METABOLIC INHIBITION ENHANCES SELECTIVE TOXICITY OF L-DOPA TOWARD MESENCEPHALIC DOPAMINE NEURONS IN-VITRO

Recent in vitro studies have described the toxicity of levodopa (L-DOP A) to dopamine (DA) neurons. We investigated whether metabolic inhibit ion with rotenone, an inhibitor of complex I of the mitochondrial resp iratory chain, may enhance the toxicity of L-DOPA toward DA neurons in mesencephalic cultures. The uptakes of DA and GABA were determined to evaluate the functional and morphological integrity of DA and non-DA neurons, respectively. Pretreatment with rotenone significantly augmen ted the toxic effect of L-DOPA on DA neurons. Interestingly, prior met abolic inhibition with rotenone rendered DA cells susceptible to a dos e (5 mu M) of L-DOPA that otherwise exhibited no toxic effect. DA upta ke was more intensely attenuated than GABA uptake after the combined e xposure to rotenone and L-DOPA. This was confirmed by cell survival es timation showing that tyrosine hydroxylase-positive DA cells are more vulnerable to the sequential exposure to the drugs than total cells. T he selective toxic effect of L-DOPA on rotenone-pretreated DA neurons was significantly blocked by antioxidants, but not antagonists of NMDA or non-NMDA glutamate receptors. This indicates that oxidative stress play a central role in mediating the selective damage of DA cells in the present experimental paradigm. Our results raise the possibility t hat long-term L-DOPA treatment could accelerate the progression of deg eneration of DA neurons in patients with Parkinson's disease where pot ential energy failure due to mitochondrial defects has been demonstrat ed to take place. (C) 1997 Elsevier Science B.V.