibrate administration elevated serum fibroblast growth factor 21 levels and reduced serum levels of triglycerides. Conclusions. Our data suggest a promising pemafibrate therapy for suppressing CNV in AMD.

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Association between fatty acid intakes and age-related macular degeneration in a Japanese population: JPHC-NEXT Eye Study

Yasukawa T*, Sasaki M*†, Motomura K, Yuki K, Kurihara T, Tomita Y, Mori K, Ozawa N, Ozawa Y, Yamagishi K†, Hanyuda A, Sawada N, Tsubota K, Tsugane S, Iso H

Transl Vis Sci Technol. (Translational Vision Science and Technology) 12 ( 1 ) 3 2023.01

Accepted

Purpose: To determine the associations between fatty acid intakes and the prevalence of age-related macular degeneration (AMD) under a population-based cross-sectional study. Methods: Residents of Chikusei City aged ≥40 years underwent systemic and eye screening. AMD was graded according to a modified version of the Age-Related Eye Disease Study classification. Dietary intake was assessed using a food frequency questionnaire and was adjusted for total energy intake. Results: Altogether, 10,788 eyes of 5394 participants, 2116 men (mean [standard devia-tion (SD)] age, 62.4 [9.4] years) and 3278 women (60.6 [9.5] years), were included. The mean daily total fat intakes were 52.8 g and 59.0 g in men and women, respectively. After adjustments for potential confounders, saturated fatty acid (SFA) intake was inversely associated with the prevalence of any AMD in men (for each energy-adjusted 1-SD increase: odds ratio [OR], 0.86; 95% confidence interval [CI], 0.74–1.00). Significant trends were found for decreasing odds ratios of AMD with increasing SFA, monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA) intake (P for trend = 0.02, 0.04, and 0.04, respectively). In women, only a significant association was observed between the second quartile of linolenic acid intake and the prevalence of any AMD (OR, 0.78; 95% CI, 0.62–0.99). Conclusions: We found an inverse association of SFA intake and a weak inverse association of MUFA and PUFA intakes with the prevalence of any AMD in a Japanese popula-tion. Translational Relevance: Adequate fatty acid intake may be necessary to prevent or decelerate AMD.

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Deep-learning-based AI for evaluating estimated nonperfusion areas requiring further examination in ultra-widefield fundus images

Inoda S, Takahashi H†, Yamagata H, Hisadome Y, Kondo Y, Tampo H, Sakamoto S, Katada Y, Kurihara T, Kawashima H, Yanagi Y

Sci Rep. (Springer Science and Business Media LLC) 12 ( 1 ) 21826 2022.12

Accepted

Abstract

We herein propose a PraNet-based deep-learning model for estimating the size of non-perfusion area (NPA) in pseudo-color fundus photos from an ultra-wide-field (UWF) image. We trained the model with focal loss and weighted binary cross-entropy loss to deal with the class-imbalanced dataset, and optimized hyperparameters in order to minimize validation loss. As expected, the resultant PraNet-based deep-learning model outperformed previously published methods. For verification, we used UWF fundus images with NPA and used Bland–Altman plots to compare estimated NPA with the ground truth in FA, which demonstrated that bias between the eNPA and ground truth was smaller than 10% of the confidence limits zone and that the number of outliers was less than 10% of observed paired images. The accuracy of the model was also tested on an external dataset from another institution, which confirmed the generalization of the model. For validation, we employed a contingency table for ROC analysis to judge the sensitivity and specificity of the estimated-NPA (eNPA). The results demonstrated that the sensitivity and specificity ranged from 83.3–87.0% and 79.3–85.7%, respectively. In conclusion, we developed an AI model capable of estimating NPA size from only an UWF image without angiography using PraNet-based deep learning. This is a potentially useful tool in monitoring eyes with ischemic retinal diseases.

