Melatonin inhibits 6-hydroxydopamine production in the brain to protect against experimental parkinsonism in rodents.
We tested the hypothesis that melatonin regulates formation of 6-hydroxydopamine (6-OHDA) in the brain and thereby protects animals from dopaminergic neurotoxicity and the development of parkinsonism in animals. Employing a ferrous-ascorbate-dopamine (FAD) hydroxyl radical ((*)OH) generating system, in the present study we demonstrate a dose-dependent attenuation of 6-OHDA generation by melatonin in vitro. Intra-median forebrain bundle infusion of FAD caused significant depletion of striatal dopamine (DA), which was blocked by melatonin. Per-oral administration of l-3,4-dihydroxyphenylalanine (L-DOPA) for 7 days caused a dose-dependent increase in the formation of 6-OHDA in the mouse striatum, which was increased synergistically by the systemic administration of the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the 7th day of L-DOPA treatment. Melatonin treatment significantly attenuated both the L-DOPA and MPTP-induced increases in the levels of striatal 6-OHDA, and protected against striatal DA depletion caused by the neurotoxin. These observations suggest a novel mode of melatonin-induced dopaminergic neuroprotection in two models of Parkinson's disease, and suggest the possible therapeutic use of this well-known antioxidant indoleamine neurohormone in parkinsonism.
Division of Cell Biology and Physiology, Laboratory of Clinical & Experimental Neuroscience, Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
Anupom
A
Borah
Kochupurackal P
KP
Mohanakumar
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D005296:Ferrous Compounds / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016627:Oxidopamine / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000517:prevention & control*
D002492:Central Nervous System Depressants; D015259:Dopamine Agents; D005296:Ferrous Compounds; C051140:iron(II)-ascorbic acid complex; D007980:Levodopa; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008550:Melatonin; D001205:Ascorbic Acid; D004298:Dopamine