Permissive role for mGlu1 metabotropic glutamate receptors in excitotoxic retinal degeneration.

Abstract

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.

• Authors: Francesca Liberatore, Domenico Bucci, Giada Mascio, Michele Madonna, Paola Di Pietro, Martina Beneventano, Alda Maria Puliti, Giuseppe Battaglia, Valeria Bruno, Ferdinando Nicoletti, Maria Rosaria Romano
• Journal: Neuroscience (Neuroscience) Vol. 363 Pg. 142-149 (Nov 05 2017) ISSN: 1873-7544 [Electronic] United States
• PMID: 28918254 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• (3,4-dihydro-2H-pyrano(2,3)b-quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone
• Neuroprotective Agents
• Quinolines
• Receptors, Metabotropic Glutamate
• metabotropic glutamate receptor type 1

Topics

• Animals
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Neuroprotective Agents (pharmacology)
• Quinolines (pharmacology)
• Receptors, Metabotropic Glutamate (metabolism)
• Retinal Degeneration (metabolism)
• Retinal Ganglion Cells (drug effects, metabolism, pathology)