Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage
Article Nov 05, 2013
P.K.K. Yeung, J. Shen, S.S.M. Chung, S.K. Chung
Background - Endothelin-1 (ET-1) is a potent vasoconstrictor, and astrocytic ET-1 is reported to play a role in the pathogenesis of cerebral ischemic injury and cytotoxic edema. However, it is still unknown whether astrocytic ET-1 also contributes to vasogenic edema and vasospasm during subarachnoid hemorrhage (SAH). In the present study, transgenic mice with astrocytic endothelin-1 over-expression (GET-1 mice) were used to investigate the pathophysiological role of ET-1 in SAH pathogenesis.
Results - The GET-1 mice experienced a higher mortality rate and significantly more severe neurological deficits, blood–brain barrier breakdown and vasogenic edema compared to the non-transgenic (Ntg) mice following SAH. Oral administration of vasopressin V1a receptor antagonist, SR 49059, significantly reduced the cerebral water content in the GET-1 mice. Furthermore, the GET-1 mice showed significantly more pronounced middle cerebral arterial (MCA) constriction after SAH. Immunocytochemical analysis showed that the calcium-activated potassium channels and the phospho-eNOS were significantly downregulated, whereas PKC-α expression was significantly upregulated in the MCA of the GET-1 mice when compared to Ntg mice after SAH. Administration of ABT-627 (ETA receptor antagonist) significantly down-regulated PKC-α expression in the MCA of the GET-1 mice following SAH.
Conclusions - The present study suggests that astrocytic ET-1 involves in SAH-induced cerebral injury, edema and vasospasm, through ETA receptor and PKC-mediated potassium channel dysfunction. Administration of ABT-627 (ETA receptor antagonist) and SR 49059 (vasopressin V1a receptor antagonist) resulted in amelioration of edema and vasospasm in mice following SAH. These data provide a strong rationale to investigate SR 49059 and ABT-627 as therapeutic drugs for the treatment of SAH patients.
The reproducibility crisis is holding back science. London-based Labstep, a start-up out of Oxford University, think that their tool can help make science more open and reproducible. That claim has now been given some concrete evidence with the announcement that the research contingent of the MRC Unit The Gambia at LSHTM will be trialling Labstep across their Banjul-based facility.READ MORE
Researchers have identified a mechanism by which brain-derived neurotrophic factor (BDNF) can suppress GABAergic transmission in hippocampus. In this article, Dr. Rajamani Selvam explains how he and his team achieved these results, and their potential impact on the treatment of neurological disease.READ MORE