Retinal Cell Degeneration in Animal Models

Niwa, Masayuki; Aoki, Hitomi; Hirata, Akihiro; Tomita, Hiroyuki; Green, Paul G.; Hara, Akira

doi:10.3390/ijms17010110

Cited by 54 publications

(38 citation statements)

References 137 publications

(149 reference statements)

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“…The interplay between these collective factors, and the exact mechanisms leading to RGC death are not fully understood. RGC death is reproducible in several animal models, and therapies aimed at preventing RGC death have shown success in animals [7]. However, further work is necessary for a deeper understanding of the biochemical mechanisms and development of innovative therapies against RGC death.…”

Section: Introductionmentioning

confidence: 99%

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

Nahomi

Nam

Rankenberg

et al. 2020

IJMS

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Background: Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. Methods: We injected KYNA intravenously or intravitreally to mice. We generated a knockout mouse strain of kynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway that produces neurotoxic 3-hydroxykynurenine. To test the effect of mild hyperglycemia on RGC protection, we used streptozotocin (STZ) induced diabetic mice. Retinal I/R injury was induced by increasing intraocular pressure for 60 min followed by reperfusion and RGC numbers were counted in the retinal flat mounts. Results: Intravenous or intravitreal administration of KYNA protected RGCs against I/R injury. The I/R injury caused a greater loss of RGCs in wild type than in KMO knockout mice. KMO knockout mice had mildly higher levels of fasting blood glucose than wild type mice. Diabetic mice showed significantly lower loss of RGCs when compared with non-diabetic mice subjected to I/R injury. Conclusion: Together, our study suggests that the absence of KMO protects RGCs against I/R injury, through mechanisms that likely involve higher levels of KYNA and glucose.

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Section: Introductionmentioning

confidence: 99%

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

Nahomi

Nam

Rankenberg

et al. 2020

IJMS

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“…Thus, 2 of 14 neuroprotective strategies to protect RGC against glaucomatous damage have been discussed for the past decades. To investigate protective mechanisms or potential therapeutic options, inter alia, the animal model of N-methyl-D-aspartate (NMDA) induced apoptosis of RGC has been established [4]. In the retina, NMDA induces excitotoxicity of RGC and subtypes of amacrine cells by hyperactivation of NMDA-type glutamate receptors, which results in an excessive Ca 2+ influx that subsequently propagates proapoptotic signaling cascades [5,6].…”

Section: Introductionmentioning

confidence: 99%

Norrin Protects Retinal Ganglion Cells from Excitotoxic Damage via the Induction of Leukemia Inhibitory Factor

Kassumeh

Leopold

Fuchshofer

et al. 2020

Cells

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Purpose: To investigate whether and how leukemia inhibitory factor (Lif) is involved in mediating the neuroprotective effects of Norrin on retinal ganglion cells (RGC) following excitotoxic damage. Norrin is a secreted protein that protects RGC from N-methyl-d-aspartate (NMDA)-mediated excitotoxic damage, which is accompanied by increased expression of protective factors such as Lif, Edn2 and Fgf2. Methods: Lif-deficient mice were injected with NMDA in one eye and NMDA plus Norrin into the other eye. RGC damage was investigated and quantified by TUNEL labeling 24 h after injection. Retinal mRNA expression was analyzed by quantitative real-time polymerase chain reaction following retinal treatment. Results: After intravitreal injection of NMDA and Norrin in wild-type mice approximately 50% less TUNEL positive cells were observed in the RGC layer when compared to NMDA-treated littermates, an effect which was lost in Lif-deficient mice. The mRNA expression for Gfap, a marker for Müller cell gliosis, as well as Edn2 and Fgf2 was induced in wild-type mice following NMDA/Norrin treatment but substantially blocked in Lif-deficient mice. Conclusions: Norrin mediates its protective properties on RGC via Lif, which is required to enhance Müller cell gliosis and to induce protective factors such as Edn2 or Fgf2.

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“…Excitotoxic degeneration of RGCs play a role in the pathophysiology of retinal disorders, such as glaucoma (Lipton, 2003;Seki and Lipton, 2008), age-related macular degeneration, and prematurity-induced retinal degeneration (Hinton et al, 1986;Tenhula et al, 1992;Lipton, 2003;Casson, 2006;Kaur et al, 2008;Seki and Lipton, 2008;Herna´ndez and Simo´, 2012). It is generally believed that glutamateinduced RGC damage is mediated by the activation of N-methyl-D-aspartate (NMDA) receptors and the resulting increase in intracellular Ca 2+ (Ferreira et al, 1996;Niwa et al, 2016). However, the value of NMDA receptors as candidate drug targets for retinal neuroprotection was questioned by the disappointing clinical data with the NMDA channel blocker, memantine, in the treatment of glaucoma (Chidlow et al, 2007;Osborne, 2009).…”

Section: Introductionmentioning

confidence: 99%

Permissive role for mGlu1 metabotropic glutamate receptors in excitotoxic retinal degeneration

et al. 2017

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Neuroprotection is an unmet need in eye disorders characterized by retinal ganglion cell (RGC) death, such as prematurity-induced retinal degeneration, glaucoma, and age-related macular degeneration. In all these disorders excitotoxicity is a prominent component of neuronal damage, but clinical data discourage the development of NMDA receptor antagonists as neuroprotectants. Here, we show that activation of mGlu1 metabotropic glutamate receptors largely contributes to excitotoxic degeneration of RGCs. Mice at postnatal day 9 were challenged with a toxic dose of monosodium glutamate (MSG, 3g/kg), which caused the death of >70% of Brn-3a RGCs. Systemic administration of the mGlu1 receptor negative allosteric modulator (NAM), JNJ16259685 (2.5mg/kg, s.c.), was largely protective against MSG-induced RGC death. This treatment did not cause changes in motor behavior in the pups. We also injected MSG to crv4 mice, which lack mGlu1 receptors because of a recessive mutation of the gene encoding the mGlu1 receptor. MSG did not cause retinal degeneration in crv4 mice, whereas it retained its toxic activity in their wild-type littermates. These findings demonstrate that mGlu1 receptors play a key role in excitotoxic degeneration of RGCs, and encourage the study of mGlu1 receptor NAMs in models of retinal neurodegeneration.

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Retinal Cell Degeneration in Animal Models

Cited by 54 publications

References 137 publications

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

Norrin Protects Retinal Ganglion Cells from Excitotoxic Damage via the Induction of Leukemia Inhibitory Factor

Permissive role for mGlu1 metabotropic glutamate receptors in excitotoxic retinal degeneration

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