Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion.
Previous studies showed a synergistic effect of melatonin and deprenyl against dopamine (DA) autoxidation in vitro. Since oxidative stress is implicated in Parkinson's disease (PD), we explored the effects of melatonin plus deprenyl administration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in C57/Bl6 mice. Melatonin, but not deprenyl prevents the inhibition of mitochondrial complex I and the oxidative damage in nigrostriatal neurons induced by MPTP. With the dose used deprenyl recovers 50% DA levels and tyrosine hydroxylase activity depressed by the neurotoxin, normalizing locomotor activity of mice. Melatonin, which was unable to counteract MPTP-induced DA depletion and inhibition of tyrosine hydroxylase activity, potentiates the effect of deprenyl on catecholamine turnover and mice ambulatory activity. These results suggest a dissociation of complex I inhibition from DA depletion in this model of Parkinson's disease. The data also support that a combination of melatonin, which improves mitochondrial electron transport chain and reduces oxidative damage, and deprenyl, which promotes the specific function of the rescued neurons, i.e. DA turnover, may be a promising strategy for the treatment of PD.
Khaldy
Hoda
H
Departamento de Fisiologi;a, Facultad de Medicina, Instituto de Biotecnologi;a, Universidad de Granada, Avenida de Madrid 11, E-18012, Granada, Spain
Escames
Germaine
G
León
Josefa
J
Bikjdaouene
Leila
L
Acuña-Castroviejo
Darío
D
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004298:Dopamine / Q000172:deficiency; D004357:Drug Synergism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D020267:MPTP Poisoning / Q000188:drug therapy*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012642:Selegiline / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects
D000975:Antioxidants; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D012642:Selegiline; D014446:Tyrosine 3-Monooxygenase; D008550:Melatonin; D004298:Dopamine