Time-dependent effects of levodopa on regional brain dopamine metabolism and lipid peroxidation

Levodopa treatment in Parkinson's disease has been suggested to contribute to disease progression through free radical generation. We compared the time course of levodopa-induced dopamine metabolism, and the resulting oxidative stress, between rat brain regions with varying dopaminergic innervation. At 1, 4, 8, and 12 h after levodopa administration (100 mg/kg), dopamine, dihydroxyphenylacetic acid, and homovanillic acid were measured in striatum and ventral midbrain, regions containing marked dopaminergic innervation, and in prefrontal cortex and cerebellum, which possess little dopaminergic innervation. Malondialdehyde, a marker of oxidative stress, was measured in additional animals. The return of dopamine and its metabolites to control concentrations tended to be slower (by 3-8 h) in cerebellum and prefrontal cortex than in dopaminergic regions. Malondialdehyde concentrations were decreased (p < 0.05) in ventral midbrain 8 h posttreatment, but increased in cerebellum 12 h posttreatment. We concluded that levodopa increases dopamine metabolism in nondopaminergic as well as dopaminergic regions, with delayed clearance of dopamine and its metabolites in nondopaminergic regions. The slower return of dopamine to control levels in nondopaminergic regions may be relevant to some of the side effects of levodopa. No support was found for the hypothesis that levodopa treatment induces oxidative stress.