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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 PLoS+One
2017 ; 12
(9
): e0184049
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gab.com Text
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The prolyl 4-hydroxylase inhibitor GSK360A decreases post-stroke brain injury and
sensory, motor, and cognitive behavioral deficits
#MMPMID28880966
Zhou J
; Li J
; Rosenbaum DM
; Zhuang J
; Poon C
; Qin P
; Rivera K
; Lepore J
; Willette RN
; Hu E
; Barone FC
PLoS One
2017[]; 12
(9
): e0184049
PMID28880966
show ga
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.