(Stroke. 1999;30:2391-2399.)
© 1999 American Heart Association, Inc.
Original Contributions |
Blockade of Central Angiotensin AT1 Receptors Improves Neurological Outcome and Reduces Expression of AP-1 Transcription Factors After Focal Brain Ischemia in Rats
From the Institute of Pharmacology, Christian-Albrechts-University of Kiel, Germany.
Correspondence to Juraj Culman MD, Institute of Pharmacology, Christian-Albrechts- University of Kiel, Hospitalstrasse 4, 24105 Kiel, Germany. E-mail juraj.culman{at}pharmakologie.uni-kiel.de
Background and Purpose—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 AT1 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 AT1 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 AT1 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 AT1 receptors improves the recovery from brain ischemia and reduces the expression of c-Fos and c-Jun proteins in the brain. Pretreatment with an AT1 receptor antagonist has beneficial effects after cerebral ischemia.
Editorial Comment
Department of Anesthesia, University of Pennsylvania, Philadelphia, Pennsylvania
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