L-dopa was the first drug approved for treatment of PD, acting to restore decreased DA levels as a result of the loss of dopaminergic neurons. This DA precursor acts locally using remaining DA neurons to synthesize DA. Peripheral metabolism of L-dopa is prevented by peripheral decarboxylase inhibitors like carbidopa. L-Dopa treatment has a number of limitations: (1) efficacy is dependent on DA neurons; as these die as a result of disease progression, L-dopa becomes less effective; and (2) L-dopa may potentiate DA neurotoxicity. DA and/or its metabolites are toxic to neurons both in vitro and in vivo, an effect that occurs via inhibition of oxidative phosphorylation, generation of reactive oxygen species, or via direct DA receptor interactions. A randomized, placebo-controlled trial ELLDOPA (earlier versus later levodopa therapy in PD) examined both the neurotoxic and the disease-modifying potential of L-dopa.71 A dose-dependent reduction in the worsening of symptoms for patients on L-dopa with no evidence of any acceleration in the rate of clinical decline was observed, suggesting a neuroprotective effect.
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