L-dopa increases nigral production of hydroxyl radicals in vivo: potential L-dopa toxicity?

Dopamine (DA) deficiency in Parkinson's disease is commonly treated with L-dihydroxyphenylalanine (L-dopa), the amino acid precursor to DA. L-dopa is neurotoxic in vitro and impairs survival of metabolically stressed neurons in vivo. We examined with microdialysis of substantia nigra in awake rats the local production of hydroxyl (OH) radicals before and after systemic L-dopa. We found a dose-dependent increase in OH radical output which paralleled the rate of dopa catabolism, was not blocked by deprenyl, and was increased further by acute inhibition of mitochondrial complex I activity. Following high L-dopa doses, catabolism of dopa-derived DA can exceed capacity of nigral mechanisms to reduce formation of or detoxify free radicals.