N-acetyl-L-methionyl-L-Dopa-methyl ester as a dual acting drug that relieves L-Dopa-induced oxidative toxicity

Abstract

Initiation and progression of Parkinson's disease seem to be linked to oxidative stress, closely related to decreased mitochondrial functions and ubiquitin proteasome system dysfunction. To date, L-Dopa is the most effective medication , although long-term treatment can enhance oxidative stress and accelerate the degenerative process of residual cells. Therefore the inhibition of oxidation of L-Dopa/dopamine and the inhibition of reactive oxygen species formation are important strategies for neuroprotective therapy. Recently, several dual acting drugs, in which L-Dopa/dopamine are covalently linked to antioxidant molecules, were shown to induce sustained delivery of both L-Dopa/dopamine in rat plasma and striatum, suggesting that these compounds might be proposed as useful agents against Parkinson's disease. Here, by analyzing GSH levels and heme oxygenase-1 expression, we investigated in primary mesencephalic neuron cultures and in newborn mice the effects of the treatment with Ac-Met-LD-OMe. Moreover, by using proteasome inhibitor-treated mice as Parkinson's disease animal model, we demonstrated the beneficial effects of the systemic administration of this novel codrug.