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Axl, Immune Checkpoint Molecules and HIF Inhibitors from the Culture Broth of Lepista luscina

Kotajima M*, Choi JH*, Kondo M, D’Alessandro-Gabazza CN, Toda M, Yasuma T, Gabazza EC, Miwa Y, Shoda C, Lee D, Nakai A, Kurihara T, Wu J, Hirai H, Kawagishi H†

Molecules. (MDPI AG) 27 ( 24 ) 8925 - 8925 2022.12

Accepted

Two compounds 1 and 2 were isolated from the culture broth of Lepista luscina. This is the first time that compound 1 was isolated from a natural source. The structure of compound 1 was identified via 1D and 2D NMR and HRESIMS data. Compounds 1 and 2 along with 8-nitrotryptanthrin (4) were evaluated for their biological activities using the A549 lung cancer cell line. As a result, 1 and 2 inhibited the expression of Axl and immune checkpoint molecules. In addition, compounds 1, 2 and 4 were tested for HIF inhibitory activity. Compound 2 demonstrated statistically significant HIF inhibitory effects on NIH3T3 cells and 1 and 2 against ARPE19 cells.

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Relationship of choroidal thickness and axial length with posterior vitreous detachment in patients with high myopia

Hanyuda A*, Torii H*, Hayashi K, Uchida A, Mori K, Yotsukura E, Ogawa M, Negishi K, Kurihara T†, Tsubota T†

Sci Rep. (Springer Science and Business Media LLC) 12 ( 1 ) 4093 2022.12

Accepted

<title>Abstract</title>Although accumulating evidence suggests a higher prevalence of posterior vitreous detachment (PVD) in highly myopic eyes, the relation between ocular biometric features and PVD stages in such eyes remains unclear. Therefore, we enrolled 170 patients with high myopia (axial length ≥ 26.0 mm) to investigate the status of PVD regarding subfoveal choroidal thickness and axial length. Utilising swept-source optical coherence tomography, we classified the PVD status into five stages. The distribution of PVD grades increased as the choroidal thickness decreased and axial length increased (P < 0.01). On adjusting for age and sex, decreased choroidal thickness and increased axial length were associated with more advanced PVD stages: odds ratios with the highest vs. lowest groups were 0.31 (95% confidence interval [CI] 0.09–1.01; Ptrend = 0.009) for choroidal thickness and 5.16 (95% CI 1.34–19.80; Ptrend = 0.002) for axial length. The inverse association between choroidal thickness and PVD status seemed stronger in women than in men (Pinteraction = 0.05). In conclusion, we firstly observed a significant trend of decreased choroidal thickness, along with increased axial length, with increased grade of PVD, particularly among women with highly myopic eyes, suggesting that advanced morphological myopic changes contribute to PVD in middle-aged adults.

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Relation between Dry Eye and Myopia Based on Tear Film Breakup Time, Higher Order Aberration, Choroidal Thickness, and Axial Length

Hazra D*, Yotsukura E*, Torii H*†, Mori K, Maruyama T, Ogawa M, Hanyuda A, Tsubota K, Kurihara T†, Negishi K†

Sci Rep. (Scientific Reports) 12 ( 1 ) 10891 2022.12

Accepted

The purpose of this study was to investigate the association between dry eye disease (DED) and myopia by evaluating higher order aberrations (HOAs) and choroidal thickness (CT). We recruited 72 myopic children with DED symptoms (mean age 12.8 years), measured the tear film breakup time (TBUT), corneal/intraocular/total ocular HOAs, CT, and axial length (AL), administered lifestyle questionnaires, and evaluated the relationships among TBUT, HOAs, CT, and AL. The TBUT was correlated significantly with the corneal HOAs and intraocular HOAs but not with the total ocular HOAs. Multiple regression analyses showed that the AL was associated significantly with the TBUT (β = − 0.067, P = 0.004), the intraocular HOAs, and total ocular HOAs but not with the corneal HOAs. The CT was associated significantly with the TBUT and AL (β = 9.15 and − 7.85, respectively; P < 0.001 and = 0.01, respectively). Our data suggested the association between DED and myopia might be independent of the HOAs. We showed that the TBUT was associated with the CT, which is related to the AL. Because the parasympathetic nervous system affects the lacrimal glands and CT, the parasympathetic nervous system might be a common upstream factor in the association between DED and myopia.

