Melatonin influences NO/NOS pathway and reduces oxidative and nitrosative stress in a model of hypoxic-ischemic brain damage

Dec 13, 2016Nitric oxide : biology and chemistry

Melatonin may reduce stress from harmful molecules by affecting nitric oxide pathways in low-oxygen brain injury

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Abstract

Melatonin administration before ischemia and hypobaric hypoxia (IH) enhances neuronal nitric oxide synthase (nNOS) expression while decreasing inducible nitric oxide synthase (iNOS) expression.

The IH model increases expression of all three nitric oxide synthase (NOS) isoforms and elevates nitrogen oxide (NOx) levels and nitrotyrosine (n-Tyr) in the cerebral cortex.
Melatonin treatment prior to IH leads to a stronger and earlier response in nNOS expression, but decreases iNOS and n-Tyr levels.
Rats treated with melatonin show a reduction in oxidative damage, as indicated by lower thiobarbituric acid reactive substances (TBARS).
IH intensifies glial fibrillary acidic protein (GFAP) expression and decreases hypoxia-inducible factor-1alpha (HIF-1α), but does not affect nuclear factor kappa B (NF-κB).
Melatonin is suggested to protect against hypoxic/ischemic damage by balancing nitric oxide release and reducing oxidative and nitrosative stress.

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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.

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