Low dose of telmisartan prevents ischemic brain damage with peroxisome proliferator-activated receptor-gamma activation in diabetic mice.
BACKGROUND
Telmisartan is a unique AT1 receptor blocker with a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonistic action. Activation of PPAR-gamma could prevent inflammation and brain damage.


METHODS
We investigated the beneficial effect of telmisartan on ischemic brain damage via PPAR-gamma 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-gamma 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.


CONCLUSIONS
These results suggest that telmisartan has a beneficial effect on stroke partly due to activation of PPAR-gamma as well as AT1 receptor blockade.
Iwanami
Jun
J
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan.
Mogi
Masaki
M
Tsukuda
Kana
K
Min
Li-Juan
LJ
Sakata
Akiko
A
Jing
Fei
F
Iwai
Masaru
M
Horiuchi
Masatsugu
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013481:Superoxides / Q000378:metabolism; D000077333:Telmisartan
C457499:2-chloro-5-nitrobenzanilide; D047228:Angiotensin II Type 1 Receptor Blockers; D000813:Anilides; D001562:Benzimidazoles; D001565:Benzoates; D016207:Cytokines; D047495:PPAR gamma; D013481:Superoxides; D019808:Losartan; D000077333:Telmisartan