Effect of a New Inhibitor of the Synthesis of 20-HETE on Cerebral Ischemia Reperfusion Injury

Abstract

Background and Purpose-Arachidonic acid that is released following cerebral ischemia can be metabolized to . 20-HETE is a potent vasoconstrictor that may contribute to ischemic injury. This study examined the effects of blockading the synthesis of 20-HETE with TS-011 on infarct size after transient occlusion of the middle cerebral artery (MCAO) of rats and after thromboembolic stroke in monkeys. Methods-Rats were treated with TS-011 or vehicle at various times after MCAO. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining and plasma levels of 20-HETE were determined by liquid chromatography mass spectrometry (LC/MS). The effect of TS-011 on infarct size was also studied in monkeys after introduction of a clot into the internal carotid artery. Results-Plasma levels of 20-HETE increased after MCAO in rats. TS-011 (0.01 to 1.0 mg/kg per hour) reduced infarct volume by 40%. Chronic administration of TS-011 for 7 days reduced neurological deficits after MCAO in rats. TS-011 given in combination with tissue plasminogen activator also improved neurological outcome in the stroke model in monkeys. Conclusion-These results suggest that blockade of the formation of 20-HETE with TS-011 may be useful for the treatment of ischemic stroke.

Increase of 20-HETE Synthase after Brain Ischemia in Rats Revealed by PET Study with 11C-Labeled 20-HETE Synthase-Specific Inhibitor

“…20-Hydroxyeicosatetraenoic acid has also been reported to induce the formation of oxygen radicals by interacting with nicotinamide adenine dinucleotide phosphate-oxidase and nitric oxide synthase (Wang et al, 2006;Cheng et al, 2008;Medhora et al, 2008). Previously, we reported that brain and plasma 20-HETE levels were significantly increased in the rat transient middle cerebral artery occlusion (tMCAO) model (Tanaka et al, 2007), and inhibition of 20-HETE synthesis by N-(3-chloro-4-morpholin-4-yl)phenyl-N'-hydroxyimido formamide (TS-011), a selective inhibitor of CYP4s, improved the autoregulatory dysfunction in the peri-infarct microcirculation and the neurologic outcomes in rat and monkey stroke models by reducing the infarct volume of the brain after ischemia (Miyata et al, 2005;Omura et al, 2006;Tanaka et al, 2007;Marumo et al, 2010). However, 20-HETE is also known to be involved in the angiogenesis induced by vascular endothelial growth factor, which is known to be upregulated in the ischemic brain after stroke for a repair process (Kovács et al, 1996;Plate et al, 1999;Zhang et al, 2002).…”

Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats

“…It also promotes the formation of oxygen radicals (15,16,20,33,36,59) and contributes to endothelial dysfunction (35,42,45,49,62). More recently, inhibitors of the synthesis of 20-HETE have been reported to reverse the fall in cerebral blood flow (CBF) following subarachnoid hemorrhage (SAH) (3,21,28,35,55) and reduce infarct size following transient cerebral ischemia (35,42,45,57). These findings suggest that 20-HETE contributes to vasospasm following SAH and ischemia-reperfusion injury in the brain.…”

“…20-hydroxyeicosatetraenoic acid; middle cerebral artery occlusion; cytochrome P-450A; N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine HYPERTENSION IS A MAJOR RISK factor for stroke, but the factors that contribute to the increased incidence and severity of ischemic stroke in hypertension remain to be determined (46). Previous studies have indicated that arachidonic acid (AA) is released into cerebrospinal fluid following cerebral ischemia (1,31,42,56). AA is converted by cytochrome P-450 (CYP) enzymes in cerebral arteries to a potent vasoconstrictor, 20-hydroxyeicosatetraenoic acid (20-HETE) (15,16,32).…”

Identification of a region of rat chromosome 1 that impairs the myogenic response and autoregulation of cerebral blood flow in fawn-hooded hypertensive rats

“…The skull was exposed, and the bone was thinned bilaterally, 6 mm lateral and 2 mm posterior to bregma, for measurement of rCBF using laser-Doppler flowmetry. Focal cerebral ischemia was induced using the intraluminal suture method as previously described (19,21). Briefly, the right common, internal and external carotid arteries were exposed through a midline incision of the neck.…”