Strategies of neuroprotection in an in vivo model of retinal degeneration induced by mitochondrial dysfunction

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Rojas-Martinez, Julio Cesar

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Current approaches to treat neurodegenerative disease provide only mild symptomatic relief but do not modify the natural history of these conditions. A large body of evidence suggests that mitochondrial dysfunction is a key event in the pathophysiology of neurodegeneration. Supporting and improving mitochondrial function has a big potential as a strategy for neuroprotection. The goal of this dissertation was to test whether interventions that target mitochondrial function are effective at preventing neurodegeneration induced by mitochondrial failure in vivo. A rodent model of optic neuropathy induced by the mitochondrial toxin rotenone was used to test the neuroprotective effects of methylene blue (MB) and near-infrared light (NIL), two interventions with mechanisms of action localized to mitochondria. This work also tested the effects of memantine, an NMDA receptor blocker, to further characterize the relationship between excitotoxicity and mitochondrial dysfunction. Neuroprotective effects were evaluated via behavioral testing of visual function and histopathological analysis of the retina. The neurochemical effects of MB, NIL and memantine were analyzed in vitro and in vivo with indicators of oxidative stress, cell respiration and catalytic activity of respiratory enzymes, including NADH dehydrogenase and cytochrome oxidase. MB, a diaminophenothiazine with potent antioxidant and unique redox properties, prevented the changes in visual function and the retinal histopathology induced by rotenone. In vitro, MB increased oxygen consumption and prevented the increases in oxidative stress in brain tissue induced by rotenone. NIL prevented the behavioral impairment and the decrease in retinal and visual pathway metabolic activity, retinal nerve fiber layer thickness and ganglion cell layer cell density induced by rotenone in a dose-dependent manner. Whole-brain cytochrome oxidase and superoxide dismutase activities were also increased in NIL-treated subjects in a dose-dependent manner, suggesting an in vivo transcranial effect of NIL. Finally, uncompetitive NMDA receptor blockade with memantine displayed neuroprotection against rotenone-induced neurodegeneration in a dose-response manner, and this effect was associated with a decrease in retinal oxidative stress and a long-term increase in neuronal energy metabolism capacity. These data constitute a proof-of-principle that interventions that target the mitochondria and support the function of the respiratory chain are effective at preventing neurodegeneration in vivo.