Neuroprotection and P450 2C11 upregulation after experimental transient ischemic attack.
OBJECTIVE
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 >50% 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.
Alkayed
Nabil J
NJ
Department of Anesthesiology and Critical Care, Johns Hopkins University School of Medicine, Baltimore, Md 21287, USA. nalkayed@jhmi.edu
Goyagi
Toru
T
Joh
Hung-Dong
HD
Klaus
Judith
J
Harder
David R
DR
Traystman
Richard J
RJ
Hurn
Patricia D
PD
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001345:Autoradiography; D001783:Blood Flow Velocity; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002560:Cerebrovascular Circulation; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D019194:Ischemic Preconditioning; D008099:Liver / Q000201:enzymology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase