We continue to study pathophysiological roles of free radicals in progressive degenerative brain disorders. To investigate the free radical chain reaction involving oxidant stress and brain injury, we developed in vivo animal models and in vitro testing procedures to evaluate neuroprotective strategies and alternative medications for slowing or halting the progressive deterioration in neurodegeneration in the brain. Based on their relative reactivity, we proposed that nitric oxide (NO*) may scavenge the more reactive hydroxyl radical (*OH) or O2-* free radicals which may lead to the annihilation of cytotoxic *OH resulting in prevention of oxidative brain injury. This working hypothesis was published in a symposium proceedings (Chiueh et al., eds. The Neurobiology of NO* and *OH). Antioxidant properties of NO* were demonstrated in brain homogenate preparations in which NO* or NO* donors (SNAP and GSNO) can suppress *OH generation and associated lipid peroxidation catalyzed by submicromolar iron. *OH can be generated in the basal ganglia through dopamine autoxidation and redox cycling of iron complexes. Lipid peroxidation and oxidative brain injury can be induced by intranigral infusion of compounds that generate *OH but not NO*. Co-administration of NO* or NO* donors protected brain neurons against oxidant injury caused by *OH in an animal model of parkinsonism. These results suggest a possible new role for NO* as a part of antioxidant defense systems in the brain, although more investigation is needed to elucidate the proposed neuroprotective mechanisms for NO* in other cellular and/or animal models of brain dysfunction. These neuroprotection projects revealed that oxidant-induced neurodegeneration can be prevented or rescued by (1) antioxidants (U-78517F, alpha-lipoic acid), (2) atypical antioxidants (deprenyl, entacapone), (3) NO* donors (SNAP, GSNO), (4) the cofactor for mitochondrial superoxide dismutase (manganese), and (5) hypothermia (decrease from 37 degrees to 31 degrees C). Although these initial studies were conducted in parkinsonian animal models, oxygen radicals are also implicated in brain injury associated with head trauma, chronic alcoholism, drug abuse, aging and Alzheimer's or AIDS dementia. The present in vivo neuroprotective data might provide a rationale for future clinical trials to slow or halt progression in degenerative brain disorders such as Parkinson's disease and perhaps Alzheimer's dem entia or aging.
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