Effects of melatonin on the nitric oxide system and protein nitration in the hypobaric hypoxic rat hippocampus

Abstract

BackgroundIt is well documented that the nitric oxide (NO) might be directly involved in brain response to hypobaric hypoxia, and could contribute to memory deficiencies. Recent studies have shown that melatonin could attenuate hypoxia or ischemia-induced nerve injuries by decreasing the production of free radicals. The present study, using immunohistochemical and immunoblot methods, aimed to explore whether melatonin treatment may affect the expression of nitric oxide system and protein nitration, and provide neuroprotection in the rat hippocampus injured by hypobaric hypoxia. Prior to hypoxic treatment, adult rats were pretreated with melatonin (100 mg/kg, i.p.) before they were exposed to the altitude chamber with 48 Torr of the partial oxygen concentration (pO2) for 7 h to mimic the ambience of being at 9000 m in height. They were then sacrificed after 0 h, 1, and 3 days of reoxygenation.ResultsThe results obtained from the immunohistochemical and immunoblotting analyses showed that the expressions of neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), nitrotyrosine (Ntyr) and Caspase 3 in the hypoxic hippocampus were increased from 0 h to 3 days of reoxygenation. Interestingly, the hypoxia-induced increase of nNOS, eNOS, iNOS, Ntyr and Caspase 3 protein expression was significantly depressed in the hypoxic rats treated with melatonin.ConclusionsActivation of the nitric oxide system and protein nitration constitutes a hippocampal response to hypobaric hypoxia and administration of melatonin could provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaric hypoxia.

1400 W ameliorates acute hypobaric hypoxia/reoxygenation-induced cognitive deficits by suppressing the induction of inducible nitric oxide synthase in rat cerebral cortex microglia

“…NO levels were initially reduced by hypoxia, which may be because insufficient oxygen levels reduce the formation of NO from L-arginine. After 1 day of reoxygenation, the level of NO was significantly increased, similarly to results reported in previous studies [11,12] . 1400W pretreatment significantly reduced the levels of NO in rat cerebral cortex tissue after 1 day of reoxygenation back to baseline levels, although it was slightly higher compared the normoxic group, it was not statistically different.…”

“…Two hours after administration of vehicle or 1400W, normoxia groups were maintained in a normoxic environment while hypoxia groups were exposed to simulated hypobaric hypoxia (HH) and reoxygenation as previously described [11,12] .…”

“…Because excessive NO generated by hypoxia-reoxygenation is caused by iNOS activity, previous studies have investigated pharmacological strategies to prevent acute hypobaric hypoxia-reoxygenation damage by inhibiting iNOS activity and reducing NO production. Melatonin can suppress hippocampal iNOS, nNOS, and eNOS overexpression, with reduced NO production after acute hypobaric hypoxia-reoxygenation [12] ; previous studies indicated that melatonin has an antioxidant and free radical scavenging effect [30] . However, the mechanism of how NOS inhibitors or melatonin prevent NOS expression has not been studied thoroughly.…”

“…Previous studies have confirmed that hypobaric hypoxia-reoxygenation can reduce the learning and memory capacity of the brain, which is related to the increase of free radical production and apoptosis or necrosis [6][7][8][9] . At the same time, there is evidence indicating that endogenous nitric oxide (NO) is directly correlated with cognitive dysfunction caused by hypobaric hypoxia-reoxygenation [10][11][12][13][14] .…”

Modifications of expression of genes and proteins involved in DNA repair and nitric oxide metabolism by carbatonides [disodium-2,6-dimethyl-1,4-dihydropyridine- 3,5-bis(carbonyloxyacetate) derivatives] in intact and diabetic rats

“…However, our model of DM was different and nerve tissue might have its peculiarities. For example, a simultaneous increase in iNOS and eNOS was observed in the hippocampus of animals subjected to hypoxia (28). On the contrary, in the paraventricular nucleus of animals with modelled insulin resistance, eNOS was down-regulated; expression of iNOS did not change (29).…”