Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson's disease.
The hypothesis that L-DOPA therapy in Parkinson's disease may augment neuronal damage and thus accelerate the progression of the disease remains controversial. In this study, we demonstrate that L-DOPA induces death of catecholaminergic cells in vitro via an active program of apoptosis. Treatment of PC12 cells with clinically applicable concentrations of L-DOPA (25-100 microM) induced cell death via a mechanism which exhibited morphological and biochemical characteristics of apoptosis, including chromatin condensation, membrane blebbing, and internucleosomal DNA fragmentation. L-DOPA-induced apoptosis was cell and drug-type specific. Toxicity is an intrinsic property of the drug molecule since it was not suppressed by inhibiting conversion of L-DOPA to dopamine. However, L-DOPA toxicity was inhibited by antioxidants, suggesting that activation of apoptosis is mediated by oxygen radicals. Our finding that L-DOPA-induced cell death in vitro occurs via apoptosis explains the lack of evidence supporting its toxicity in vivo, since apoptotic neurons are rapidly phagocytosed in vivo without causing damage to surrounding tissue. Furthermore, since apoptosis is an active cellular program which can be modulated, we suggest clinical approaches for decreasing L-DOPA toxicity, thus preventing acceleration of neuronal damage in Parkinson's disease.
Walkinshaw
G
G
Physiology, Pharmacology, and Toxicology Group, School of Biological Sciences, University of Manchester, United Kingdom.
Waters
C M
CM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002395:Catecholamines / Q000502:physiology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000494:pharmacology*; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects*; D010300:Parkinson Disease / Q000628:therapy; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D002395:Catecholamines; D017382:Reactive Oxygen Species; D007980:Levodopa