Role of melatonin and the nitric oxide donor ISMN in a model of brain ischemic-hypobaric hypoxia

Nitric oxide (NO) is a versatile diffusible signaling molecule with physiological actions involved in neuromodulation, immune response, and vasodilatation. In addition, NO appears to be key in brain hypoxic or ischemic injury. Many studies have demonstrated a neuroprotective effect for melatonin based on its antioxidant activity. In this fashion, we have optimized an experimental model of ischemia followed by a hypobaric hypoxia (I + HH) period associated to co-administration of NO donor isosorbide mononitrate (ISMN) and melatonin, in order to study: (1) the localization and activity of iNOS and eNOS, and protein nitration in the brain of rats submitted to the above mentioned model after two reoxygenation periods (0 and 2 h) and (2) the effect of the administration of both drugs in the brain of rats submitted to this hypoxic model after the same reoxygenation periods. Our results show that the co-administration of ISMN and melatonin induces an increase of eNOS vascular localization after ischemia-hypoxia while it does not influence iNOS in situ expression. Regarding NO activity measured as NADPH-diaphorase histochemistry, it is remarkable that at the 0 h point, no signal was detected. On the other hand, protein nitration-related damage in both reoxygenation times is decreased when both drugs are supplied. In summary, ISMN and melatonin co-administration induces the main changes observed in the parameters analyzed after ischemia-hypoxia. Supported by MICINN (SAF2008-03938).