PMID- 27940344 OWN - NLM STAT- MEDLINE DCOM- 20180410 LR - 20180410 IS - 1089-8611 (Electronic) IS - 1089-8603 (Linking) VI - 62 DP - 2017 Jan 30 TI - Melatonin influences NO/NOS pathway and reduces oxidative and nitrosative stress in a model of hypoxic-ischemic brain damage. PG - 32-43 LID - S1089-8603(16)30169-0 [pii] LID - 10.1016/j.niox.2016.12.001 [doi] AB - 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-1alpha), but did not change nuclear factor kappa B (NF-kappaB); 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. CI - Copyright (c) 2016 Elsevier Inc. All rights reserved. FAU - Blanco, Santos AU - Blanco S AD - Area of Cell Biology, Department of Experimental Biology, University of Jaen, Campus Las Lagunillas s/n, 23071, Jaen, Spain. Electronic address: sblanco@ujaen.es. FAU - Hernandez, Raquel AU - Hernandez R AD - Area of Cell Biology, Department of Experimental Biology, University of Jaen, Campus Las Lagunillas s/n, 23071, Jaen, Spain. Electronic address: rhernand@ujaen.es. FAU - Franchelli, Gustavo AU - Franchelli G AD - Area of Cell Biology, Department of Experimental Biology, University of Jaen, Campus Las Lagunillas s/n, 23071, Jaen, Spain. Electronic address: r6.gustavo@gmail.com. FAU - Ramos-Alvarez, Manuel Miguel AU - Ramos-Alvarez MM AD - Area of Methodology of the Behavioural Sciences, Department of Psychology, University of Jaen, Campus Las Lagunillas s/n, 23071, Jaen, Spain. Electronic address: mramos@ujaen.es. FAU - Peinado, Maria Angeles AU - Peinado MA AD - Area of Cell Biology, Department of Experimental Biology, University of Jaen, Campus Las Lagunillas s/n, 23071, Jaen, Spain. Electronic address: apeinado@ujaen.es. LA - eng PT - Journal Article DEP - 20161208 PL - United States TA - Nitric Oxide JT - Nitric oxide : biology and chemistry JID - 9709307 RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Hif1a protein, rat) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Reactive Oxygen Species) RN - 0 (Thiobarbituric Acid Reactive Substances) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type I) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 1.6.99.1 (NADPH Dehydrogenase) RN - JL5DK93RCL (Melatonin) SB - IM MH - Animals MH - Cerebral Cortex/metabolism MH - Glial Fibrillary Acidic Protein/metabolism MH - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism MH - Hypoxia-Ischemia, Brain/*metabolism MH - Male MH - Melatonin/*pharmacology MH - NADPH Dehydrogenase/metabolism MH - Nitric Oxide/*metabolism MH - Nitric Oxide Synthase Type I/metabolism MH - Nitric Oxide Synthase Type II/metabolism MH - Nitric Oxide Synthase Type III/metabolism MH - Nitrosative Stress/*drug effects MH - Oxidative Stress/*drug effects MH - Rats, Wistar MH - Reactive Oxygen Species/metabolism MH - Thiobarbituric Acid Reactive Substances/metabolism OTO - NOTNLM OT - Antioxidant: oxidative and nitrosative stress OT - Hypobaric hypoxia OT - Ischemia OT - Melatonin OT - Nitric oxide EDAT- 2016/12/13 06:00 MHDA- 2018/04/11 06:00 CRDT- 2016/12/13 06:00 PHST- 2016/09/23 00:00 [received] PHST- 2016/11/28 00:00 [revised] PHST- 2016/12/03 00:00 [accepted] PHST- 2016/12/13 06:00 [pubmed] PHST- 2018/04/11 06:00 [medline] PHST- 2016/12/13 06:00 [entrez] AID - S1089-8603(16)30169-0 [pii] AID - 10.1016/j.niox.2016.12.001 [doi] PST - ppublish SO - Nitric Oxide. 2017 Jan 30;62:32-43. doi: 10.1016/j.niox.2016.12.001. Epub 2016 Dec 8.