Published Online
on May 12, 2005

A more recent version of this article appeared on June 1, 2005

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Submitted on February 14, 2005
Accepted on March 14, 2005

Neuroprotection by Hypoxic Preconditioning Involves Oxidative Stress-Mediated Expression of Hypoxia-Inducible Factor and Erythropoietin

Jing Liu MD, PhD; Purnima Narasimhan PhD; Fengshan Yu MD; and Pak H. Chan PhD^*

From the Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California.

^* To whom correspondence should be addressed. E-mail: phchan{at}stanford.edu.

Background and Purpose--Hypoxic preconditioning is an endogenous protection against subsequent lethal hypoxia, but the mechanism involved is not understood. Hypoxia is followed by reactive oxygen species (ROS) production and induces hypoxia-inducible factor (HIF) and its downstream factor erythropoietin (Epo), which is associated with neuroprotection. We hypothesized that these endogenous processes may contribute to hypoxic preconditioning.

Methods--We used a mouse neuronal culture model, with 2 hours of hypoxia as preconditioning followed by 15 hours of hypoxic insult, and examined the expression of HIF-1, Epo, and their downstream proteins by Western blotting. Copper/zinc-superoxide dismutase (SOD1) transgenic (Tg) mice were used to detect the effect of ROS. Cell survival and apoptosis were detected by mitogen-activated protein 2 quantification, apoptotic-related DNA fragmentation, and caspase-3 fragmentation. Antisense Epo was used to block endogenously produced Epo.

Results--Hypoxic preconditioning was protective in wild-type (Wt) neurons but not in neurons obtained from SOD1 Tg mice. In Wt neurons, HIF-1 and Epo expression showed a greater increase after hypoxia compared with Tg neurons and reached a higher level with preconditioned hypoxia, followed by pJak2, pStat5, and nuclear factor B (NF-B) expression. Antisense Epo decreased these downstream proteins and the neuroprotection of hypoxic preconditioning.

Conclusions--Hypoxic preconditioning induces ROS, which may downregulate the threshold for production of HIF-1 and Epo expression during subsequent lethal hypoxia, thus exerting neuroprotection through the Jak2-Stat5 and NF-B pathways.

Key words: superoxide dismutase

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