Neuroprotection for Parkinson's disease: a new approach for a new millennium

Parkinson's disease (PD) is the only neurodegenerative disorder in which ph armacological intervention has resulted in a marked decrease in morbidity a nd a significant delay in mortality. However, the medium to long-term effic acy of this pharmacotherapy, mainly consisting of dopaminomi-metics like L- dopa and dopamine receptor agonists, suffers greatly from the unrelenting p rogression of the disease process underlying PD, i.e., the degeneration of neuromelanin-containing, dopaminergic neurones in the substantia nigra. Eff orts concentrated on understanding the mechanisms of dopaminergic cell deat h in Parkinson's disease have led to identification of a large variety of p athogenetic factors, including excessive release of oxygen free radicals du ring enzymatic dopamine breakdown, impairment of mitochondrial function, pr oduction of inflammatory mediators, loss of trophic support, and apoptosis. Therapeutic approaches aimed at correcting these abnormalities are current ly being evaluated on their efficacy as neuroprotectants for PD. Here, we f ocus on the process of dopamine auto-oxidation, the chain of reactions lead ing to the formation of neuromelanin, as an often overlooked, yet obvious p athogenetic factor. In particular, we discuss the option of drug-mediated s timulation of endogenous mechanisms responsible for the detoxification of d opamine auto-oxidation products as a novel means of neuroprotection in Park inson's disease.