Blockade of central angiotensin AT(1) receptors improves neurological outcome and reduces expression of AP-1 transcription factors after focal brain ischemia in rats.
OBJECTIVE
Angiotensin-converting enzyme inhibitors have been shown to protect against stroke in hypertensive rats and to improve neurological outcome after cerebral ischemia in normotensive rats. The present study was designated to test the hypothesis that blockade of brain AT(1) receptors improves the recovery from focal cerebral ischemia and reduces expression of AP-1 transcription factors c-Fos and c-Jun, which have been associated with programmed cell death and neurodegeneration.


METHODS
Experiments were carried out in normotensive male Wistar rats. Focal cerebral ischemia was induced by middle cerebral artery occlusion lasting for 90 minutes and followed by reperfusion. The selective AT(1) receptor antagonist irbesartan was infused intracerebroventricularly over a 5-day period before the induction of ischemia at a dose that inhibited brain but not vascular AT(1) receptors. Twenty-four hours after ischemia, neurological outcome was evaluated and expression of c-Fos and c-Jun proteins in the brain was studied immunocytochemically.


RESULTS
Focal brain ischemia resulted in a strong induction of c-Fos and c-Jun proteins in the cortex, which positively correlated with the degree of neurological deficits. Treatment of rats with irbesartan significantly improved neurological outcome of focal cerebral ischemia when compared with the vehicle-treated group and markedly reduced the expression of c-Fos and c-Jun proteins in the cortex on the ligated side of the brain. Irbesartan pretreatment completely abolished the ischemia-induced c-Fos expression in the hippocampus.


CONCLUSIONS
The present study shows a relationship between c-Fos and c-Jun expression and neurological outcome after focal brain ischemia. Our data indicate that long-term blockade of central AT(1) receptors improves the recovery from brain ischemia and reduces the expression of c-Fos and c-Jun proteins in the brain. Pretreatment with an AT(1) receptor antagonist has beneficial effects after cerebral ischemia.
Dai
W J
WJ
Institute of Pharmacology, Christian-Albrechts-University of Kiel, Germany.
Funk
A
A
Herdegen
T
T
Unger
T
T
Culman
J
J
D000704:Analysis of Variance; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001157:Arterial Occlusive Diseases / Q000503:physiopathology; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D002408:Catheters, Indwelling; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007260:Infusion Pumps; D007276:Injections, Intraventricular; D000077405:Irbesartan; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D020768:Middle Cerebral Artery / Q000503:physiopathology; D009410:Nerve Degeneration / Q000503:physiopathology; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D014677:Pharmaceutical Vehicles; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000235:genetics
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D018696:Neuroprotective Agents; D014677:Pharmaceutical Vehicles; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D013777:Tetrazoles; D018808:Transcription Factor AP-1; D000077405:Irbesartan