Cerebroprotective action of telmisartan by inhibition of macrophages/microglia expressing HMGB1 via a peroxisome proliferator-activated receptor gamma-dependent mechanism.
Telmisartan is known to block angiotensin (Ang) II type-1 receptors (AT(1)R), and also activate peroxisome proliferator-activated receptor gamma (PPARgamma) signaling. Recently, PPARgamma 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 2h before and 2h after MCA occlusion. Infarct size was determined at 24h 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 24h 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, PPARgamma 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 PPARgamma-dependent HMGB1 inhibiting mechanism.
Haraguchi
Tamami
T
Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
Takasaki
Kotaro
K
Naito
Tetsuya
T
Hayakawa
Kazuhide
K
Katsurabayashi
Shutaro
S
Mishima
Kenichi
K
Iwasaki
Katsunori
K
Fujiwara
Michihiro
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D024243:HMGB1 Protein / Q000096:biosynthesis* / Q000097:blood; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D000077333:Telmisartan
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001562:Benzimidazoles; D001565:Benzoates; D024243:HMGB1 Protein; D018696:Neuroprotective Agents; D047495:PPAR gamma; D000077333:Telmisartan