COMPARISON OF NEUROTOXICITY FOLLOWING REPEATED ADMINISTRATION OF L-DOPA, D-DOPA, AND DOPAMINE TO EMBRYONIC MESENCEPHALIC DOPAMINE NEURONS IN CULTURES DERIVED FROM FISHER-344 AND SPRAGUE-DAWLEY DONORS

Levodopa is the most efficacious and widely used symptomatic drug for Parkinson's disease (PD), There is currently, however, a great deal of interest focused on the possibility that levodopa-induced increases i n dopamine (DA) turnover may increase oxidative damage derived from th e breakdown of DA, Increased oxidative damage following levodopa may c ontribute to the progressive degeneration of remaining host nigral neu rons as well as interfere with development and function of embryonic n igral neurons in neural grafting trials, There is abundant evidence th at levodopa is toxic to embryonic nigral DA neurons in both cell cultu re and neural grafting models, These findings have prompted a number o f studies on mechanisms of levodopa toxicity to identify effective mea ns of ameliorating potential oxidative stress related to levodopa in P D, In the current study we have utilized cultures of embryonic nigral DA neurons to address the fundamental question of whether levodopa-ind uced toxicity is related to DA production or whether dopa itself contr ibutes to cell death, We compared the degree of nigral DA cell death f ollowing chronic administration of: 1) levodopa (e.g.: l-dopa); 2) its less active stereoisomer d-dopa; and 3) DA, We examined the rank orde r of toxicity of these compounds in two species of rats, Fisher 344 (F 344) and Sprague-Dawley (SD), Results indicate a toxicity profile of: DA > l-dopa > > d-dopa, In addition, although there was no difference in response of F344 and SD cultures to I-dopa, the SD cultures were si gnificantly more susceptible to the neurotoxic effects of DA, Taken co llectively, these results suggest that levodopa-induced toxicity is re lated primarily to DA production rather than oxidation of dopa to toxi c metabolites, and that some strain related differences do exist. (C) 1997 Elsevier Science Inc.