Attenuation of focal brain ischemia by telmisartan, an angiotensin II type 1 receptor blocker, in atherosclerotic apolipoprotein E-deficient mice

Abstract

The effects of an angiotensin II (Ang II) type 1 (AT1) receptor blocker (ARB) on focal brain ischemia and atherosclerotic lesions were explored in atherosclerotic apolipoprotein E-deficient (ApoEKO) mice treated with a high-cholesterol diet (HCD). The ischemic brain area and neurological deficit 24 h after middle cerebral artery (MCA) occlusion were significantly greater in ApoEKO mice treated with HCD for 10 weeks than in those with a normal standard diet. The reduction of cerebral surface blood flow in the penumbral region and the increase in superoxide production in the ischemic area were exaggerated in HCD-treated ApoEKO mice. Histological analysis showed atherosclerotic changes in the proximal aorta and: deposition of lipid droplets in the arterial wall in the brain. Administration of an ARB, telmisartan (0.3 mg/kg/day), for the last 2 weeks after 8 weeks of HCD feeding attenuated the ischemic brain area, the neurological deficit, the superoxide production in the ischemic area, and the reduction of cerebral blood flow in the penumbra, without significantly changing blood pressure or serum cholesterol level. Telmisartan also decreased atherosclerotic lesion formation in the proximal aorta of HCD-treated ApoEKO mice, although it did not remarkably change lipid deposition in the cerebral arteries. These results suggest that the blockade of the AT1 receptor attenuates ischemic brain damage induced in an atherosclerosis model. This inhibitory action is mediated through the attenuation of the reduction in cerebral blood flow and of oxidative stress in the brain; it also mediated through telmisartan's anti-atherosclerotic effect.