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.

当严格调节时，反应性氮素（RNS），包括一氧化氮（NO），是重要的细胞信使，但在缺氧或局部缺血和再氧化期间RNS的产生不受调节，这对不耐缺氧的大脑有害。因此，在缺氧/缺血和复氧过程中保持NO稳态可能是耐缺氧大脑的标志。与大多数哺乳动物不同，裸mole鼠（NMRs; Heterocephalus glaber）能够耐受体内反复缺氧。尽管有一些证据表明NMR脑可以耐受缺氧/缺血，但对于潜在的神经保护机制知之甚少，尚未研究其对复氧损伤的耐受性。我们假设在缺氧/缺血性应激以及复氧后，NMR脑比缺氧耐缺氧的小鼠脑更好地维持NO稳态。为了测试这一点，我们将成人NMR和小鼠皮质切片暴露于从正常氧（21％O ₂）到缺氧（<1％O ₂）或缺血（缺氧葡萄糖，OGD），然后再充氧，同时测量神经元NO的产生。我们报告说，核磁共振皮质神经元在缺氧/ OGD期间保持NO稳态，并避免在复氧时NO爆发。相反，小鼠皮层神经元在OGD中维持NO稳态，但没有缺氧，并且在再灌注时表现为NO爆发。这表明在波动的O ₂利用率期间维持NO稳态可能是针对耐缺氧NMR脑的缺氧/缺血和复氧损伤的神经保护机制。