Levodopa: effect on cell death and the natural history of Parkinson's disease

This review article considers the question of whether or not levodopa is toxic in Parkinson's disease (PD). l-dopa is the most effective symptomatic treatment for PD and has provided benefit for millions of patients. However, there has been a longstanding concern that l-dopa might be toxic and accelerate neuronal degeneration and clinical progression as a consequence of reactive oxygen species generated by the drug's oxidative metabolism. In vitro, l-dopa can induce degeneration of dopaminergic neurons, but it is not clear that the effects of the drug on cultured dopamine neurons reflect what happens in the PD brain. In vivo, l-dopa has not been demonstrated to have toxic effects on dopamine neurons in normal, dopamine-lesioned, or oxidatively stressed animal models, but none of these models precisely replicates the PD condition. Clinical trials have tested the effect of l-dopa on clinical progression and have not demonstrated any findings indicative of toxicity. However, the symptomatic and long-duration effects of the drug could mask ongoing neuronal degeneration. Furthermore, l-dopa induces a greater decline in imaging measures of dopaminergic function than placebo or dopamine agonists, consistent with toxicity. Pathological studies have not demonstrated evidence of accelerated loss of dopamine neurons, but prospective and properly controlled studies with stereological unbiased counting have not been performed. Thus, although there is no hard evidence to suggest that l-dopa is toxic in PD patients, the issue has not been fully resolved. It is generally recommended that physicians continue to use l-dopa, but in the lowest dose that provides satisfactory clinical control.