Endothelin-1 leads to increased necrotic cell density in the brain after transient focal cerebral ischemia

Abstract

A transgenic (Tg) mouse model was developed to study the role of astrocytic endothelin-1 (ET-1) in cerebral injury. We have previously shown that this over-expression of ET-1 in the brain did not affect the development of the mouse embryo and the brain since no gross abnormalities were observed in Tg mouse brains. However, Tg mice displayed an increase in cerebral infarct size and more severe neurological deficits upon focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO) as reported previously. By quantitative PCR analyses, we observed that wildtype (WT) animals displayed a 2.5 fold increase in ET-1 mRNA levels in the ipsilateral brain after MCAO as we expected whereas Tg mice showed a 17.5 fold increase in ET-1 mRNA levels when compared to WT animals under both sham-operation and MCAO. Interestingly, when we examined the brain sections of the MCAO animals, we observed that there were fewer apoptotic cells but more necrotic cells in the lesion core of cerebral infarct regions in Tg mice when compared to their WT littermates. Our data suggested that ET-1 overexpression resulted in larger infarct size with more severe neurological deficits and increased cell death after MCAO. Yet, the relatively higher density of necrotic vs. apoptotic cells in the lesion core suggested that ET-1 may contribute to increased necrotic cell density in the brain after transient focal cerebral ischemia. Supported by Research Grants Council (Hong Kong)