Levodopa neurotoxicity: experimental studies versus clinical relevance

Levodopa therapy remains the major form of treatment for the symptoms of Parkinson's disease (PD). However, there has been a suspicion that its use may hasten the progression of nigral cell degeneration. This concept is based on the ability of levodopa to generate reactive oxygen species and the apparent involvement of oxidative stress as a component of the degenerative process that occurs in PD. Indeed, in vitro autoxidation of levodopa causes oxidative stress, leading to neuronal destruction by necrosis or apoptosis. However, its chronic administration to normal rats or primates has not been associated with clear evidence for destruction of the nigrostriatal pathway. In contrast, in situations in which the nigrostriatal tract is already damaged, there is some evidence to suggest that levodopa treatment can produce further cell destruction associated with oxidative processes. However, levodopa does not appear to be toxic to the development of fetal nigral neurons or to the survival of fetal cell transplants. There is no clinical evidence to suggest that levodopa has adverse effects on dopamine cells in normal humans or on the viability of remaining dopaminergic cells in patients with PD. However, it is only now that specific clinical trials designed to examine the potential neurotoxicity of levodopa are being undertaken.