Abstract 113: GSK360A Inhibits Prolyl 4-Hydroxylase, Upregulates Hypoxia Inducible Factors (HIF) and Provides Protection from Ischemic Stroke-Induced Injury and Sensory-Motor-Cognitive Deficits

Background: Hypoxia inducible factors (HIFs) are transcription factors that are upregulated by decreased oxygen tension and ischemic preconditioning. HIFs increase angiogenesis, erythropoiesis, cell proliferation/survival and energy metabolism and decrease inflammation. GSK360A is a novel, orally active prolyl 4-hydroxylase (PHD) inhibitor that upregulates HIF-1α signaling and can protect the failing heart. Since GSK360A upregulates systems involved in ischemic tolerance, its administration prior to surgery/ischemia could be beneficial. GSK360A effects in cerebral ischemia have not been explored. Method: Male Sprague Dawley rats received 2 hours transient middle cerebral artery occlusion (tMCAO) followed by 22 hours of reperfusion. GSK dose selection was based on previous pharmacodynamic data on HIF system upregulation that was verified in these studies. Vehicle (1% Methyl cellulose) or GSK360A (30 mg/kg) was administered by oral gavage at 18 and 5 hr prior to tMCAO. Measurements were made of kidney erythropoietin (EPO) mRNA and protein over 1 day, modified neurological severity score (mNSS) over 5 and 24 hrs, cognitive performance (Active Place Avoidance; APA) and motor activity at 3-4 weeks and terminal brain infarction were made. Different groups of rats (N=5-10 per group) were studied over 1 day to 4 weeks. Results: GSK360A increased kidney EPO mRNA and protein up to 80-fold (p<0.01) by 5 hr post-stroke. Stroke increased mNNS that was reduced by GSK360A (31% and 20%, p<0.05) at 5 and 24 hr post-stroke onset. Stroke-induced decreases in APA performance, reflecting cognitive dysfunction, was reduced (p<0.01) by GSK360A without affecting motor activity. GSK360A also reduced brain infarction (30%, p<0.05). Conclusions: This is the first demonstration of GSK360A brain protection and long-term improvement in post-stroke neurological outcome, including beneficial effects to reduce stroke-induced loss in cognitive function. These data suggest that pre-stroke administration of GSK360A can produce PHD inhibition that stimulates HIF signaling useful for high-stroke-risk situations. In addition, its use prior to surgery might reduce the probability of post-surgical cognitive decline.