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Low dose of telmisartan prevents ischemic brain damage with peroxisome proliferator-activated receptor-γ activation in diabetic mice

Iwanami, Jun; Mogi, Masaki; Tsukuda, Kana; Min, Li-Juan; Sakata, Akiko; Jing, Fei; Iwai, Masaru; Horiuchi, Masatsugu

doi: 10.1097/HJH.0b013e32833a551a
Original papers: Stroke

Background Telmisartan is a unique AT1 receptor blocker with a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonistic action. Activation of PPAR-γ could prevent inflammation and brain damage.

Method We investigated the beneficial effect of telmisartan on ischemic brain damage via PPAR-γ activation as well as AT1 receptor blockade. Eight-week-old male KK-Ay mice were subjected to middle cerebral artery occlusion. Before middle cerebral artery occlusion, they were administered telmisartan or losartan, with or without GW9662, a PPAR-γ antagonist, for 2 weeks. Ischemic area, neurological score, oxidative stress, inflammation and cerebral blood flow were assessed 24 h after middle cerebral artery occlusion.

Results Administration of telmisartan, losartan, GW9662 and these AT1 receptor blockers with GW9662 had no significant effect on blood pressure. KK-Ay mice exhibited a significant increase in the ischemic area compared with C57BL6 mice. Treatment with telmisartan decreased the ischemic area and improved the neurological score compared with the no-treatment group, with an increase in cerebral blood flow and a reduction in superoxide production and expression of inflammatory cytokines. These protective effects of telmisartan were partially attenuated by coadministration of GW9662, although GW9662 treatment alone had no significant effect on ischemic area. Losartan treatment showed a reduction in ischemic area compared with nontreated KK-Ay mice. However, coadministration of GW9662 had no effect on the losartan-mediated reduction in ischemic area.

Conclusion These results suggest that telmisartan has a beneficial effect on stroke partly due to activation of PPAR-γ as well as AT1 receptor blockade.

Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan

Received 18 September, 2009

Revised 8 March, 2010

Accepted 26 March, 2010

Correspondence to Dr Masatsugu Horiuchi, MD, PhD, Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791 0295, Japan Tel: +81 89 960 5249; fax: +81 89 960 5251; e-mail:

© 2010 Lippincott Williams & Wilkins, Inc.