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

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.

A(1) and A(3) adenosine receptors alter glutathione status in an organ-specific manner and influence the changes after inhibition of gamma-glutamylcysteine ligase.

Adenosine levels are increased in stress and act as anti-oxidant and anti-inflammatory mediators by binding to 4 G-protein-coupled receptors. Using genetically modified mice lacking A(1) and A(3) adenosine receptors, treated with ip buthionine-[S,R]-sulphoximine injections to inhibit gamma-glutamylcysteine ligase, the question was addressed whether these receptors modulate the responses to the stress related to altered glutathione levels. This study determined organ glutathione levels and expression of two sub-units of gamma-glutamylcysteine ligase and the cationic x(c)-transporter and found that deletion of one or both adenosine receptors influenced the responses in an organ-specific manner. The lack of A(1) and A(3) adenosine receptors is related to decreased basal glutathione content and down-regulation of gamma-glutamylcysteine ligase sub-units in several organs. Moreover, responses to buthionine-[S,R]-sulphoximine were different. For example, the lack of A(3) adenosine receptors, or their blockade of A(3) by MRS 1191, caused a marked increase in gene expression, which was not observed in mice lacking both A(1) and A(3) receptors. The results indicate that A(1) and A(3) adenosine receptors play a role in antioxidant responses and their role differs in an organ-specific way.