Nitric oxide homeostasis is maintained during acute in vitro hypoxia and following reoxygenation in naked mole-rat but not mouse cortical neurons

Abstract

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.