Levodopa in Parkinson's disease - Neurotoxicity issue laid to rest?

Orally administered levodopa remains the most effective symptomatic treatme nt for Parkinson's disease. The introduction of levodopa therapy is often d elayed, however, because of the fear that it might be toxic for the remaini ng dopaminergic neurons, and thus accelerate the deterioration of the patie nt's condition. Evidence for levodopa toxicity comes mainly from in vitro studies which hav e demonstrated that levodopa can damage dopaminergic neurons by a mechanism that probably involves oxidative stress. It is widely accepted, however, t hat levodopa is not toxic for healthy animals and humans who do not have Pa rkinson's disease. It has been argued that the lesioned mesostriatal dopami nergic system could be more vulnerable to levodopa-induced toxicity, becaus e the brain extracellular concentrations attained by levodopa are higher wh en the dopaminergic system is damaged, and remaining dopaminergic neurons e xperience a process of compensatory hyperactivity. Evidence for in vivo levodopa toxicity in animal models of Parkinson's dise ase is scarce and contradictory. A comprehensive recent study failed to fin d any evidence of levodopa toxicity in rats with either moderate or severe lesions of the mesostriatal dopaminergic system. Concerning the hypothesis of toxicity, some recent reports have shown that levodopa can have trophic effects on dopaminergic neurons in vitro, and our own work has shown that long term levodopa therapy promotes recovery of st riatal dopaminergic markers in rats with moderate nigrostriatal lesions. Gi ven that neither epidemiological nor clinical studies have ever provided ev idence to support that long term levodopa administration can accelerate the progression nf Parkin-disease, we believe that levodopa therapy should not be delayed on the basis of an unconfirmed hypothesis.