DOPAMINE NEUROTOXICITY - INHIBITION OF MITOCHONDRIAL RESPIRATION

Dopamine, due to metabolism by monoamine oxidase or autoxidation, can generate toxic products such as hydrogen peroxide, oxygen-derived radi cals, semiquinones, and quinones and thus exert its neurotoxic effects . Intracerebroventricular injection of dopamine into rats pretreated w ith the monoamine oxidase nonselective inhibitor pargyline caused mort ality in a dose-dependent manner with LD(50) = 90 mu g. Norepinephrine was less effective with LD(50) = 141 mu g. The iron chelator desferri oxamine completely protected against dopamine-induced mortality. In th e absence of pargyline more rats survived, indicating that the product s of dopamine enzymatic metabolism are not the main contributors to do pamine-induced toxicity. Biochemical analysis of frontal cortex and st riatum from rats that received a lethal dose of dopamine did not show any difference from control rats in lipid and protein peroxidation and glutathione reductase and peroxidase activities. Moreover, dopamine s ignificantly reduced the formation of iron-induced malondialdehyde in vitro, thus suggesting that earlier events in cell damage are involved in dopamine toxicity. Indeed, dopamine inhibited mitochondrial NADH d ehydrogenase activity with IC50 = 8 mu M, and that of norepinephrine w as twice as much (IC50 = 15 mu M). Dopamine-induced inhibition of NADH dehydrogenase activity was only partially reversed by desferrioxamine , which had no effect on norepinephrine-induced inhibition. These resu lts suggest that catecholamines can cause toxicity not only by inducin g an oxidative stress state but also possibly through direct interacti on with the mitochondrial electron transport system. The latter was fu rther supported by the ability of ADP to reverse dopamine-induced inhi bition of NADH dehydrogenase activity in a dose-dependent manner.