Cerebroprotective action of telmisartan by inhibition of macrophages/microglia expressing HMGB1 via a peroxisome proliferator-activated receptor γ-dependent mechanism

Telmisartan is known to block angiotensin (Ang) II type-1 receptors (AT1R), and also activate peroxisome proliferator-activated receptor γ (PPARγ) signaling. Recently, PPARγ has been implicated as a regulator of cellular proliferation and inflammatory responses. In the present study, we investigated the anti-inflammatory effects of telmisartan on middle cerebral artery (MCA) occlusion in mice. Telmisartan was administered orally to mice at 2 h before and 2 h after MCA occlusion. Infarct size was determined at 24 h after MCA occlusion. In addition, cerebral blood flow (CBF) was measured during MCA occlusion. The effect of telmisartan on inflammatory markers, including Iba1 (macrophage/microglia marker) immunoreactivity and plasma high-mobility group box1 (HMGB1), was also investigated at 24 h after MCA. Telmisartan significantly decreased the infarct area in dose-dependent manner without affecting CBF. Furthermore, the cerebroprotective effect of telmisartan was inhibited by GW9662, PPARγ antagonist. Telmisartan significantly decreased the number of Iba1-positive cells expressing HMGB1 and decreased plasma HMGB1 levels. These effects were partially inhibited by GW9662. These data suggest that telmisartan may be a potential treatment for post-ischemic injury by partially inhibiting the inflammatory reaction after cerebral ischemia via a PPARγ-dependent HMGB1 inhibiting mechanism.