Reactive nitrogen species (RNS), including nitric oxide (NO), are important cellular messengers when tightly regulated, but unregulated production of RNS during hypoxia or ischemia and reoxygenation is deleterious to hypoxia-intolerant brain. Therefore, maintaining NO homeostasis during hypoxia/ischemia and reoxygenation may be a hallmark of hypoxia-tolerant brain. Unlike most mammals, naked mole-rats (NMRs; Heterocephalus glaber) are tolerant of repeated bouts of hypoxia in vivo. Although there is some evidence that NMR brain is tolerant of hypoxia/ischemia, little is known about the underlying neuroprotective mechanism(s), and their tolerance to reoxygenation injury has not been examined. We hypothesized that NMR brain would maintain NO homeostasis better than hypoxia-intolerant mouse brain during hypoxic/ischemic stresses and following reoxygenation. To test this, we exposed adult NMR and mouse cortical slices to transitions from normoxia (21% O2) to hypoxia (< 1% O2) or ischemia (oxygen glucose deprivation, OGD), followed by reoxygenation, while measuring neuronal NO production. We report that NMR cortical neurons maintain NO homeostasis during hypoxia/OGD and avoid bursts of NO upon reoxygenation. Conversely, mouse cortical neurons maintain NO homeostasis in OGD but not hypoxia and exhibit a burst of NO upon reperfusion. This suggests that maintenance of NO homeostasis during fluctuating O2 availability may be a contributing neuroprotective mechanism against hypoxia/ischemia and reoxygenation injury in hypoxia-tolerant NMR brain.
Keywords: Free radicals; Ischemia; Oxygen glucose deprivation; Reactive nitrogen species; Reperfusion.
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