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Updated: Mar 30, 2026
Morphometric Analyses of Retinal Sections
Published on: February 19, 2012
Protective Effects of Everolimus against N-Methyl-D-aspartic Acid-Induced Retinal Damage in Rats
Ikumi Hayashi1, Yuto Aoki, Daiki Asano
1Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.
Abstract:
We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-D-aspartic acid (NMDA)-induced retinal neurotoxicity, but the mechanism underlying this protection is not fully understood. The present study aimed to examine the effects of everolimus, another inhibitor of mTOR, on neuronal cell loss and inflammation in a rat model of NMDA-induced retinal neurotoxicity, and to determine whether the extracellular signal-regulated kinase (ERK) pathway contributes to the protective effect of everolimus. Intravitreal injection of NMDA (200 nmol) resulted in (1) cell loss in the ganglion cell layer, (2) increase in the numbers of CD45-positive leukocytes and Iba1-positive microglia, and (3) phosphorylation of ribosomal protein S6 (pS6), a downstream indicator of mTOR activity. Simultaneous injection of everolimus with NMDA significantly attenuated these NMDA-induced responses. The neuroprotective effect of everolimus was almost completely prevented by the mitogen-activated protein kinase/ERK kinase inhibitor U0126 (1 nmol). NMDA increased the level of phosphorylated ERK (pERK) in Müller cells, and increase in pERK levels was also observed after co-injection of NMDA and everolimus. These results suggest that everolimus has a neuroprotective effect against NMDA-induced retinal neurotoxicity, an effect that seems to be mediated partly by activation of the ERK pathway in Müller cells.
Insights
Everolimus, an mTOR inhibitor, protects against NMDA-induced retinal neurotoxicity by reducing cell loss and inflammation. This protective effect involves the extracellular signal-regulated kinase (ERK) pathway in Müller cells.
Area of Science:
- Neuroscience
- Ophthalmology
- Pharmacology
Background:
- Rapamycin (mTOR inhibitor) shows neuroprotection against NMDA excitotoxicity.
- The precise mechanism of mTOR inhibitor-mediated retinal protection remains unclear.
- Everolimus, another mTOR inhibitor, was investigated for its neuroprotective potential.
Purpose of the Study:
- To evaluate everolimus's effect on NMDA-induced retinal neurotoxicity in rats.
- To investigate the role of the extracellular signal-regulated kinase (ERK) pathway in everolimus's protective mechanism.
- To assess changes in neuronal cell loss, inflammation, and mTOR activity.
Main Methods:
- Intravitreal injection of N-methyl-D-aspartic acid (NMDA) in a rat model.
- Administration of everolimus concurrently with NMDA.
- Assessment of ganglion cell layer loss, leukocyte and microglia infiltration.
- Measurement of phosphorylated ribosomal protein S6 (pS6) and phosphorylated ERK (pERK) levels.
- Inhibition of the ERK pathway using U0126.
Main Results:
- NMDA induced significant retinal neurotoxicity, including cell loss and inflammation.
- Everolimus treatment markedly attenuated NMDA-induced cell loss and inflammation.
- The protective effect of everolimus was significantly reduced by the ERK inhibitor U0126.
- NMDA increased pERK levels in Müller cells, an effect sustained with everolimus co-administration.
Conclusions:
- Everolimus demonstrates significant neuroprotective effects against NMDA-induced retinal toxicity.
- The ERK pathway, particularly in Müller cells, plays a crucial role in mediating everolimus's neuroprotection.
- These findings suggest a potential therapeutic strategy for retinal neurodegenerative conditions.
