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

作者：Li Dongdong; Bai Tao; Brorson James R^*

来源：Experimental Neurology, 2011, 230(2): 302-310.

DOI：10.1016/j.expneurol.2011.05.009

• Hypoxia
• Adaptation
• Ischemia
• Reperfusion
• Neuroprotection
• Hypoxia-inducible factor
• Prolyl hydroxylase
• Excitotoxicity
• Glutamate

Continuous exposure of cultured cortical neurons to moderate hypoxia (1% O(2)) elevates cellular accumulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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 72 h 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-1 alpha stabilization, also protected neurons against simulated ischemia-reperfusion injury. Nevertheless, genetic deletion of HIF-1 alpha 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-1 alpha-independent mechanisms, produces strong protective effects against excitotoxic and ischemia-reperfusion related injury.

• 出版日期2011-8