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Nicotinamide Mononucleotide Protects against Retinal Dysfunction in a Murine Model of Carotid Artery Occlusion

Lee D, Tomita Y, Miwa Y, Jeong H, Shinojima A, Ban N, Yamaguchi S, Nishioka K, Negishi K, Yoshino J, Kurihara T†

Intl J Mol Sci. (MDPI AG) 23 ( 23 ) 14711 2022.11

Last author, Corresponding author, Accepted, ISSN 16616596

Cardiovascular abnormality-mediated retinal ischemia causes severe visual impairment. Retinal ischemia is involved in enormous pathological processes including oxidative stress, reactive gliosis, and retinal functional deficits. Thus, maintaining retinal function by modulating those pathological processes may prevent or protect against vision loss. Over the decades, nicotinamide mononucleotide (NMN), a crucial nicotinamide adenine dinucleotide (NAD+) intermediate, has been nominated as a promising therapeutic target in retinal diseases. Nonetheless, a protective effect of NMN has not been examined in cardiovascular diseases-induced retinal ischemia. In our study, we aimed to investigate its promising effect of NMN in the ischemic retina of a murine model of carotid artery occlusion. After surgical unilateral common carotid artery occlusion (UCCAO) in adult male C57BL/6 mice, NMN (500 mg/kg/day) was intraperitoneally injected to mice every day until the end of experiments. Electroretinography and biomolecular assays were utilized to measure ocular functional and further molecular alterations in the retina. We found that UCCAO-induced retinal dysfunction was suppressed, pathological gliosis was reduced, retinal NAD+ levels were preserved, and the expression of an antioxidant molecule (nuclear factor erythroid-2-related factor 2; Nrf2) was upregulated by consecutive administration of NMN. Our present outcomes first suggest a promising NMN therapy for the suppression of cardiovascular diseases-mediated retinal ischemic dysfunction.

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Pemafibrate, a potent selective peroxisome proliferator-activated receptor α modulator, a promising novel treatment for ischemic retinopathy?

Lee D, Tomita Y, Negishi K, Kurihara T†

Neural Regen Res. (Medknow) 18 ( 7 ) 1495 - 1496 2022.11

Last author, Corresponding author, Accepted, ISSN 1673-5374

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Therapeutic roles of PPARα activation in ocular ischemic diseases

Lee D*, Tomita Y*, Negishi K, Kurihara T†

Histol Histopathol. (Histology and histopathology) 38 ( 4 ) 18542 - 401 2022.10

Last author, Corresponding author, Accepted, ISSN 02133911

Ocular ischemia is one of the leading causes of blindness. It is related to various ocular diseases and disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma, and corneal injury. Ocular ischemia occurs due to an abnormal supply of oxygen and nutrients to the eye, resulting in ocular metabolic dysfunction. These changes can be linked with pathologic conditions in the eye, such as inflammation, neovascularization, and cell death, ultimately leading to vision loss. The current treatment care for ocular ischemia is limited. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor protein functioning in regulating lipid metabolism, fatty acid oxidation, and glucose homeostasis. Recently, PPARα activation has been suggested as a useful therapeutic target in treating ocular ischemia. However, its applications have not been well summarized. In this review, we cover an overview of the therapeutic roles of PPARα activation in various ocular ischemic conditions with recent experimental evidence and further provide clinical implications of its therapeutic applications. Our review will enable more approaches to comprehensively understand the therapeutic roles of PPARα activation for preventing ocular ischemic diseases.

