Chronic treatment with Losartan and Cerebral Ischemic Tolerance

Author(s): Zonghang Zhao, Ursula I. Tuor and Phil Barber

Clinical trials have suggested that Losartan has beneficial effects on preventing stroke beyond its antihypertensive properties. Although there is evidence for Losartan reducing ischemic damage following a highly localized type of stroke, its role in larger focal and global ischemic insults and the importance of blood pressure change are not known. We hypothesized that pre-treatment with Losartan would enhance the tolerance of the brain to both global and focal ischemia. Two weeks prior to ischemia, rats were administered either Losartan 50 mg/day in their drinking water or vehicle (water) alone. The neuroprotective effects of Losartan were assessed by either global ischemia using 10 minutes of four-vessel occlusion (4-VO) or 90 minutes of focal ischemia by distal middle cerebral artery occlusion. Seven days after 4-VO, histological assessment of cellular injury in the hippocampal CA1 region was performed. In addition, brain injury following transient MCAO was assessed by magnetic resonance imaging and histology. Losartan pretreatment reduced neuronal damage following global ischemia, as detected by 92% versus 46% neuronal cell death in CA1 region for Control and Losartan groups, respectively (p<0.001). Following transient ischemia, pre-treatment with Losartan resulted in a reduced infarct volume: measured as 41% ± 10% versus 26% ± 12% of the hemisphere in control and Losartan groups, respectively (p<0.04). These protective effects were observed in spite of 12-15 % reductions in blood pressure in the Losartan treated group. Our results demonstrate that pre-treatment with Losartan enhances the tolerance of the brain to either global or focal ischemia and provides further evidence for Losartan as a treatment for stroke prevention.