Melatonin and its brain metabolite N(1)-acetyl-5-methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice.
Melatonin prevents mitochondrial failure in models of sepsis through its ability to inhibit the expression and activity of both cytosolic (iNOS) and mitochondrial (i-mtNOS) inducible nitric oxide synthases. Because Parkinson's disease (PD), like sepsis, is associated with iNOS induction, we assessed the existence of changes in iNOS/i-mtNOS and their relation with mitochondrial dysfunction in the MPTP model of PD, which also displays increased iNOS expression. We also evaluated the role of melatonin (aMT) and its brain metabolite, N(1)-acetyl-5-methoxykynuramine (AMK), in preventing i-mtNOS induction and mitochondrial failure in this model of PD. Mitochondria from substantia nigra (SN) and, to a lesser extent, from striatum (ST) showed a significant increase in i-mtNOS activity, nitrite levels, oxidative stress, and complex I inhibition after MPTP treatment. MPTP-induced i-mtNOS was probably related to mitochondrial failure, because its prevention by aMT and AMK reduced oxidative/nitrosative stress and restored complex I activity. These findings represent the first experimental evidence of a potential role for i-mtNOS in the mitochondrial failure of PD and support a novel mechanism in the neuroprotective effects of aMT and AMK.
Centro de Investigación Biomédica, Instituto de Biotecnología, Universidad de Granada, Granada, Spain.
Víctor
V
Tapias
Germaine
G
Escames
Luis C
LC
López
Ana
A
López
Encarnación
E
Camacho
María D
MD
Carrión
Antonio
A
Entrena
Miguel A
MA
Gallo
Antonio
A
Espinosa
Darío
D
Acuña-Castroviejo
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D042967:Electron Transport Complex I / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D007735:Kynuramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects* / Q000201:enzymology
D024101:Mitochondrial Proteins; D009573:Nitrites; D007735:Kynuramine; C032131:N-acetyl-5-methoxy kynurenamine; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; D042967:Electron Transport Complex I; D008550:Melatonin; D002118:Calcium