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Melatonin and its brain metabolite N 1 ‐acetyl‐5‐methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice
Author(s) -
Tapias Víctor,
Escames Germaine,
López Luis C.,
López Ana,
Camacho Encarnación,
Carrión María D.,
Entrena Antonio,
Gallo Miguel A.,
Espinosa Antonio,
AcuñaCastroviejo Darío
Publication year - 2009
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22123
Subject(s) - mptp , nitric oxide synthase , oxidative stress , melatonin , mitochondrion , nitric oxide , substantia nigra , metabolite , biology , neuroprotection , chemistry , biochemistry , microbiology and biotechnology , pharmacology , endocrinology , dopamine , dopaminergic
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. © 2009 Wiley‐Liss, Inc.