DEPRENYL AND DESMETHYLSELEGILINE PROTECT MESENCEPHALIC NEURONS FROM TOXICITY INDUCED BY GLUTATHIONE DEPLETION

Oxidative stress is thought to play an important role in the pathogene sis of Parkinson's disease (PD). Glutathione (GSH), a major cellular a ntioxidant, is decreased in the substantia nigra pars compacta of PD p atients. The aim oi the present study was to investigate whether depre nyl and its desmethyl metabolite, putative neuroprotective agents in t he treatment of PD, could protect cultured rat mesencephalic neurons f rom cell death caused by GSH depletion due to treatment with L-buthion ine-(S,R)-sulfoximine (BSO). BSO (10 mu M) caused extensive cell death after 48 hr, as demonstrated by disruption of cellular integrity and release of lactate dehydrogenase into the culture medium, Both depreny l and desmethylselegiline, at concentrations of 5 and 50 mu M, signifi cantly protected dopaminergic neurons from toxicity without preventing the BSO-induced loss in GSH. Protection was not associated with monoa mine oxidase type B inhibition in that pargyline, a potent MAO inhibit or, was ineffective and pretreatment with pargyline did not prevent th e protective effects of deprenyl, Protection was not associated with i nhibition of dopamine uptake by deprenyl because the dopamine uptake i nhibitor mazindol did not diminish BSO toxicity, The antioxidant ascor bic acid (200 mu M) also protected against BSO-induced cell death, sug gesting that oxidative events were involved. This study demonstrates t hat deprenyl and its desmethyl metabolite can diminish cell death asso ciated with GSH depletion.