Protective Effect of the 20-HETE Inhibitor HET0016 on Brain Damage after Temporary Focal Ischemia

Poloyac, Samuel M.; Zhang, Yuqing; Bies, Robert R.; Kochanek, Patrick M.; Graham, Steven H.

doi:10.1038/sj.jcbfm.9600309

Cited by 66 publications

(76 citation statements)

References 42 publications

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“…The finding that inhibitors of the synthesis of 20-HETE lower blood pressure by 10 -15 mmHg in SHR is consistent with this hypothesis (52,64). 20-HETE is also a potent constrictor of cerebral arteries, and the blockade of this pathway reduces infarct size following transient cerebral ischemia in normotensive rats (16,32,35,40,42,45). However, the effect of 20-HETE inhibitors on ischemic stroke in hypertensive rats has not been determined.…”

Section: Discussionsupporting

confidence: 75%

“…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.…”

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confidence: 99%

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

Dunn¹,

Renić²,

Flasch³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

126

132

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Dunn KM, Renic M, Flasch AK, Harder DR, Falck J, Roman RJ. Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 295: H2455-H2465, 2008. First published October 17, 2008 doi:10.1152/ajpheart.00512.2008.-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. 20-hydroxyeicosatetraenoic acid (20-HETE) has been reported to be a potent constrictor of cerebral arteries, and inhibitors of 20-HETE formation reduce infarct size following cerebral ischemia. The present study examined whether elevated production of 20-HETE in the cerebral vasculature could contribute to the larger infarct size previously reported after transient middle cerebral artery occlusion (MCAO) in hypertensive strains of rat [spontaneously hypertensive rat (SHR) and spontaneously hypertensive stroke-prone rat (SHRSP)]. The synthesis of 20-HETE in the cerebral vasculature of SHRSP measured by liquid chromatography-tandem mass spectrometry was about twice that seen in Wistar-Kyoto (WKY) rats. This was associated with the elevated expression of cytochrome P-450 (CYP)4A protein and CYP4A1 and CYP4A8 mRNA. Infarct volume after transient MCAO was greater in SHRSP (36 Ϯ 4% of hemisphere volume) than in SHR (19 Ϯ 5%) or WKY rats (5 Ϯ 2%). This was associated with a significantly greater reduction in regional cerebral blood flow (rCBF) in SHR and SHRSP than in WKY rats during the ischemic period (78% vs. 62%). In WKY rats, rCBF returned to 75% of control following reperfusion. In contrast, SHR and SHRSP exhibited a large (166 Ϯ 18% of baseline) and sustained (1 h) postischemic hyperperfusion. Acute blockade of the synthesis of -formamidine (HET0016; 1 mg/kg) reduced infarct size by 59% in SHR and 87% in SHRSP. HET0016 had no effect on the fall in rCBF during MCAO but eliminated the hyperemic response. HET0016 also attenuated vascular O2•Ϫ formation and restored endothelium-dependent dilation in cerebral arteries of SHRSP. These results indicate the production of 20-HETE is elevated in the cerebral vasculature of SHRSP and contributes to oxidative stress, endothelial dysfunction, and the enhanced sensitivity to ischemic stroke in this hypertensive model. 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). 20-HETE has been reported to play an important...

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Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

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

Dunn¹,

Renić²,

Flasch³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

126

132

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“…2), but most of the EETs were converted to their corresponding DiHETEs. The systemic administration of HET0016 (1 mg/kg) inhibited the synthesis of 20-HETE in the brain by Ͼ90% as previously reported by others (38). HET0016 did not inhibit, but rather increased, epoxygenase activity slightly, as defined by the sum of the formation of EETs and DiHETEs metabolites.…”

Section: Resultsmentioning

confidence: 48%

Interaction of nitric oxide, 20-HETE, and EETs during functional hyperemia in whisker barrel cortex

Liu

Falck

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Nitric oxide (NO) modulates vasodilation in cerebral cortex during sensory activation. NO is known to inhibit the synthesis of 20-HETE, which has been implicated in arteriolar constriction during astrocyte activation in brain slices. We tested the hypothesis that the attenuated cerebral blood flow (CBF) response to whisker stimulation seen after NO synthase (NOS) inhibition requires 20-HETE synthesis and that the ability of an epoxyeicosatrienoic acids (EETs) antagonist to reduce the CBF response is blunted after NOS inhibition but restored with simultaneous blockade of 20-HETE synthesis. In anesthetized rats, the increase in CBF during whisker stimulation was attenuated after the blockade of neuronal NOS with 7-nitroindazole. Subsequent administration of the 20-HETE synthesis inhibitor N-hydroxy-NЈ-(4-n-butyl-2-methylphenyl)formamidine (HET0016) restored the CBF response to control levels. After the administration of 7-nitroindazole, the inhibitory effect of an EETs antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) on the CBF response was lost, whereas the simultaneous administration of 7-nitroindazole and HET0016 restored the inhibitory effect of 14,15-EEZE. The administration of HET0016 alone had only a small effect on the evoked CBF response in rats. Furthermore, in neuronal NOS ϩ/ϩ and NOS Ϫ/Ϫ mice, HET0016 administration did not increase the CBF response to whisker stimulation. In neuronal NOS ϩ/ϩ mice, HET0016 also blocked the reduction in the response seen with acute NOS inhibition. These results indicate that 20-HETE synthesis normally does not substantially restrict functional hyperemia. Increased NO production during functional activation may act dynamically to suppress 20-HETE synthesis or downstream signaling and permit EETs-dependent vasodilation. With the chronic loss of neuronal NOS in mice, other mechanisms apparently suppress 20-HETE synthesis or signaling. eicosanoids; epoxyeicosatrienoic acid; functional activation; mouse; rat; vibrissae; 20-hydroxyeicosatetraenoic acid WHEN NEURONS IN A specific brain region increase their activity, local blood flow increases in a temporally and spatially coordinated manner. The physiological mechanisms that underlie this functional coupling are complex and involve adenosine (13,31,39), nitric oxide (NO) (12, 29), arachidonic acid metabolites derived from cyclooxygenase (34) and cytochrome P-450 (CYP) epoxygenase (36) enzymes, Ca 2ϩ -activated K ϩ (K Ca ) channels, and inward-rectifier K ϩ channels (17).Although NO is required for functional hyperemia in cerebellum (50), NO may not be an essential mediator in cerebral cortex. Neuronal NO synthase (nNOS) null mice (nNOS Ϫ/Ϫ ) and endothelial NOS (eNOS) null mice retain normal cerebral blood flow (CBF) responses to whisker stimulation (6,29). Further work demonstrated that NO may act in a permissive fashion in the cerebral cortex to enable vasodilation by other mediators. Inhibition of NOS decreases basal cGMP and increases vascular tone. Restoration of vascular tone after NOS inhibition with either an...

