Over-expression of endothelin-1 in astrocytes lead to chronic cognitive deficit and brain edema after transient middle cerebral artery occlusion

Abstract

Previously, we demonstrated that transgenic mice with the overexpression of endothelin-1 (ET-1) in astrocyte (GET-1) displayed more severe sensorimotor deficits, larger infarct volume and edema after 2 hours of middle cerebral artery occlusion (MCAO) and 22 hours of reperfusion. However, it is not clear whether astrocytic ET-1 has chronic functional deficit after transient MCAO. Here, GET-1 and non-transgenic mice were challenged with 30 minutes of ischemia followed by 1, 3, 7 days and 1, 3 or 5 months of reperfusion. Cognitive deficit was determined by testing their spatial reference memory as well as evaluating their brain lesion and edema by T2-weighted MRI (T2WI). T2WI results indicated that severe brain infarct and edema occurred 3 days after injury in GET-1 mice in the cortex and hippocampus. In addition, glial fibillary acidic protein (GFAP) staining revealed that the number of reactivated astrocytes was increased dramatically in the similar areas with T2WI positive signal. Progressive tissue loss was subsequently observed in the same areas when assessed 3 months after injury. In line with the imaging and histological data, GET-1 mice exhibited severe spatial reference memory impairment when assessed 7 days and 3 months after injury. Taken together, astrocytic ET-1 contributed to cognitive function deficit associated with brain edema and infarct induced by short duration of ischemia.