Adaptation to moderate hypoxia protects cortical neurons against ischemia-reperfusion injury and excitotoxicity independently of HIF-1α.

Continuous exposure of cultured cortical neurons to moderate hypoxia (1% O(2)) elevates cellular accumulation of hypoxia-inducible factor-1α (HIF-1α) and improves basal survival of cultured cortical neurons. We examined the effects of adaptation to moderate hypoxia on the vulnerability of cultured neurons to the acute injury of simulated ischemia-reperfusion. Cortical neurons cultured continuously in 1% O(2) were markedly protected against simulated ischemia-reperfusion, with protection persisting through 72h after ischemia. Neurons from 1% O(2) conditions were also highly resistant to glutamate-induced NMDA receptor-dependent excitotoxic injury, despite expression of NMDA receptors at levels not significantly changed from controls. Inhibition of prolyl hydroxylase, mimicking cellular signaling effects of hypoxia including HIF-1α stabilization, also protected neurons against simulated ischemia-reperfusion injury. Nevertheless, genetic deletion of HIF-1α expression did not diminish the protection of neurons adapted to 1% O(2) from excitotoxicity or ischemia-reperfusion injury, nor did it prevent the protective effect of prolyl hydroxylase inhibition. We conclude that chronic exposure to moderate hypoxia, through HIF-1α-independent mechanisms, produces strong protective effects against excitotoxic and ischemia-reperfusion related injury.