Leads for the development of neuroprotective treatment in Parkinson's disease and brain imaging methods for estimating treatment efficacy

Patients suffering from Parkinson's disease display severe and progressive deficits in motor behavior, predominantly as a consequence of the degenerat ion of dopaminergic neurons, located in the mesencephalon and projecting to striatal regions. The cause of Parkinson's disease is still an enigma. Con sequently, the pharmacotherapy of Parkinson's disease consists of symptomat ic treatment, with in particular L-dihydroxyphenylalanine (L-DOPA) and/or d opamine receptor agonists. These induce a dramatic initial improvement. How ever, serious problems gradually develop during long-term treatment. Theref ore, a more rational, c.q. causal treatment is needed which requires the in troduction of compounds ameliorating the disease process itself. The develo pment of such compounds necessitates (1) more information on the etiopathog enesis, i.e., the cascade of events that ultimately leads to degeneration o f the dopaminergic neurons, and (2) brain imaging methods, to estimate the extent of the degeneration of the dopaminergic neurons in the living patien t. This is not only important for the early diagnosis, but will also allow to monitor the effectiveness of alleged neuroprotective compounds on a long itudinal base. In this paper, etiopathogenic mechanisms are highlighted alo ng the line of the oxidative stress hypothesis and within this framework, a ttention is mainly focused on the putative role of glutathione, dopamine au to-oxidation and phase II biotransformation enzymes. Especially, drugs able to increase the activity of phase II biotransformation enzymes seem to eli cit a broad-spectrum (neuro)protective response and look very promising lea ds for the development of neuroprotective treatment strategies in Parkinson 's disease. New developments in brain imaging methods (single photon emissi on computed tomography (SPECT) and positron emission tomography (PET)) to v isualize the integrity of the striatal dopaminergic neurons in humans are h ighlighted as well. Especially, the introduction of radioligands that bind selectively to the dopamine transporter seems to be a significant step forw ard for the early diagnosis of Parkinson's disease. Performing these brain imaging studies with fixed time intervals does not only create the possibil ity to follow the degeneration rate of the dopaminergic neurons in Parkinso n's disease but also provides the opportunity to estimate therapeutic effec ts of putative neuroprotective agents in the individual patient. (C) 1999 E lsevier Science B.V. All rights reserved.