Glutamate excitotoxicity in glaucoma: truth or fiction? By AJ Lotery

Osborne, Neville N.; Chidlow, Glyn; Wood, J. K.

doi:10.1038/sj.eye.6702234

Cited by 13 publications

(9 citation statements)

References 7 publications

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“…A misconception has been that, for excitotoxicity to occur, elevated glutamate levels must be detected in the retina/ocular fluids of experimental animals or humans with glaucoma [27], [28]. Excess glutamate release is a hallmark of acute brain injuries with fast and severe neural tissue damage [29], but this is not necessarily characteristic of a slow, progressing neurodegenerative disease such as glaucoma.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of the RNA Editing Enzyme ADAR2 Contributes to RGC Death in a Mouse Model of Glaucoma

2014

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Glaucoma is a progressive neurodegenerative disease of retinal ganglion cells (RGCs) associated with characteristic axon degeneration in the optic nerve. Excitotoxic damage due to increased Ca2+ influx, possibly through NMDA-type glutamate receptors, has been proposed to be a cause of RGC dysfunction and death in glaucoma. Recent work has found that expression of another potentially critical receptor, the Ca2+-permeable AMPA receptor (CP-AMPAR), is elevated during various pathological conditions (including ALS and ischemia), resulting in increased neuronal death. Here we test the hypothesis that CP-AMPARs contribute to RGC death due to elevated Ca2+ influx in glaucoma. AMPA receptors are impermeable to Ca2+ if the tetrameric receptor contains a GluA2 subunit that has undergone Q/R RNA editing at a site in the pore region. The activity of ADAR2, the enzyme responsible for this RNA editing, generally ensures that the vast majority of GluA2 proteins are edited. Here, we demonstrate that ADAR2 levels decrease in a mouse model of glaucoma in which IOP is chronically elevated. Furthermore, using an in vitro model of RGCs, we find that knockdown of ADAR2 using siRNA increased the accumulation of Co2+ in response to glutamate, and decreased the rectification index of AMPA currents detected electrophysiologically, indicating an increased Ca2+ permeability through AMPARs. The RGCs in primary culture also exhibited increased excitotoxic cell death following knock down of ADAR2. Furthermore, cell death was reversed by NASPM, a specific blocker for CP-AMPARs. Together, our data suggest that chronically elevated IOP in adult mice reduces expression of the ADAR2 enzyme, and the loss of ADAR2 editing and subsequent disruption of GluA2 RNA editing might potentially play a role in promoting RGC neuronal death as observed in glaucoma.

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Section: Discussionmentioning

confidence: 99%

Down-Regulation of the RNA Editing Enzyme ADAR2 Contributes to RGC Death in a Mouse Model of Glaucoma

2014

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“…Although an elevation of glutamate concentration in the vitreous humor was reported [89, 90], the following studies could not reproduce these results [91–94]. However, an elevation in the glutamate level in the vitreous humor is not necessary to induce excitotoxicity in the experimental animals or humans with glaucoma [95, 96]. It is because glutamate increase is likely to occur only in localized areas of the retina or optic nerve at any one time during glaucomatous neurodegeneration.…”

Section: Abnormalities Of Glutamate Metabolismmentioning

confidence: 99%

Abnormalities in Glutamate Metabolism and Excitotoxicity in the Retinal Diseases

Ishikawa

2013

Scientifica

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In the physiological condition, glutamate acts as an excitatory neurotransmitter in the retina. However, excessive glutamate can be toxic to retinal neurons by overstimulation of the glutamate receptors. Glutamate excess is primarily attributed to perturbation in the homeostasis of the glutamate metabolism. Major pathway of glutamate metabolism consists of glutamate uptake by glutamate transporters followed by enzymatic conversion of glutamate to nontoxic glutamine by glutamine synthetase. Glutamate metabolism requires energy supply, and the energy loss inhibits the functions of both glutamate transporters and glutamine synthetase. In this review, we describe the present knowledge concerning the retinal glutamate metabolism under the physiological and pathological conditions.

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“…12 Among these hypotheses, evidence regarding the role of glutamate in RGC death has been controversial, and, to date, the role of increased levels of glutamate in RGC death in glaucomatous damage has never been substantiated. 13,14 However, after inducing excitotoxicity by N-methyl-D-aspartic acid (NMDA) or kainic acid (KA), a number of studies on rodents and primates have shown that excitotoxicity does play a role in the death of RGCs because antagonists against NMDA and non-NMDA receptors have been shown to offer neuroprotection. [15][16][17][18] Although studies in animal models of excitotoxicity have shown that NMDA, and non-NMDA receptor antagonists offer neuroprotection, the underlying mechanisms are still not well understood.…”

mentioning

confidence: 99%

Excitotoxicity Upregulates SARM1 Protein Expression and Promotes Wallerian-Like Degeneration of Retinal Ganglion Cells and Their Axons

Massoll¹,

Mando²,

Chintala³

2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. This study investigated the role of sterile alpha/Armadillo/Toll-Interleukin receptor homology domain 1 protein (SARM1) in Wallerian-like degeneration of retinal ganglion cells (RGCs) and their axons after inducing excitotoxicity. METHODS.To induce excitotoxicity, kainic acid (KA) was injected into the vitreous humor of B6.Cg-Tg(Thy1-YFP)HJrs/J mice. Control mice received PBS. At 24, 48, and 72 hours after injection, degeneration of RGCs and their axons in the retina was determined by fundus imaging, and axonal degeneration in the optic nerves was determined by fluorescence microscopy. SARM1 protein levels were determined by Western blot analysis and SARM1 tissue localization was determined by immunohistochemistry. Causal role of SARM1 in KAmediated degeneration of RGCs and their axons was determined by treating the eyes with KA along with Sarm1 silencer siRNA. RESULTS.Fundus imaging and microscopic analysis indicated that KA promoted Wallerian-like degeneration of RGCs and axons in KA-treated eyes, but not in PBS-treated eyes. Quantitative analysis indicated a significant increase in degeneration of RGCs and their axons in KA-treated injected eyes, but not in PBS-treated eyes. Compared with low levels of SARM1 protein in retinal protein extracts, retinal cross sections, and optic nerve from PBS-treated eyes, SARM1 protein levels were increased in KA-treated eyes. Finally, treatment of eyes with KA along with a Sarm1 silencer siRNA attenuated KA-mediated degeneration of RGCs and their axons significantly. CONCLUSIONS.Results presented in this study, for the first time, show that KA-mediated upregulation of SARM1 protein promotes Wallerian-like degeneration of RGCs and their axons.

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Glutamate excitotoxicity in glaucoma: truth or fiction? By AJ Lotery

Cited by 13 publications

References 7 publications

Down-Regulation of the RNA Editing Enzyme ADAR2 Contributes to RGC Death in a Mouse Model of Glaucoma

Down-Regulation of the RNA Editing Enzyme ADAR2 Contributes to RGC Death in a Mouse Model of Glaucoma

Abnormalities in Glutamate Metabolism and Excitotoxicity in the Retinal Diseases

Excitotoxicity Upregulates SARM1 Protein Expression and Promotes Wallerian-Like Degeneration of Retinal Ganglion Cells and Their Axons

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