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

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

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