Angiotensin II Type 1 Receptor Blocker Telmisartan Reduces Cerebral Infarct Volume and Peri-infarct Cytosolic Phospholipase A2 Level in Experimental Stroke
Angiotensin II Type 1 Receptor Blocker Telmisartan Reduces Cerebral Infarct Volume and Peri-infarct Cytosolic Phospholipase A2 Level in Experimental Stroke
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DOI：
10.1089/neu.2009.0965
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发表时间：
2009-12-01
影响因子：
4.2
通讯作者：
Hori, Tomokatsu
中科院分区：
文献类型：
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作者：
Kobayashi, Tomonori;Kawamata, Takakazu;Hori, Tomokatsu
血管紧张素II型1受体（AT(1)R）阻滞剂（ARB）替米沙坦是一种独特的药物，具有神经保护作用，并作为过氧化物酶体增殖激活受体γ的激动性配体。我们制作了大脑中动脉闭塞大鼠模型，并在闭塞后24小时检测脑梗死体积、免疫组织化学定位和参与神经毒性的胞质磷脂酶A(2) （cPLA(2)）的蛋白表达水平。用不同剂量替米沙坦或对照剂预处理7 d的大鼠（n=8）进行比较。1.0mg/kg给药组与其他给药组和载药组相比，梗死面积明显减少。此外，替米沙坦1.0mg/kg预处理能显著改善前肢和后肢放置试验的感觉运动功能。在组织病理学上，药物预处理大鼠脑梗死周围皮质区神经元出现急性缺血改变，而替米沙坦预处理大鼠神经元表现正常。免疫组织化学表明，cPLA(2)反应性局限于缺血神经元，而不局限于完整神经元。免疫印迹显示，替米沙坦治疗的大鼠梗死周围皮层总和活性cPLA(2)蛋白表达水平明显低于给药大鼠。目前的研究结果提供了体内证据，表明替米沙坦可以减少脑梗死体积和梗死周围皮层中cPLA(2)蛋白的表达，提示脑缺血时神经保护和cPLA(2)信号的抑制之间存在关联。
The angiotensin II type 1 receptor (AT(1)R) 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 A(2) (cPLA(2)), which is involved in neurotoxicity, in brains obtained 24 h 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, cPLA(2) reactivity was localized in ischemic neurons but not in intact neurons. On immunoblots, protein expression levels of total and active cPLA(2) 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 cPLA(2) protein expression in peri-infarct cortex, suggesting an association between neuroprotection and inhibition of cPLA(2) signaling in cerebral ischemia.