Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage.
Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.
Jung
Keun-Hwa
KH
Stroke and Neural Stem Cell Laboratory, Department of Neurology, Clinical Research Institute, Seoul National University Hospital, 28, Yongon-Dong, Chongro-Gu, Seoul, 110-744, Republic of Korea.
Chu
Kon
K
Lee
Soon-Tae
ST
Kim
Se-Jeong
SJ
Song
Eun-Cheol
EC
Kim
Eun-Hee
EH
Park
Dong-Kyu
DK
Sinn
Dong-In
DI
Kim
Jeong-Min
JM
Kim
Manho
M
Roh
Jae-Kyu
JK
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics; D051381:Rats; D000077333:Telmisartan; D015854:Up-Regulation / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D018696:Neuroprotective Agents; D047495:PPAR gamma; D052250:Nitric Oxide Synthase Type III; D000077333:Telmisartan