Levodopa is toxic to dopamine neurons in an in vitro but not an in vivo model of oxidative stress

Levodopa is the "gold standard" for the symptomatic treatment of Parkinson's disease (PD). There is a theoretical concern, however, that levodopa might accelerate the rate of nigral degeneration, because it undergoes oxidative metabolism and is toxic to cultured dopaminergic neurons. Most in vivo studies do not show evidence of levodopa toxicity; levodopa is not toxic to normal rodents, nonhuman primates, or humans and is not toxic to dopamine neurons in dopamine-lesioned rodents or nonhuman primates in most studies. However, the potential for levodopa to be toxic in vivo has not been tested under conditions of oxidative stress such as exist in PD. To assess whether levodopa is toxic under these circumstances, we have examined the effects of levodopa on dopamine neurons in mesencephalic cultures and rat pups in which glutathione synthesis has been inhibited by L-buthionine sulfoximine. Levodopa toxicity to cultured dopaminergic neurons was enhanced by glutathione depletion and diminished by antioxidants. In contrast, treatment of neonatal rats with levodopa, administered either alone or in combination with glutathione depletion, did not cause damage to the dopamine neurons of the substantia nigra or changes in striatal levels of dopamine and its metabolites. This study provides further evidence to support the notion that although levodopa can be toxic to dopamine neurons in vitro, it is not likely to be toxic to dopamine neurons in vivo and specifically in conditions such as PD.