Nonhypotensive Dose of Telmisartan Attenuates Cognitive Impairment Partially Due to Peroxisome Proliferator-Activated Receptor-γ Activation in Mice With Chronic Cerebral Hypoperfusion
Nonhypotensive Dose of Telmisartan Attenuates Cognitive Impairment Partially Due to Peroxisome Proliferator-Activated Receptor-γ Activation in Mice With Chronic Cerebral Hypoperfusion
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DOI：
10.1161/strokeaha.110.583948
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发表时间：
2010-08-01
期刊：
影响因子：
8.3
通讯作者：
Takahashi, Ryosuke
中科院分区：
文献类型：
--
作者：
Washida, Kazuo;Ihara, Masafumi;Takahashi, Ryosuke
背景和目的-替米沙坦，血管紧张素II 1型受体阻滞剂与过氧化物酶体增殖物激活受体-γ-调节活性的影响，对空间工作记忆障碍的小鼠进行了调查慢性脑hyporperfusion. Methods-成年C57 BL/6 J雄性小鼠进行双侧颈总动脉狭窄使用外部微线圈。双侧颈总动脉狭窄后，小鼠每天经口给予低剂量替米沙坦（1 mg/kg/天）、高剂量替米沙坦（10 mg/kg/天）或溶剂（含或不含过氧化物酶体增殖物激活受体-γ拮抗剂GW 9662（1 mg/kg/天）），持续30天。在双侧颈总动脉狭窄后30天测量大脑单核细胞趋化蛋白-1和肿瘤坏死因子-α的mRNA表达，用Kluver-Barrera染色分析死后大脑的脱髓鞘变化，并对胶质细胞、氧化应激和血管内皮细胞标记物进行免疫染色。空间工作记忆进行了评估Y-迷宫test.Results-Mean收缩压和脑血流量没有降低低剂量替米沙坦，但显着降低高剂量替米沙坦。低剂量替米沙坦可显著减轻空间工作记忆障碍伴神经胶质细胞活化、少突胶质细胞丢失和白色物质脱髓鞘变化，但高剂量替米沙坦可引起这些变化。与GW 9662联合治疗部分抵消了低剂量替米沙坦的这种积极作用。与此一致，低剂量替米沙坦降低了血管内皮细胞的氧化应激程度和单核细胞趋化蛋白-1和肿瘤坏死因子-α的mRNA水平，与vehicle. Conclusions相比，替米沙坦的抗炎和抗氧化作用部分由过氧化物酶体增殖物激活受体-γ激活发挥，但不是其降压作用，对慢性脑灌注不足后认知障碍和白色物质损害具有保护作用。（中风。2010; 41：1798-1806.）
Background and Purpose-The effect of telmisartan, an angiotensin II Type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma-modulating activity, was investigated against spatial working memory disturbances in mice subjected to chronic cerebral hypoperfusion.Methods-Adult C57BL/6J male mice were subjected to bilateral common carotid artery stenosis using external microcoils. Mice received a daily oral administration of low-dose telmisartan (1 mg/kg per day), high-dose telmisartan (10 mg/kg per day), or vehicle with or without peroxisome proliferator-activated receptor-gamma antagonist GW9662 (1 mg/kg per day) for all treatments for 30 days after bilateral common carotid artery stenosis. Cerebral mRNA expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha was measured 30 days after bilateral common carotid artery stenosis, and postmortem brains were analyzed for demyelinating change with Kluver-Barrera staining and immunostained for glial, oxidative stress, and vascular endothelial cell markers. Spatial working memory was assessed by the Y-maze test.Results-Mean systolic blood pressure and cerebral blood flow did not decrease with low-dose telmisartan but significantly decreased with high-dose telmisartan. Low-dose telmisartan significantly attenuated, but high-dose telmisartan provoked, spatial working memory impairment with glial activation, oligodendrocyte loss, and demyelinating change in the white matter. Such positive effects of low-dose telmisartan were partially offset by cotreatment with GW9662. Consistent with this, low-dose telmisartan reduced the degree of oxidative stress of vascular endothelial cells and the mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha compared with vehicle.Conclusions-Anti-inflammatory and antioxidative effects of telmisartan that were exerted in part by peroxisome proliferator-activated receptor-gamma activation, but not its blood pressure-lowering effect, have protective roles against cognitive impairment and white matter damage after chronic cerebral hypoperfusion. (Stroke. 2010; 41: 1798-1806.)