Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Stroke. 2010 Aug;41(8):1798-806. doi: 10.1161/STROKEAHA.110.583948. Epub 2010 Jul 1.
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.
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 Klüver-Barrera staining and immunostained for glial, oxidative stress, and vascular endothelial cell markers. Spatial working memory was assessed by the Y-maze test.
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.
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.
本研究旨在探讨血管紧张素 II 型 1 型受体阻滞剂替米沙坦（具有过氧化物酶体增殖物激活受体-γ调节活性）对慢性大脑低灌注引起的空间工作记忆障碍的影响。
成年 C57BL/6J 雄性小鼠采用外部微线圈行双侧颈总动脉狭窄术。术后 30 天，小鼠每日口服低剂量替米沙坦（1mg/kg/天）、高剂量替米沙坦（10mg/kg/天）或载体，同时或不给予过氧化物酶体增殖物激活受体-γ拮抗剂 GW9662（1mg/kg/天）。在双侧颈总动脉狭窄术后 30 天，测量单核细胞趋化蛋白-1 和肿瘤坏死因子-α的脑 mRNA 表达，并用 Klüver-Barrera 染色分析脱髓鞘变化，并用免疫组化分析神经胶质、氧化应激和血管内皮细胞标志物。空间工作记忆通过 Y 迷宫测试进行评估。
低剂量替米沙坦不降低平均收缩压和脑血流量，但高剂量替米沙坦显著降低。低剂量替米沙坦显著减轻，但高剂量替米沙坦引起空间工作记忆障碍，伴有神经胶质激活、少突胶质细胞丢失和白质脱髓鞘改变。GW9662 的共同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，与载体相比，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。
替米沙坦的抗炎和抗氧化作用部分通过过氧化物酶体增殖物激活受体-γ的激活发挥作用，而不是通过降低血压发挥作用，对慢性大脑低灌注后认知障碍和白质损伤具有保护作用。
