title: Melatonin influences NO/NOS pathway and reduces oxidative and nitrosative stress in a model of hypoxic-ischemic brain damage.
abstract: In this work, using a rat model combining ischemia and hypobaric hypoxia (IH), we evaluate the relationships between the antioxidant melatonin and the cerebral nitric oxide/nitric oxide synthase (NO/NOS) system seeking to ascertain whether melatonin exerts its antioxidant protective action by balancing this key pathway, which is highly involved in the cerebral oxidative and nitrosative damage underlying these pathologies. The application of the IH model increases the expression of the three nitric oxide synthase (NOS) isoforms, as well as nitrogen oxide (NOx) levels and nitrotyrosine (n-Tyr) impacts on the cerebral cortex. However, melatonin administration before IH makes nNOS expression response earlier and stronger, but diminishes iNOS and n-Tyr expression, while both eNOS and NOx remain unchanged. These results were corroborated by nicotine adenine dinucleotide phosphate diaphorase (NADPH-d) staining, as indicative of in situ NOS activity. In addition, the rats previously treated with melatonin exhibited a reduction in the oxidative impact evaluated by thiobarbituric acid reactive substances (TBARS). Finally, IH also intensified glial fibrillary acidic protein (GFAP) expression, reduced hypoxia-inducible factor-1alpha (HIF-1α), but did not change nuclear factor kappa B (NF-κB); meanwhile, melatonin did not significantly affect any of these patterns after the application of the IH model. The antioxidant melatonin acts on the NO/NOS system after IH injury balancing the release of NO, reducing peroxynitrite formation and protecting from nitrosative/oxidative damage. In addition, this paper raises questions concerning the classical role of some controversial molecules such as NO, which are of great consequence in the final fate of hypoxic neurons. We conclude that melatonin protects the brain from hypoxic/ischemic-derived damage in the first steps of the ischemic cascade, influencing the NO/NOS pathway and reducing oxidative and nitrosative stress.
authors.affiliation: Area of Cell Biology, Department of Experimental Biology, University of Jaén, Campus Las Lagunillas s/n, 23071, Jaén, Spain. Electronic address: sblanco@ujaen.es.
authors.forename: Santos
authors.initials: S
authors.lastname: Blanco
authors.affiliation: Area of Cell Biology, Department of Experimental Biology, University of Jaén, Campus Las Lagunillas s/n, 23071, Jaén, Spain. Electronic address: rhernand@ujaen.es.
authors.forename: Raquel
authors.initials: R
authors.lastname: Hernández
authors.affiliation: Area of Cell Biology, Department of Experimental Biology, University of Jaén, Campus Las Lagunillas s/n, 23071, Jaén, Spain. Electronic address: r6.gustavo@gmail.com.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Franchelli
authors.affiliation: Area of Methodology of the Behavioural Sciences, Department of Psychology, University of Jaén, Campus Las Lagunillas s/n, 23071, Jaén, Spain. Electronic address: mramos@ujaen.es.
authors.forename: Manuel Miguel
authors.initials: MM
authors.lastname: Ramos-Álvarez
authors.affiliation: Area of Cell Biology, Department of Experimental Biology, University of Jaén, Campus Las Lagunillas s/n, 23071, Jaén, Spain. Electronic address: apeinado@ujaen.es.
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Peinado
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D000073039:Nitrosative Stress / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009252:NADPH Dehydrogenase; D008550:Melatonin
keywords: Antioxidant: oxidative and nitrosative stress; Hypobaric hypoxia; Ischemia; Melatonin; Nitric oxide