Angiotensin II Type 1 Receptor Blocker Telmisartan Reduces Cerebral Infarct Volume and Peri-infarct Cytosolic Phospholipase A2 Level in Experimental Stroke

摘要

The angiotensin II type 1 receptor (AT₁R) blocker (ARB) telmisartan is a unique drug that has a neuroprotective action and acts as an agonistic ligand for peroxisome proliferator-activated receptor-gamma. We produced rat models of middle cerebral artery occlusion and examined infarct volume as well as immunohistochemical localization and protein expression levels of cytosolic phospholipase A₂ (cPLA₂), which is involved in neurotoxicity, in brains obtained 24h after occlusion. Rats pretreated for 7 days with various doses of telmisartan or vehicle (n=8) were compared. The infarct volume was significantly reduced in the 1.0mg/kg dosage group compared with that of other dosage groups and vehicle group. Furthermore, pretreatment with telmisartan 1.0mg/kg induced significant amelioration of sensorimotor function in forelimb and hindlimb placing tests. Histopathologically, neurons in the peri-infarct cortical regions of vehicle-pretreated rats showed acute ischemic changes, but neurons in telmisartan-pretreated rats appeared normal. Immunohistochemically, cPLA₂ reactivity was localized in ischemic neurons but not in intact neurons. On immunoblots, protein expression levels of total and active cPLA₂ in peri-infarct cortex were significantly reduced in telmisartan-treated rats compared with vehicle-treated rats. The present results provide in vivo evidence that telmisartan reduces cerebral infarct volume and cPLA₂ protein expression in peri-infarct cortex, suggesting an association between neuroprotection and inhibition of cPLA₂ signaling in cerebral ischemia.