Drug treatment of Parkinson's disease - Time for phase II

Parkinson's disease (PD) is a neurodegenerative syndrome for which at prese nt no cure is available; therapy consists mainly of amelioration of the sym ptoms with L-Dopa and/or dopamine (DA) agonists. Development of an effectiv e causal therapy should be focussed on preventing or at lease retarding the neurodegenerative process underlying the disease. At the cellular level, P D is characterized by degeneration of neuromelanin-containing dopaminergic neurons in the substantia nigra. Neuromelanin formation is the outcome of a process generally known as DA autooxidation, a chain of oxidation reaction s in which highly neurotoxic DA-quinones are produced. The level of these D A-quinones, as estimated by the occurrence of their cysteinyl conjugates, i s reported to be increased in the Parkinsonian substantia nigra. Hence, sti mulation of pathways implicated in the detoxication of DA-quinones in the b rain may provide neuroprotection in PD. Besides their inactivation through non-enzymatic antioxidants such as ascorbic acid and glutathione, DA-quinon es are efficiently inactivated enzymatically by NAD(P)H:quinone oxidoreduct ase (NQO) and glutathione one transferase(s), both of which are expressed i n the human substantia nigra. The activity of these enzymes, which belong t o the group of phase II biotransformation enzymes, can he up-regulated by a large variety of compounds. These compounds, including dithiolethiones, ph enolic anti-oxidants, and isothiocyanates, have been shown to be active bot h in vitro and in vivo. Thus, considering the role of phase II biotransform ation enzymes, in particular NQO and glutathione transferase(s), in the det oxication of DA-quinones, we propose that phase II enzyme inducers warrant evaluation on their neuroprotective potential in PD. (C) 2000 Elsevier Scie nce Inc.