Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson's disease.

Abstract

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 ,uM) 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 drugtype 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. (J. Clin. Invest. 1995Invest. . 95:2458Invest. -2464

The role of apoptosis in the pathogenesis and treatment of diseases

“…Excessive toxicity of some treatments could also involve induction of apoptosis; toxicity of L-DOPA for the treatment of Parkinson's disease was recently related to the induction of apoptosis in target cells, suggesting that modulation of this phenomenon could prevent the acceleration of neuronal damage in this disease [109].…”

Neuroprotective Effects of Herbal Butanol Extracts from Gynostemma pentaphyllum on the Exposure to Chronic Stress in a 6-Hydroxydopamine- Lesioned Rat Model of Parkinson's Disease Treated with or Without L-DOPA

“…L-DOPA treatment in MPTP-induced PD rodents increased the striatal 6-OHDA levels, which may be sensitized by monoamine oxidase inhibitor (Borah & Mohanakumar, 2010). Long-term treatment with L-DOPA caused disabling motor side effects in PD and alleviated oxidative stress-induced neurotoxicity by ROS formation against striatal dopaminergic neurons and PC12 cells (Basma et al, 1995;Walkinshaw & Waters, 1995;Migheli et al, 1999). Subchronic or chronic L-DOPA treatment resulted in increased levels of dopamine and hydroxyl-free radicals in the striatum (Pandey et al, 2009).…”

Apoptosis and Autoimmune Disorders

“…These include acquired immunodeficiency syndrome (AIDS; Ameison & Capron, 1991), cancer (Ling et al, 1993), Parkinson's disease (Walkinshaw & Waters, 1995), and Alzheimer's disease (Landfield et al, 1992). Abnormally elevated levels of apoptosis have been found in the lymph nodes of HIV-infected persons (Muro-Cacho et al, 1995).…”