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“…Recent studies have indicated that inhibitors of the synthesis and/or action of 20-HETE markedly reduce infarct size after transient occlusion of the middle cerebral artery in the rat and primate (26,28,31,39) but have no effect on cerebral perfusion during the ischemic period (28,31). Moreover, inhibitors of 20-HETE synthesis are effective in reducing infarct size in the brain even when administered up to 4 h after reperfusion (26).…”

Section: Discussionmentioning

confidence: 99%

“…It is also produced by brain tissue (39). Plasma levels of 20-HETE increase after transient cerebral ischemia (26), and inhibitors of the synthesis and/or action of 20-HETE markedly reduce infarct size after cerebral ischemia (26,28,31,39). The mechanism of the neuroprotective effects of inhibitors of the synthesis and/or actions of 20-HETE remains unknown.…”

mentioning

confidence: 99%

Protective effect of 20-HETE inhibition in a model of oxygen-glucose deprivation in hippocampal slice cultures

Renić¹,

Kumar²,

Gebremedhin³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Recent studies have indicated that inhibitors of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) may have direct neuroprotective actions since they reduce infarct volume after ischemia reperfusion in the brain without altering blood flow. To explore this possibility, the present study used organotypic hippocampal slice cultures subjected to oxygen-glucose deprivation (OGD) and reoxygenation to examine whether 20-HETE is released by organotypic hippocampal slices after OGD and whether it contributes to neuronal death through the generation of ROS and activation of caspase-3. The production of 20-HETE increased twofold after OGD and reoxygenation. Blockade of the synthesis of 20-HETE with N-hydroxy-N=-(4-butyl-2-methylphenol)formamidine (HET0016) or its actions with a 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, reduced cell death, as measured by the release of lactate dehydrogenase and propidium iodide uptake. Administration of a 20-HETE mimetic, 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5,14-20-HEDE), had the opposite effect and increased injury after OGD. The death of neurons after OGD was associated with an increase in the production of ROS and activation of caspase-3. These effects were attenuated by HET0016 and potentiated after the administration of 5,14-20-HEDE. These findings indicate that the production of 20-HETE by hippocampal slices is increased after OGD and that inhibitors of the synthesis or actions of 20-HETE protect neurons from ischemic cell death. The protective effect of 20-HETE inhibitors is associated with a decrease in superoxide production and activation of caspase-3. 20-hydroxyeicosatetraenoic acid; brain; ischemic injury; superoxide; caspase-3 20-HYDROXYEICOSATETRAENOIC ACID (20-HETE) is a potent vasoconstrictor that is produced from -hydroxylation of arachidonic acid (AA) by cytochrome P-450 (CYP) enzymes in cerebral arteries (8,12). It is also produced by brain tissue (39). Plasma levels of 20-HETE increase after transient cerebral ischemia (26), and inhibitors of the synthesis and/or action of 20-HETE markedly reduce infarct size after cerebral ischemia (26,28,31,39). The mechanism of the neuroprotective effects of inhibitors of the synthesis and/or actions of 20-HETE remains unknown. They were initially assumed to improve cerebral perfusion. However, recent studies (28, 31) have demonstrated that inhibitors of the synthesis of 20-HETE have no effect on regional cerebral blood flow during the ischemic period and only attenuate the delayed postischemic fall in cerebral blood flow. Moreover, the previous finding that inhibitors of the synthesis of 20-HETE can reduce infarct size in the brain even when administered 4 h after reperfusion (26) suggests that these drugs may enhance the survival of neurons after ischemic injury independent of their effects on cerebral blood flow.In this regard, there is increasing evidence that 20-HETE stimulates oxidative stress through several mechanisms, including the activation of NADPH oxidase, phosphorylation and uncoupling ...

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Protective Effect of the 20-HETE Inhibitor HET0016 on Brain Damage after Temporary Focal Ischemia

Cited by 66 publications

References 42 publications

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

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

Interaction of nitric oxide, 20-HETE, and EETs during functional hyperemia in whisker barrel cortex

Protective effect of 20-HETE inhibition in a model of oxygen-glucose deprivation in hippocampal slice cultures

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