Protective effect of harmalol and harmaline on MPTP neurotoxicity in the mouse and dopamine-induced damage of brain mitochondria and PC12 cells.
The present study elucidated the protective effect of beta-carbolines (harmaline, harmalol, and harmine) on oxidative neuronal damage. MPTP treatment increased activities of total superoxide dismutase, catalase, and glutathione peroxidase and levels of malondialdehyde and carbonyls in the basal ganglia, diencephalon plus midbrain of brain compared with control mouse brain. Coadministration of harmalol (48 mg/kg) attenuated the MPTP effect on the enzyme activities and formation of tissue peroxidation products. Harmaline, harmalol, and harmine attenuated both the 500 microM MPP(+)-induced inhibition of electron flow and membrane potential formation and the 100 microM dopamine-induced thiol oxidation and carbonyl formation in mitochondria. The scavenging action of beta-carbolines on hydroxyl radicals was represented by inhibition of 2-deoxy-D-ribose degradation. Harmaline and harmalol (100 microM) attenuated 200 microM dopamine-induced viability loss in PC12 cells. The beta-carbolines (50 microM) attenuated 50 microM dopamine-induced apoptosis in PC12 cells. The compounds alone did not exhibit significant cytotoxic effects. The results indicate that beta-carbolines attenuate brain damage in mice treated with MPTP and MPP(+)-induced mitochondrial damage. The compounds may prevent dopamine-induced mitochondrial damage and PC12 cell death through a scavenging action on reactive oxygen species and inhibition of monoamine oxidase and thiol oxidation.
Lee
C S
CS
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Korea. Department of Neurology, Korean Veterans Hospital, Seoul, Korea. leecs@cau.ac.kr
Han
E S
ES
Jang
Y Y
YY
Han
J H
JH
Ha
H W
HW
Kim
D E
DE
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology* / Q000633:toxicity; D004579:Electron Transport / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D006246:Harmaline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D015227:Lipid Peroxidation / Q000187:drug effects; D020267:MPTP Poisoning / Q000517:prevention & control*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents; D016716:PC12 Cells; D051381:Rats
D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; C007904:harmalol; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006246:Harmaline; D004298:Dopamine