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 (harmaline, harmalol and harmine) against oxidative damage of brain mitochondria, synaptosomes and PC12 cells induced by either dopamine or 6-hydroxydopamine. Harmaline, harmalol and antioxidant enzymes (superoxide dismutase/SOD and catalase) decreased the alteration of mitochondrial swelling and membrane potential induced by 200 microM dopamine or 100 microM 6-hydroxydopamine. Deprenyl attenuated the dopamine-induced mitochondrial dysfunction but did not reduce the effect of 6-hydroxydopamine. While beta-carbolines inhibited the electron flow in mitochondria, they did not enhance the depressant effect of catecholamines. beta-Carbolines and antioxidant enzymes reversed the depression of synaptosomal Ca2+ uptake induced by 10 microM catecholamines. The compounds inhibited the catecholamine-induced thioredoxin reductase inhibition, thiol oxidation and carbonyl formation in mitochondria and synaptosomes. beta-Carbolines decreased the reactive species-induced deoxyribose degradation. Harmaline and harmalol reduced the catecholamine-induced loss of the transmembrane potential and of cell viability in PC12 cells. beta-Carbolines alone did not show a significant cytotoxic effect on PC12 cells. The results suggest that beta-carbolines may attenuate the dopamine- or 6-hydroxydopamine-induced alteration of brain mitochondrial and synaptosomal functions, and viability loss in PC12 cells, by a scavenging action on reactive oxygen species and inhibition of thiol oxidation.
Kim
D H
DH
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Korea.
Jang
Y Y
YY
Han
E S
ES
Lee
C S
CS
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003855:Deoxyribose / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology*; D006246:Harmaline / Q000031:analogs & derivatives / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D016627:Oxidopamine / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects / Q000502:physiology; D010539:Permeability / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000473:pathology; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism
D018696:Neuroprotective Agents; D011506:Proteins; D013438:Sulfhydryl Compounds; C007904:harmalol; D003855:Deoxyribose; D016627:Oxidopamine; D006246:Harmaline; D013880:Thioredoxin-Disulfide Reductase; D002118:Calcium; D004298:Dopamine