Neuroprotection and P450 2C11 Upregulation After Experimental Transient Ischemic Attack

Abstract

Background and Purpose-Transient ischemic attack (TIA) is a risk factor for stroke. However, TIA may also serve as a preconditioning stimulus, reducing damage from subsequent stroke. We tested the hypothesis that experimental TIA induces expression of P450 2C11, an arachidonic acid epoxygenase that produces vasodilator epoxyeicosatrienoic acids, leading to increased tissue perfusion and reduced stroke damage. Methods-Wistar rats underwent three 10-minute middle cerebral artery occlusions (TIA) or sham surgery. Three days later, animals were subjected to 2-hour middle cerebral artery occlusion and 24 hours of reperfusion. Brains were stained with 2,3,5-triphenyltetrazolium chloride for infarct size measurement or processed for quantification of P450 2C11 mRNA and protein with the use of RNase protection assay and Western blotting. Regional cerebral blood flow (CBF) at the end of 2-hour ischemia was measured in separate groups of rats with iodoantipyrine autoradiography. Results-Cerebral infarct was reduced by Ͼ50% in TIA-versus sham-preconditioned animals. 2C11 mRNA and protein were increased in ipsilateral hemisphere by 3 days after TIA but not sham surgery. Induction of 2C11 by TIA was also evident in ipsilateral hemisphere at 24 hours after 2-hour middle cerebral artery occlusion and 24 hours of reperfusion. End-ischemic regional CBF was not different between TIA-and sham-pretreated groups. Conclusions-We conclude that experimental TIA induces ischemic tolerance by a mechanism temporally linked to upregulation of P450 2C11. Enzyme induction does not attenuate ischemic severity by amplifying end-ischemic CBF.

Cytochrome P450 4A Isoform Inhibitory Profile of N-Hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016), a Selective Inhibitor of 20-HETE Synthesis

“…[23][24][25] In the cerebral circulation, formation of 11,12-EET catalyzed by CYP2C11 plays a critical role in the regulation of cerebral blood flow and neuroprotection against ischemic stroke. 26,27) On the other hand, 20-HETE catalyzed by CYP4A has potent vasoconstrictor effect in cerebral artery and contributes to reduction of cerebral blood flow after subarachnoid hemorrhage. 19) To examine the selective inhibition of HET0016 for CYP4A isoforms, we also examined the ability of HET0016 to inhibit the production of 11,12-EET by CYP2C11.…”

Soluble Epoxide Hydrolase Is a Main Effector of Angiotensin II–Induced Hypertension

“…Central effects of sEH inhibition should be considered seriously because a substantial portion of the response to angiotensin II is mediated via central AT1 receptors in the stria vascularis. 30 However, although EETs are known to be generated by astrocytes in response to glutamate release from neighboring neurons 31 and the upregulation of CYP 2C11 elicits neuroprotective effects during transient experimental ischemic attack, 32 little is known about the role and expression of the sEH in the brain.…”

CBF Changes Associated with Focal Ischemic Preconditioning in the Spontaneously Hypertensive Rat

“…Nitric oxide is also implicated in cellular PC mechanisms (Nandagopal et al, 2001), independent of vascular effects. Conversely, induction of the arachidonic acid epoxygenase, P454 2C11, would be expected to increase levels of vasodilatory epoxyeicosatrienoic acids in preconditioned brain (Alkayed et al, 2002), providing a further mechanism that could contribute to perfusion effects of PC.…”

“…In the context of focal ischemia, infarct volumes are reduced by prior global (Simon et al, 1993) or focal ischemia (Barone et al, 1998;Chen et al, 1996;Matsushima and Hakim, 1995), by inflammatory signaling molecules such as lipopolysaccharide (LPS) (Tasaki et al, 1997), by spreading depression (Matsushima et al, 1996;Otori et al, 2003), or even by remote cortical injury that does not induce spreading depression (Muramatsu et al, 2004). A role of perfusion changes in PC has been largely discounted, based on numerous studies that failed to identify cerebral blood flow (CBF) differences between naïve and preconditioned animals during acute intervals after subsequent occlusion, using autoradiographic (Alkayed et al, 2002;Chen et al, 1996;Dawson et al, 1999), hydrogen clearance (Matsushima and Hakim, 1995;Matsushima et al, 1996) or laser Doppler measurements (Barone et al, 1998). Recent results indicate that basal CBF might even be reduced in a preconditioned hemisphere, perhaps secondary to decreases in metabolic rate after treatments that produce cortical injury (Muramatsu et al, 2004;Otori et al, 2003).…”