Neuroprotective effects of memantine in a mouse model of retinal degeneration induced by rotenone.

This is the first report of the in vivo effectiveness of memantine as a neuroprotective agent against rotenone-induced retinal toxicity. We tested the hypothesis that uncompetitive NMDAR blockade with memantine prevents mitochondrial dysfunction-related neurodegeneration in vivo, using a mouse model of retinal ganglion cell layer (GCL) degeneration induced by rotenone, a mitochondrial complex I inhibitor. Rotenone induced an increase in cell death and oxidative stress in GCL compared to controls, and these changes were prevented by the co-administration of memantine. The neurotoxic effect of rotenone was also reflected as a decrease in total cell density in GCL and GCL+nerve fiber layer thickness. These changes were also prevented by co-administration of memantine in a dose-dependent manner. In addition, memantine induced an increase in long-term retinal energy metabolic capacity. The results suggest that NMDAR activation contributes to cell death induced by mitochondrial dysfunction and that uncompetitive NMDAR blockade may be used as a neuroprotective strategy against mitochondrial dysfunction in neurodegenerative diseases.