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Short-Term Exposure to Violet Light Emitted from Eyeglass Frames in Myopic Children: A Randomized Pilot Clinical Trial

Torii H*†, Mori K*, Takashi Okano T, Kondo S, Yang HY, Yotsukura E, Hanyuda A, Ogawa M, Negishi K, Kurihara T†, Tsubota K†

J Clin Med. (Journal of Clinical Medicine) 11 ( 20 ) 6000 2022.10

Corresponding author, Accepted

Violet light (VL), 360–400 nm wavelength, is contained in the sunlight and is an effective element for myopia suppression. This study is to investigate the safety and efficacy of novel eyeglasses that emit VL from the frames. This is a double-masked, randomized, pilot clinical trial conducted in a clinic in Japan. Forty-three children with myopia were enrolled. Participants were randomly assigned to two groups, wearing VL-emitting eyeglass frames (VLf) that emitted VL of 310 μW/cm2 (VLf group, n = 22) or pseudo-placebo eyeglass frames with a minimal emission of VL (<10 μW/cm2) (control group, n = 21). The exposure time was 3 h per day. The primary outcomes were visual acuity, tear film break-up time, corneal endothelial cell density, and the slit-lamp/fundus examinations. The secondary outcome was the 6-month changes in the axial lengths and cycloplegic refractions. Forty-one (95%) participants were included; twenty-one in the VLf group and twenty in the control group. No significant differences were seen in any safety evaluation. Significant changes were seen in axial elongation, choroidal thickness, and cycloplegic refractions in the subgroup analysis of 8- to 10-year-old children (p < 0.05), but otherwise no significant differences were seen. The VLf showed short-term safety and effectiveness against myopia progression.

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Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes

Ikeda SI, Kurihara T†, Jiang X, Miwa Y, Lee D, Serizawa N, Jeong H, Mori K, Katada Y, Kunimi H, Ozawa N, Shoda C, Ibuki M, Negishi K, Torii H, Tsubota K†

Nat Commun. (Springer Science and Business Media LLC) 13 ( 1 ) 5859 2022.10

Corresponding author, Accepted

Abstract

Axial length is the primary determinant of eye size, and it is elongated in myopia. However, the underlying mechanism of the onset and progression of axial elongation remain unclear. Here, we show that endoplasmic reticulum (ER) stress in sclera is an essential regulator of axial elongation in myopia development through activation of both PERK and ATF6 axis followed by scleral collagen remodeling. Mice with lens-induced myopia (LIM) showed ER stress in sclera. Pharmacological interventions for ER stress could induce or inhibit myopia progression. LIM activated all IRE1, PERK and ATF6 axis, and pharmacological inhibition of both PERK and ATF6 suppressed myopia progression, which was confirmed by knocking down above two genes via CRISPR/Cas9 system. LIM dramatically changed the expression of scleral collagen genes responsible for ER stress. Furthermore, collagen fiber thinning and expression of dysregulated collagens in LIM were ameliorated by 4-PBA administration. We demonstrate that scleral ER stress and PERK/ATF6 pathway controls axial elongation during the myopia development in vivo model and 4-PBA eye drop is promising drug for myopia suppression/treatment.

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Degeneration of retinal ganglion cells in hypoxic responses: hypoxia-inducible factor inhibition, a new therapeutic insight

Lee D, Kunimi H, Negishi K, Kurihara T†

Neural Regen Res. (Neural Regeneration Research) 17 ( 10 ) 2230 - 2231 2022.10

Accepted, ISSN 16735374

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Nicotinamide Mononucleotide Prevents Retinal Dysfunction in a Mouse Model of Retinal Ischemia/Reperfusion Injury

Lee D, Tomita Y, Miwa Y, Shinojima A, Ban N, Yamaguchi S, Nishioka K, Negishi K, Yoshino J, Kurihara T†

Int J Mol Sci. (International Journal of Molecular Sciences) 23 ( 19 ) 11228 2022.09

