The Effect of Melatonin on Retinal Ganglion Cell Survival in Ischemic Retina

Park, Sangwoo; Lee, Hyoseok; Sung, Myongsoon; Kim, Sujin

doi:10.4068/cmj.2012.48.2.116

Cited by 26 publications

(19 citation statements)

References 51 publications

(40 reference statements)

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“…HIF-1α has been determined to play vital roles in certain ischemic diseases, such as ischemic stroke, liver, kidney ischemia/reperfusion injury [66][67][68], and retinal ischemic injury [69], but the exact mechanisms in acute glaucoma remain unclear. Previous studies have demonstrated that HIF-1α can mediate NLRP3 inflammasome activation and IL-1β secretion [70][71][72].…”

Section: Discussionmentioning

confidence: 99%

NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma

Chen

Deng

Gan

et al. 2020

Mol Neurodegeneration

103

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Background: Acute glaucoma, characterized by a sudden elevation in intraocular pressure (IOP) and retinal ganglion cells (RGCs) death, is a major cause of irreversible blindness worldwide that lacks approved effective therapies, validated treatment targets and clear molecular mechanisms. We sought to explore the potential molecular mechanisms underlying the causal link between high IOP and glaucomatous RGCs death.Methods: A murine retinal ischemia/ reperfusion (RIR) model and an in vitro oxygen and glucose deprivation/ reoxygenation (OGDR) model were used to investigate the pathogenic mechanisms of acute glaucoma.Results: Our findings reveal a novel mechanism of microglia-induced pyroptosis-mediated RGCs death associated with glaucomatous vision loss. Genetic deletion of gasdermin D (GSDMD), the effector of pyroptosis, markedly ameliorated the RGCs death and retinal tissue damage in acute glaucoma. Moreover, GSDMD cleavage of microglial cells was dependent on caspase-8 (CASP8)-hypoxia-inducible factor-1α (HIF-1α) signaling. Mechanistically, the newly identified nucleotide-binding leucine-rich repeat-containing receptor (NLR) family pyrin domain-containing 12 (NLRP12) collaborated with NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing protein 4 (NLRC4) downstream of the CASP8-HIF-1α axis, to elicit pyroptotic processes and interleukin-1β (IL-1β) maturation through caspase-1 activation, facilitating pyroptosis and neuroinflammation in acute glaucoma. Interestingly, processing of IL-1β in turn magnified the CASP8-HIF-1α-NLRP12/ NLRP3/NLRC4-pyroptosis circuit to accelerate inflammatory cascades.Conclusions: These data not only indicate that the collaborative effects of NLRP12, NLRP3 and NLRC4 on pyroptosis are responsible for RGCs death, but also shed novel mechanistic insights into microglial pyroptosis, paving novel therapeutic avenues for the treatment of glaucoma-induced irreversible vision loss through simultaneously targeting of pyroptosis.

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Section: Discussionmentioning

confidence: 99%

NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma

Chen

Deng

Gan

et al. 2020

Mol Neurodegeneration

103

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“…[12][13][14][15][16][17] In this study, we investigated the effect of transient ischemia in the retina 21 days after I/R, common model to investigate degenerative diseases of the retina. 18 We used a combination of ERG measurements and immunohistology to analyze the effects of ischemia on the different retinal cell types including RGCs, amacrine cells, bipolar cells, and glia cells. Additionally, we investigated apoptotic processes and the activation of phagocytes in the ischemic retina.…”

mentioning

confidence: 99%

Loss of Inner Retinal Neurons After Retinal Ischemia in Rats

Schmid¹,

Renner²,

Dick³

et al. 2014

Invest. Ophthalmol. Vis. Sci.

104

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PURPOSE. Ischemia is a risk factor for eye diseases like ocular vein occlusion or glaucoma. To investigate effects of ischemia-reperfusion (I/R) a lot of different animal models are used, studying one or two different cell types, which creates heterogeneity of data. The aim of this study was to investigate the function and morphology of the whole retina and different retinal cell types in an I/R model. METHODS. I/R was induced by elevating the intraocular pressure in the right eyes of rats. Twenty-one days after ischemia, electroretinogram measurements were performed. Changes in layer thickness were investigated. Changes of RGC, amacrine-, rod bipolar-, and glia cells as well as presence of apoptosis were analyzed immunohistologically. RESULTS. A-wave-and b-wave amplitudes were decreased; histology showed a reduction of RGC-and inner plexiform layer thickness and a 29% loss of RGCs occurred in ischemic eyes (P ¼ 0.016). An increase of apoptotic cells was detected in the GCL and INL of ischemic retinas (P < 0.05). Also, a loss of cholinergic amacrine cells (control: 11 6 1 cells/mm, I/R: 4 6 1 cells/mm, P < 0.001), but no change in rod bipolar cell numbers was noted. CONCLUSIONS. Our study allowed a comparison of the effects of I/R for different retinal cell types. Cells in the outer retina seemed to be more resistant to ischemic damage compared with cells of the inner retina. We hypothesize that a degenerative process, like a secondary wave of apoptosis, occurs 21 days after I/R, causing progressive damage in the retina.

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“…Additionally, and in experimental models of optic neuritis and retinal ischemia, melatonin treatment inhibits glial reactivity and reduces the expression of hypoxia inducible factor ‐1α, COX‐2, and TNF‐α genes (Figure ) . It is, thereby, also acting as a neuroprotective agent.…”

Section: Melatonin and Aging‐related Eye Diseasesmentioning

confidence: 99%

“…[113][114][115]117 Additionally, and in experimental models of optic neuritis and retinal ischemia, melatonin treatment inhibits glial reactivity and reduces the expression of hypoxia inducible factor -1α, COX-2, and TNF-α genes (Figure 2). 241,242 It is, thereby, also acting as a neuroprotective agent. In relation to these effects, Jiang and colleagues have demonstrated that melatonin decreases the production of VEGF by Müller cells, the main retinal glial cells, under high glucose concentration.…”

Section: The Therapeutic Potential Of Melatonin In Glaucomamentioning

confidence: 99%

The role and therapeutic potential of melatonin in age‐related ocular diseases

Crooke

Huete-Toral

Colligris

et al. 2017

Journal of Pineal Research

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The eye is continuously exposed to solar UV radiation and pollutants, making it prone to oxidative attacks. In fact, oxidative damage is a major cause of age-related ocular diseases including cataract, glaucoma, age-related macular degeneration, and diabetic retinopathy. As the nature of lens cells, trabecular meshwork cells, retinal ganglion cells, retinal pigment epithelial cells, and photoreceptors is postmitotic, autophagy plays a critical role in their cellular homeostasis. In age-related ocular diseases, this process is impaired, and thus, oxidative damage becomes irreversible. Other conditions such as low-grade chronic inflammation and angiogenesis also contribute to the development of retinal diseases (glaucoma, age-related macular degeneration and diabetic retinopathy). As melatonin is known to have remarkable qualities such as antioxidant/antinitridergic, mitochondrial protector, autophagy modulator, anti-inflammatory, and anti-angiogenic, it can represent a powerful tool to counteract all these diseases. The present review analyzes the role and therapeutic potential of melatonin in age-related ocular diseases, focusing on nitro-oxidative stress, autophagy, inflammation, and angiogenesis mechanisms.

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The Effect of Melatonin on Retinal Ganglion Cell Survival in Ischemic Retina

Cited by 26 publications

References 51 publications

NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma

NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma

Loss of Inner Retinal Neurons After Retinal Ischemia in Rats

The role and therapeutic potential of melatonin in age‐related ocular diseases

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