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Neuroprotective effects of memantine in a mouse model of retinal degeneration induced by rotenone
Julio C Rojas1, Jose A Saavedra, F Gonzalez-Lima
1Institute for Neuroscience, University of Texas at Austin, Austin, TX 78712, USA.
Abstract:
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.
Insights
Memantine protects retinal ganglion cells from rotenone-induced toxicity by blocking NMDA receptors (NMDARs). This study demonstrates memantine
Area of Science:
- Neuroscience
- Ophthalmology
- Toxicology
Background:
- Mitochondrial dysfunction is implicated in neurodegenerative diseases.
- Rotenone, a mitochondrial complex I inhibitor, induces retinal toxicity.
- N-methyl-D-aspartate receptors (NMDARs) play a role in neuronal cell death.
Purpose of the Study:
- To investigate the in vivo neuroprotective efficacy of memantine against rotenone-induced retinal toxicity.
- To test if uncompetitive NMDAR blockade with memantine prevents mitochondrial dysfunction-related neurodegeneration.
Main Methods:
- A mouse model was used to induce retinal ganglion cell layer (GCL) degeneration using rotenone.
- Memantine was co-administered with rotenone to assess its protective effects.
- Evaluated cell death, oxidative stress, cell density, and retinal layer thickness.
Main Results:
- Rotenone increased GCL cell death and oxidative stress, which were prevented by memantine.
- Memantine prevented rotenone-induced decreases in GCL cell density and GCL+nerve fiber layer thickness.
- Memantine administration increased long-term retinal energy metabolic capacity.
Conclusions:
- NMDAR activation contributes to cell death resulting from mitochondrial dysfunction.
- Uncompetitive NMDAR blockade with memantine shows neuroprotective potential.
- Memantine may serve as a therapeutic strategy for mitochondrial dysfunction in neurodegenerative conditions.