Last author, Corresponding author, Accepted, ISSN 16616596

Retinal ischemia/reperfusion (I/R) injury can cause severe vision impairment. Retinal I/R injury is associated with pathological increases in reactive oxygen species and inflammation, resulting in retinal neuronal cell death. To date, effective therapies have not been developed. Nicotinamide mononucleotide (NMN), a key nicotinamide adenine dinucleotide (NAD+) intermediate, has been shown to exert neuroprotection for retinal diseases. However, it remains unclear whether NMN can prevent retinal I/R injury. Thus, we aimed to determine whether NMN therapy is useful for retinal I/R injury-induced retinal degeneration. One day after NMN intraperitoneal (IP) injection, adult mice were subjected to retinal I/R injury. Then, the mice were injected with NMN once every day for three days. Electroretinography and immunohistochemistry were used to measure retinal functional alterations and retinal inflammation, respectively. The protective effect of NMN administration was further examined using a retinal cell line, 661W, under CoCl2-induced oxidative stress conditions. NMN IP injection significantly suppressed retinal functional damage, as well as inflammation. NMN treatment showed protective effects against oxidative stress-induced cell death. The antioxidant pathway (Nrf2 and Hmox-1) was activated by NMN treatment. In conclusion, NMN could be a promising preventive neuroprotective drug for ischemic retinopathy.

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Vascular endothelial growth factor from retinal pigment epithelium is essential in choriocapillaris and axial length maintenance

Zhang Y*, Jeong H*, Mori K, Ikeda SI, Shoda C, Miwa Y, Nakai A, Chen J, Ma Z, Jiang X, Torii H, Kubota Y, Negishi K, Kurihara T†, Tsubota K†

PNAS Nexus (Oxford University Press (OUP)) 1 ( 4 ) pgac166 2022.08

Corresponding author, Accepted

Abstract

Myopia, which prevalence is rapidly increasing, causes visual impairment; however, the onset mechanism of pathological axial length (AL) elongation remains unclear. A highly vascularized choroid between the retinal pigment epithelium (RPE) and sclera not only maintains physiological activities, but also contributes to ocular development and growth regulation. Vascular endothelial growth factor (VEGF) secreted from the RPE to the choroid is essential for retinal function and maintenance of the choriocapillaris. Herein, we demonstrated that the loss of VEGF secreted from the RPE caused abnormal choriocapillaris development and AL elongation, with features similar to those of the lens-induced myopia (LIM) mouse model, whereas VEGF overexpression by knocking-out von Hippel–Lindau (VHL) specific to the RPE expands the choriocapillaris and shortens the AL. Additionally, LDL Receptor Related Protein 2 (LRP2) deletion in the RPE downregulated VEGF expression and leads to pathological AL elongation. Furthermore, high myopia patients without choriocapillaris demonstrated longer ALs than did those with preserved choriocapillaris. These results suggest that physiological secretion of VEGF from the RPE is required for proper AL development by maintaining the choriocapillaris. The pinpoint application of VEGF to the choriocapillaris may become a potential intervention for the prevention and treatment of axial myopia progression.

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Automatic segmentation of non-perfusion area from fluorescein angiography using deep learning with uncertainty estimation

Masayoshi K*, Katada Y*, Ozawa N, Ibuki M, Negishi K, Kurihara T†

Inform Med Unlocked. (Elsevier BV) 32 101060 - 101060 2022.08

Last author, Corresponding author, Accepted, ISSN 2352-9148

The non-perfusion area (NPA) of the retina is an important indicator in the visual prognosis of patients with retinal vein occlusion. Therefore, automatic detection of NPA will help its management. Deep learning models for NPA segmentation in fluorescein angiography have been reported. However, typical deep learning models do not adequately address the uncertainty of the prediction, which may lead to missed lesions and difficulties in working with medical professionals. In this study, we developed deep segmentation models with uncertainty estimation using Monte Carlo dropout and compared the accuracy of prediction and reliability of uncertainty in different models (U-Net, PSPNet, and DeepLabv3+) and uncertainty measures (standard deviation and mutual information). The study included 403 Japanese fluorescein angiography images of retinal vein occlusion. The mean Dice scores were 65.6 ± 9.6%, 66.8 ± 12.3%, and 73.6 ± 9.4% for U-Net, PSPNet, and DeepLabv3+, respectively. The uncertainty scores were best for U-Net, which suggests that the model complexity may deteriorate the quality of uncertainty estimation. Over-looked lesions and inconsistent prediction led to high uncertainty values. The results indicated that the uncertainty estimation would help decrease the risk of missed lesions.

