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A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage

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Takizawa, Shunya Dan, Takashi Uesugi, Tsuyoshi Nagata, Eiichiro Takagi, Shigeharu Van Ypersele de Strihou, Charles [UCL] Miyata, Toshio

Angiotensin II receptor blockers (ARBs) have a potent ability to inhibit oxidative stress and advanced glycation, in addition to their protective effects originated from blood pressure lowering and angiotensin II type 1 receptor (AT(1))-blockade. To obtain a pharmacological tool to dissect the mechanisms of ARBs' protective benefits in experimental stroke, we synthesized a novel ARB-derivative, R-147176, which is 6,700 times less potent than olmesartan in AT(1)-binding inhibition and therefore has a minimal antihypertensive effect, but retains marked inhibitory effects on oxidative stress and advanced glycation. We evaluated the effect of R-147176 (10-30 mg/kg per day), administered orally or intravenously, on brain infarct volume in transient thread occlusion and photothrombotic models in rats. The antioxidative and antiinflammatory properties were also investigated. R-147176 significantly reduced infarct volume, without influence on blood pressure, in both models. R-147176 significantly reduced the numbers of ED-1-positive cells and of TUNEL-positive cells, and protein carbonyl formation in the damaged brain. This ARB derivative, despite its significantly lower AT1 affinity and virtually no antihypertensive effect, ameliorated ischemic cerebral damage through antioxidative and antiinflammatory properties. These findings suggest potential usefulness of R-147176 as a pharmacological tool to investigate the ARBs' protective effect in experimental stroke and open new therapeutic avenues. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1665-1672; doi:10.1038/jcbfm.2009.82; published online 17 June 2009

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2009
Language Anglais
Journal information "Journal of Cerebral Blood Flow and Metabolism" - Vol. 29, no. 10, p. 1665-1672 (2009)
Peer reviewed yes
Publisher Nature Publishing Group ((United States) New York)
issn 0271-678X
e-issn 1559-7016
Publication status Publié
Affiliations UCL - (SLuc) Service de néphrologie
UCL - MD/MINT - Département de médecine interne
Keywords Angiotensin receptor ; Blood pressure ; Cerebral infarction ; Neuroprotection ; Oxidative stress
Links
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Bibliographic reference Takizawa, Shunya ; Dan, Takashi ; Uesugi, Tsuyoshi ; Nagata, Eiichiro ; Takagi, Shigeharu ; et. al. A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage. In: Journal of Cerebral Blood Flow and Metabolism, Vol. 29, no. 10, p. 1665-1672 (2009)
Permanent URL http://hdl.handle.net/2078.1/35271