Telmisartan, a partial agonist of peroxisome proliferator-activated receptor gamma, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia.
Telmisartan, an angiotensin type 1 receptor blocker (ARB), is used for hypertension to control blood pressure and has been shown to have a partial agonistic effect on peroxisome proliferator-activated receptor gamma (PPARgamma). Recently, the ligand of PPARgamma has been implicated in cerebroprotection due to its anti-inflammatory effect. In this study, we investigated whether telmisartan has a cerebroprotective effect on memory impairment and neuronal cell death induced by repeated cerebral ischemia. Repeated cerebral ischemia (RI: 10 min x 2) significantly induced impairment of spatial memory and hippocampal apoptosis in rats. Fourteen-day pre- and post-ischemic administration of telmisartan (0.3, 1, 3mg/kg/day, p.o.) increased the number of correct choices and reduced the number of errors made in the eight-arm radial maze task in a dose-dependent manner in RI treated rats. TUNEL-positive cells in the hippocampus CA1 areas were also reduced following 14-day administration of telmisartan (3mg/kg/day, p.o.). Seven-day post-ischemic administration of telmisartan improved spatial memory and reduced TUNEL-positive cells while 7-day pre-ischemic administration of telmisartan did not. These effects of telmisartan were inhibited by the PPARgamma antagonist, GW9662. On further experiment, 7-day post-ischemic administration of telmisartan reduced the expression of caspase-3 in the hippocampus, and this effect was also inhibited by GW9662. These results suggest that telmisartan improves memory impairment and reduces neuronal apoptosis via a PPARgamma-dependent caspase-3 inhibiting mechanism. Telmisartan, which has the unique character of having both ARB and PPARgamma agonistic effect, will be useful for preventing memory impairment after cerebrovascular disease.
Haraguchi
Tamami
T
Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
Iwasaki
Katsunori
K
Takasaki
Kotaro
K
Uchida
Kanako
K
Naito
Tetsuya
T
Nogami
Ai
A
Kubota
Kaori
K
Shindo
Taro
T
Uchida
Naoki
N
Katsurabayashi
Shutaro
S
Mishima
Kenichi
K
Nishimura
Ryoji
R
Fujiwara
Michihiro
M
D000704:Analysis of Variance; D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology; D047495:PPAR gamma / Q000819:agonists; D051381:Rats; D017208:Rats, Wistar; D013037:Spatial Behavior / Q000187:drug effects*; D000077333:Telmisartan; D013997:Time Factors
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D053148:Caspase 3; D000077333:Telmisartan