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Retinal degeneration induced in a mouse model of ischemia–reperfusion injury and its management by pemafibrate treatment

Lee D, Nakai A, Miwa Y, Tomita Y, Kunimi H, Chen J, Ikeda SI, Tsubota K, Negishi K, Kurihara T†

FASEB J. (FASEB Journal) 36 ( 9 ) e22497 2022.08

Last author, Corresponding author, Accepted, ISSN 08926638

Retinal ischemia–reperfusion (I/R) injury is a common cause of visual impairment. To date, no effective treatment is available for retinal I/R injury. In addition, the precise pathological mechanisms still need to be established. Recently, pemafibrate, a peroxisome proliferator-activated receptor α (PPARα) modulator, was shown to be a promising drug for retinal ischemia. However, the role of pemafibrate in preventing retinal I/R injury has not been documented. Here, we investigated how retinal degeneration occurs in a mouse model of retinal I/R injury by elevation of intraocular pressure and examined whether pemafibrate could be beneficial against retinal degeneration. Adult mice were orally administered pemafibrate (0.5 mg/kg/day) for 4 days, followed by retinal I/R injury. The mice were continuously administered pemafibrate once every day until the end of the experiments. Retinal functional changes were measured using electroretinography. Retina, liver, and serum samples were used for western blotting, quantitative PCR, immunohistochemistry, or enzyme linked immunosorbent assay. Retinal degeneration induced by retinal inflammation was prevented by pemafibrate administration. Pemafibrate administration increased the hepatic PPARα target gene expression and serum levels of fibroblast growth factor 21, a neuroprotective molecule in the eye. The expression of hypoxia-response and pro-and anti-apoptotic/inflammatory genes increased in the retina following retinal I/R injury; however, these changes were modulated by pemafibrate administration. In conclusion, pemafibrate is a promising preventive drug for ischemic retinopathies.

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Children in Tokyo Have a Long Sustained Axial Length from Age 3 Years: The Tokyo Myopia Study

Maruyama T*, Yotsukura E*, Torii H*†, Mori K, Inokuchi M, Tokumura M, Hazra D, Ogawa M, Hanyuda A, Tsubota K, Kurihara T†, Negishi K†

J Clin Med. (Journal of Clinical Medicine) 11 ( 15 ) 4413 2022.07

Corresponding author, Accepted

Background: myopia prevalence is high among Japanese schoolchildren, but the underlying causes are unclear. Objective: To examine the distributions of ocular biometry and refraction and their associations with lifestyle variables among Japanese schoolchildren. Methods: This cross-sectional school-based study included 2140 children aged 3–14 years in Tokyo, Japan, and evaluated the distributions under non-cycloplegic conditions and the associated environmental factors. Results: The prevalence of spherical equivalent (SE) ≤−0.75 diopter among preschoolers (aged 3–6 years), elementary school students (aged 6–11 years), and junior high school students (aged 12–14 years) was 49.7%, 72.4%, and 87.7%, respectively. Multiple linear regression analyses showed that the time spent using digital devices was associated positively with lens thickness (β = 0.010; p < 0.050) but not SE, axial length, or vitreous chamber depth. The time spent reading was associated negatively with lens thickness (β = −0.012; p < 0.050), SE (β = −0.152; p < 0.010), axial length (β = 0.110; p < 0.001), and vitreous chamber depth (β = 0.110; p < 0.001). Conclusions: The data indicated that almost half of preschoolers may be myopic. The association with the lens thickness differed depending on the type of near work performed.

