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NEUROPHARMACOLOGY

Blockade of AT1 Receptor Reduces Apoptosis, Inflammation, and Oxidative Stress in Normotensive Rats with Intracerebral Hemorrhage

Stroke and Neural Stem Cell Laboratory, Department of Neurology, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea (K.-H.J., K.C., S.-T.L., S.-J.K., E.-C.S., E.-H.K., D.-K.P., D.-I.S., J.-M.K., M.K., J.-K.R.); Program in Neuroscience, Neuroscience Research Institute of Seoul National University Medical Research Center, Seoul National University, Seoul, Republic of Korea (K.-H.J., K.C., S.-T.L., D.-I.S., M.K., J.-K.R.); and Division of Epidemic Intelligence Service, Korea Center for Disease Control and Prevention, Seoul, Republic of Korea (K.-H.J.)

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 and decrease oxidative stress, apoptotic signal, tumor necrosis factor-, 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.

Address correspondence to: Dr. Jae-Kyu Roh, Department of Neurology, Seoul National University Hospital, 28, Yongon-Dong, Chongro-Gu, Seoul, 110-744, Republic of Korea. E-mail: rohjk{at}snu.ac.kr

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