Catechol-O-methyltransferase inhibition attenuates levodopa toxicity in mesencephalic dopamine neurons

Inhibition of catechol-O-methyltransferase (COMT; EC 2.1.1.6) is a new ther apeutic strategy in the treatment of Parkinson's disease. However, nothing is known about the effects of COMT inhibition on levodopa (L-dopa)-induced toxicity in dopamine (DA) neurons. Therefore we evaluated the effects of th e selective COMT inhibitors Ro 41-0960, OR-486, and tolcapone alone and in combination with L-dopa in primary mesencephalic cultures from rat. Neither COMT inhibitor affected the growth of tyrosine hydroxylase immunoreactive (THir) cells with concentrations up to 10 mu M when studied alone. However, Ro 41-0960 reduced the L-dopa-induced THir cell loss after 24 h in a dose- dependent manner, shifting the TD50 value from 21 mu M in the absence to 71 mu M in the presence of 1 mu M Ro 41-0960 (P < .01) without affecting surv ival of non-DA neurons. OR-486 and the clinically used COMT inhibitor tolca pone showed similar effects. In contrast, toxicity induced by D-dopa was no t altered by COMT inhibitors. Furthermore, the primary metabolite of L-dopa formed by COMT, 3-O-methyldopa, and the methyl group donor S-adenosyl-L-me thionine used by COMT did not alter THir neuron survival and L-dopa-induced toxicity, respectively, with concentrations up to 100 mu M. These data dem onstrate that COMT inhibition attenuates L-dopa toxicity toward DA neurons in vitro, but probably not by preventing 3-O-methyldopa production or cellu lar S-adenosyl-L-methionine depletion.