Publication Date

2007

Document Type

Thesis

Committee Members

Yanfang Chen (Advisor)

Degree Name

Master of Science (MS)

Abstract

Angiotensin (Ang) AT1 receptors are considered to play an important role in ischemic stroke via degenerative processes leading to cell death. Recent clinical and basic studies show that systemic blockade of Ang AT1 receptors reduces brain lesion in ischemic stroke. In this study we evaluated whether blockade of central Ang AT1 receptors protects the brain from ischemia and inflammation during ischemic stroke. Adult male C57BL/6 mice were divided into two groups for chronic intracerebroventricular (ICV) infusion of a selective Ang AT1 receptor antagonist, losartan (Los, n=18, 2 ug/hr) or isotonic saline (Con, n=20) using osmotic minipump. Twelve days post infusion, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). The success of MCAO was verified by measurement of cerebral blood flow (CBF) using laser-Doppler flowmetry. Neurological deficits due to ischemic damage of neuronal cells were evaluated 24 hours after MCAO. Brains were removed 48 hrs after MCAO and the degree of damage due to ischemia was determined using triphenyltetrazolium chloride (TTC) staining. The expression of Ang AT1 receptors, matrix metalloproteinase-2 (MMP-2) and myeloperoxidase (MPO) was carried out using western blot analysis. Immunohistochemistry was performed to determine the inflammatory cell infiltration in control vs. losartan treated mice. Focal cerebral ischemia resulted in overexpression of Ang AT1 receptor ischemic hemisphere compared to non-ischemic hemisphere (27%, p<0.05) suggesting a role of Ang AT1 receptor in ischemia. We also found a significant increase in the expression of MPO and MMP-2 in ischemic vs. non-ischemic hemispheres. Pretreatment with losartan significantly improved neurological deficits and infarct volume compared to control mice (p < 0.05). Parelleling these effects on ischemia, losartan pretreatment also reduced (~50%) the reactive upregulation of MPO (P < 0.05) and inflammatory cells (neutrophils and macrophages, P < 0.01) in the ischemic area. These results support a role for Ang AT1 receptors in cerebral ischemia and inflammation produced by stroke.

Page Count

61

Department or Program

Department of Pharmacology and Toxicology

Year Degree Awarded

2007

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