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 radicals, semiquinones, and quinones and thus exert its neurotoxic effects. Intracerebroventricular injection of dopamine into rats pretreated with the monoamine oxidase nonselective inhibitor pargyline caused mortality in a dose-dependent manner with LD50 = 90 micrograms. Norepinephrine was less effective with LD50 = 141 micrograms. The iron chelator desferrioxamine completely protected against dopamine-induced mortality. In the absence of pargyline more rats survived, indicating that the products of dopamine enzymatic metabolism are not the main contributors to dopamine-induced toxicity. Biochemical analysis of frontal cortex and striatum 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 significantly 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 dehydrogenase activity with IC50 = 8 microM, and that of norepinephrine was twice as much (IC50 = 15 microM). Dopamine-induced inhibition of NADH dehydrogenase activity was only partially reversed by desferrioxamine, which had no effect on norepinephrine-induced inhibition. These results suggest that catecholamines can cause toxicity not only by inducing an oxidative stress state but also possibly through direct interaction with the mitochondrial electron transport system. The latter was further supported by the ability of ADP to reverse dopamine-induced inhibition of NADH dehydrogenase activity in a dose-dependent manner.
Ben-Shachar
D
D
Department of Psychiatry-Rambam Medicine Center, Haifa, Israel.
Zuk
R
R
Glinka
Y
Y
D000818:Animals; D004298:Dopamine / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000378:metabolism; D016019:Survival Analysis
D009498:Neurotoxins; D009245:NADH Dehydrogenase; D010100:Oxygen; D004298:Dopamine; D009638:Norepinephrine