Levodopa toxicity and apoptosis.

Many in vitro studies have shown that levodopa is a potent toxin which is lethal to various cultured neuronal and non-neuronal cells. The in vitro toxicity of levodopa is linked mainly to its auto-oxidation, which generates a variety of harmful free radical species including superoxide, hydrogen peroxide, and hydroxyl radicals, and also semiquinones and quinones produced via the dopa-melanin metabolic route. Such toxic effects of levodopa can be blocked by co-treatment with antioxidants, particularly thiol-containing compounds. Several studies have shown that levodopa kills cells by triggering apoptosis, an active, intrinsic cell suicide program. Exposure of cultured neurons to levodopa induced the characteristic apoptotic cascade, including cell shrinkage, membrane blebbing, and nuclear and DNA fragmentation. Although levodopa is extremely toxic in vitro, there is no evidence that it damages nigrostriatal dopaminergic neurons in vivo in experimental animals and in patients with Parkinson's disease (PD). Likewise, although there is some evidence for the occurrence of apoptosis in the parkinsonian substantia nigra, it is not known whether levodopa administration is capable of inducing or accelerating programmed cell death of residual pigmented nigral neurons in PD.