Kono Syoichiro, Kurata Tomoko, Sato Kota, Omote Yoshio, Hishikawa Nozomi, Yamashita Toru, Deguchi Kentaro, Abe Koji
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan.
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan.
J Stroke Cerebrovasc Dis. 2015 Mar;24(3):537-47. doi: 10.1016/j.jstrokecerebrovasdis.2014.09.037. Epub 2014 Dec 19.
Telmisartan is a highly lipid-soluble angiotensin receptor blocker (ARB), which improves insulin sensitivity and reduces triglyceride levels and, thus, is called metabo-sartan. We examined the effects of telmisartan on neurovascular unit (N-acetylglucosamine oligomer [NAGO], collagen IV, and glial fibrillary acidic protein [GFAP]) and neuroinflammation (matrix metalloproteinase-9 [MMP-9] and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR-SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups, that is, vehicle group, low-dose telmisartan group (.3 mg/kg/d), and high-dose telmisartan group (3 mg/kg/d, postoral). Immunohistologic analysis at ages 6, 12, and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV-positive basement membrane and progressive increases of MMP-9-positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low-dose telmisartan reduced such changes without lowering blood pressure (BP), and high-dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long-lasting inflammation after tMCAO in SHR-SR, which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke.
替米沙坦是一种高度脂溶性的血管紧张素受体阻滞剂（ARB），它能改善胰岛素敏感性并降低甘油三酯水平，因此被称为代谢沙坦。我们研究了替米沙坦对耐中风自发性高血压大鼠（SHR-SR）脑内神经血管单元（N-乙酰葡糖胺寡聚物[NAGO]、IV型胶原和胶质纤维酸性蛋白[GFAP]）以及神经炎症（基质金属蛋白酶-9[MMP-9]和炎性小体）的影响。12周龄时，SHR-SR接受90分钟的短暂大脑中动脉闭塞（tMCAO），并分为以下3组，即溶剂组、低剂量替米沙坦组（0.3毫克/千克/天）和高剂量替米沙坦组（3毫克/千克/天，口服）。6、12和18个月龄时的免疫组织学分析显示，溶剂组大脑皮质中NAGO阳性内皮细胞和IV型胶原阳性基底膜逐渐减少，而MMP-9阳性神经元、GFAP阳性星形胶质细胞和NLRP3阳性炎性小体逐渐增加。低剂量替米沙坦可减轻这些变化而不降低血压（BP），高剂量替米沙坦在降低血压的同时进一步改善了这些变化。目前的研究结果表明，持续性高血压在SHR-SR的tMCAO后引起了持久的炎症，加速了神经血管破坏和炎性小体出现，并且替米沙坦通过其在缺血性中风后存活的高血压大鼠脑中的多效性作用大大减轻了这种炎症并保护了神经血管单元。
