Abstract
There is interest in pharmacologic preconditioning for end-organ protection by targeting the HIF system. This can be accomplished by inhibition of prolyl 4-hydroxylase (PHD). GSK360A is an orally active PHD inhibitor that has been previously shown to protect the failing heart. We hypothesized that PHD inhibition can also protect the brain from injuries and resulting behavioral deficits that can occur as a result of surgery. Thus, our goal was to investigate the effect of pre-stroke surgery brain protection using a verified GSK360A PHD inhibition paradigm on post-stroke surgery outcomes. Vehicle or an established protective dose (30 mg/kg, p.o.) of GSK360A was administered to male Sprague-Dawley rats. Initially, GSK360A pharmacokinetics and organ distribution were determined, and then PHD-HIF pharmacodynamic markers were measured (i.e., to validate the pharmacological effects of the GSK360A administration regimen). Results obtained using this validated PHD dose-regimen indicated significant improvement by GSK360A (30mg/kg); administered at 18 and 5 hours prior to transient middle cerebral artery occlusion (stroke). GSK360A exposure and plasma, kidney and brain HIF-PHD pharmacodynamics endpoints (e.g., erythropoietin; EPO and Vascular Endothelial Growth Factor; VEGF) were measured. GSK360A provided rapid exposure in plasma (7734 ng/ml), kidney (45–52% of plasma level) and brain (1–4% of plasma level), and increased kidney EPO mRNA (80-fold) and brain VEGF mRNA (2-fold). We also observed that GSK360A increased plasma EPO (300-fold) and VEGF (2-fold). Further assessments indicated that GSK360A reduced post-stroke surgery neurological deficits (47–64%), cognitive dysfunction (60–75%) and brain infarction (30%) 4 weeks later. Thus, PHD inhibition using GSK360A pretreatment produced long-term post-stroke brain protection and improved behavioral functioning. These data support PHD inhibition, specifically by GSK360A, as a potential strategy for pre-surgical use to reduce brain injury and functional decline due to surgery-related cerebral injury.
Highlights
A short duration of ischemia can provide significant brain protection to subsequent long-duration ischemia
GSK360A is a potent inhibitor of hypoxia inducible factor (HIF)-prolyl 4-hydroxylase (PHD) (PHD1>PHD2 % PHD3) and capable of activating the HIF-1a pathway in a variety of cell types including neonatal rat ventricular myocytes and H9C2 cells
We demonstrate that GSK360A activates HIF transcription as seen in ischemic tolerance to result in brain protection and improved sensory, motor and cognitive outcomes
Summary
A short duration of ischemia (i.e., ischemic preconditioning; IP) can provide significant brain protection to subsequent long-duration ischemia (i.e., termed ischemic tolerance; IT). IP induced IT has been shown in the human nervous system and heart [10, 11] suggesting that we can capture these endogenous neuroprotective mechanisms for use to protect the brain and heart in surgical patients. A major mechanism for IP-induced IT is signaling that occurs via the increased activity of hypoxia inducible factor (HIF), a master regulator of oxygen homeostasis. The breadth and depth of inducing this “IP-like” protective signaling has been suggested to offer new opportunities for stroke therapeutic intervention in the face of much pessimism over many failed clinical stroke trials [13, 14]. The HIF signaling pathway is well-defined and provides opportunities to use chemical agents/drugs that stimulate this endogenous protective pathway
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