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Lipidomic analysis revealed n‐3 polyunsaturated fatty acids suppressed choroidal thinning and myopia progression in mice

Mori K*, Kuroha S*, Hou J, Jeong H, Ogawa M, Ikeda SI, Kang JX, Negishi K, Torii H, Arita M†, Kurihara T†, Tsubota K

FASEB J. (Wiley) 36 ( 6 ) e22312 2022.06

Accepted, ISSN 08926638

Myopia is increasing worldwide and its preventable measure should urgently be pursued. N-3 polyunsaturated fatty acids (PUFAs) have been reported to have various effects such as vasodilative and anti-inflammatory, which myopia may be involved in. This study is to investigate the inhibitory effect of PUFAs on myopia progression. A lens-induced myopia (LIM) model was prepared using C57B L6/J 3-week-old mice, which were equipped with a -30 diopter lens to the right eye. Chows containing two different ratios of n-3/n-6 PUFA were administered to the mice, and myopic shifts were confirmed in choroidal thickness, refraction, and axial length in the n-3 PUFA-enriched chow group after 5 weeks. To exclude the possibility that the other ingredients in the chow may have taken the suppressive effect, fat-1 transgenic mice, which can produce n-3 PUFAs endogenously, demonstrated significant suppression of myopia. To identify what elements in n-3 PUFAs took effects on myopia suppression, enucleated eyes were used for targeted lipidomic analysis, and eicosapentaenoic acid (EPA) were characteristically distributed. Administration of EPA to the LIM model confirmed the inhibitory effect on choroidal thinning and myopia progression. Subsequently, to identify the elements and the metabolites of fatty acids effective on myopia suppression, targeted lipidomic analysis was performed and it demonstrated that metabolites of EPA were involved in myopia suppression, whereas prostaglandin E2 and 14,15-dihydrotestosterone were associated with progression of myopia. In conclusion, EPA and its metabolites are related to myopia suppression and inhibition of choroidal thinning.

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Multiple Factors Causing Myopia and the Possible Treatments: A Mini Review

Shinojima A, Negishi K, Tsubota K, Kurihara T†

Front Public Health. (Frontiers in Public Health) 10 897600 2022.05

The myopia epidemic has become a global public health problem. Although myopia is progressing worldwide, the recent coronavirus infections 2019 (COVID-19) outbreak has spurred myopia progression. The current evidence-based treatments for humans are atropine eye drops, optical treatment with defocus, use of orthokeratology, extending proximity working distance, pausing from near work every half hour and increased time outside the home. Studies on myopia using animal models have been conducted for more than 40 years. In recent years, new mechanisms of myopia suppression have been revealed from animal experiments such as inflammation control, intraocular pressure control, light control, and the activity of early growth response protein 1 control. This mini-review provides a summary of the scientific evidence currently available on the control of myopia, and the possible treatments mitigating myopia.

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Ocular Ischemic Syndrome and Its Related Experimental Models

Lee D*, Tomita Y*, Yang L, Negishi K, Kurihara T†

Int J Mol Sci. (MDPI AG) 23 ( 9 ) 5249 - 5249 2022.05

Accepted, ISSN 16616596

Ocular ischemic syndrome (OIS) is one of the severe ocular disorders occurring from stenosis or occlusion of the carotid arteries. As the ophthalmic artery is derived from the branch of the carotid artery, stenosis or occlusion of the carotid arteries could induce chronic ocular hypoperfusion, finally leading to the development of OIS. To date, the pathophysiology of OIS is still not clearly unraveled. To better explore the pathophysiology of OIS, several experimental models have been developed in rats and mice. Surgical occlusion or stenosis of common carotid arteries or internal carotid arteries was conducted bilaterally or unilaterally for model development. In this regard, final ischemic outcomes in the eye varied depending on the surgical procedure, even though similar findings on ocular hypoperfusion could be observed. In the current review, we provide an overview of the pathophysiology of OIS from various experimental models, as well as several clinical cases. Moreover, we cover the status of current therapies for OIS along with promising preclinical treatments with recent advances. Our review will enable more comprehensive therapeutic approaches to prevent the development and/or progression of OIS.

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