Protective effect of harmaline and harmalol against dopamine- and 6-hydroxydopamine-induced oxidative damage of brain mitochondria and synaptosomes, and viability loss of PC12 cells

The present study elucidated the protective effect of beta -carbolines (har maline, harmalol and harmine) against oxidative damage of brain mitochondri a, synaptosomes and PC12 cells induced by either dopamine or 6-hydroxydopam ine. Harmaline, harmalol and antioxidant enzymes (superoxide dismutase/SOD and catalase) decreased the alteration of mitochondrial swelling and membra ne potential induced by 200 mum dopamine or 100 mum 6-hydroxydopamine. Depr enyl attenuated the dopamine-induced mitochondrial dysfunction but did not reduce the effect of 6-hydroxydopamine. While beta -carbolines inhibited th e electron flow in mitochondria, they did not enhance the depressant effect of catecholamines. beta -Carbolines and antioxidant enzymes reversed the d epression of synaptosomal Ca2+ uptake induced by 10 mum catecholamines. The compounds inhibited the catecholamine-induced thioredoxin reductase inhibi tion, thiol oxidation and carbonyl formation in mitochondria and synaptosom es. beta -Carbolines decreased the reactive species-induced deoxyribose deg radation. Harmaline and harmalol reduced the catecholamine-induced loss of the transmembrane potential and of cell viability in PC12 cells. beta -Carb olines alone did not show a significant cytotoxic effect on PC12 cells. The results suggest that beta -carbolines may attenuate the dopamine- or 6-hyd roxydopamine-induced alteration of brain mitochondrial and synaptosomal fun ctions, and viability loss in PC12 cells, by a scavenging action on reactiv e oxygen species and inhibition of thiol oxidation.