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.
Rojas
Julio C
JC
Institute for Neuroscience, University of Texas at Austin, Austin, TX 78712, USA.
Saavedra
Jose A
JA
Gonzalez-Lima
F
F
D000818:Animals; D016923:Cell Death; D004734:Energy Metabolism / Q000187:drug effects; D004785:Environmental Pollutants; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007306:Insecticides; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D008808:Mice, Inbred CBA; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012162:Retinal Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012402:Rotenone; D016896:Treatment Outcome
D004785:Environmental Pollutants; D018691:Excitatory Amino Acid Antagonists; D007306:Insecticides; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D012402:Rotenone; D008559:Memantine