2010年8月
Nonhypotensive dose of telmisartan attenuates cognitive impairment partially due to peroxisome proliferator-activated receptor-γ activation in mice with chronic cerebral hypoperfusion
Stroke
- 巻
- 41
- 号
- 8
- 開始ページ
- 1798
- 終了ページ
- 1806
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1161/STROKEAHA.110.583948
Background and Purpose-: The effect of telmisartan, an angiotensin II Type 1 receptor blocker with peroxisome proliferator-activated receptor-γ- 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-γ 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-α 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. 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-α compared with vehicle. Conclusions-: Anti-inflammatory and antioxidative effects of telmisartan that were exerted in part by peroxisome proliferator-activated receptor-γ activation, but not its blood pressure-lowering effect, have protective roles against cognitive impairment and white matter damage after chronic cerebral hypoperfusion. © 2010 American Heart Association, Inc.
- リンク情報
- ID情報
-
- DOI : 10.1161/STROKEAHA.110.583948
- ISSN : 0039-2499
- PubMed ID : 20595663
- SCOPUS ID : 77955171963