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- Publisher Website: 10.1186/1471-2202-14-131
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Article: Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage
Title | Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage |
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Authors | |
Keywords | Astrocytes Brain edema Endothelium Subarachnoid hemorrhage Vasospasm |
Issue Date | 2013 |
Publisher | BioMed Central Ltd. The Journal's web site is located at http://www.biomedcentral.com/bmcneurosci/ |
Citation | B M C Neuroscience, 2013, v. 14, p. article no. 131 How to Cite? |
Abstract | 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-alpha 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-alpha 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. |
Persistent Identifier | http://hdl.handle.net/10722/195658 |
ISSN | 2023 Impact Factor: 2.4 2023 SCImago Journal Rankings: 0.666 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Yeung, PKK | en_US |
dc.contributor.author | Shen, J | en_US |
dc.contributor.author | Chung, SS | en_US |
dc.contributor.author | Chung, SK | en_US |
dc.date.accessioned | 2014-03-07T04:20:58Z | - |
dc.date.available | 2014-03-07T04:20:58Z | - |
dc.date.issued | 2013 | en_US |
dc.identifier.citation | B M C Neuroscience, 2013, v. 14, p. article no. 131 | en_US |
dc.identifier.issn | 1471-2202 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/195658 | - |
dc.description.abstract | 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-alpha 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-alpha 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. | en_US |
dc.language | eng | en_US |
dc.publisher | BioMed Central Ltd. The Journal's web site is located at http://www.biomedcentral.com/bmcneurosci/ | - |
dc.relation.ispartof | B M C Neuroscience | en_US |
dc.rights | B M C Neuroscience. Copyright © BioMed Central Ltd. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | Astrocytes | - |
dc.subject | Brain edema | - |
dc.subject | Endothelium | - |
dc.subject | Subarachnoid hemorrhage | - |
dc.subject | Vasospasm | - |
dc.title | Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage | en_US |
dc.type | Article | en_US |
dc.identifier.email | Yeung, PKK: ykkp@hkucc.hku.hk | en_US |
dc.identifier.email | Shen, J: shenjg@hku.hk | en_US |
dc.identifier.email | Chung, SK: skchung@hkucc.hku.hk | en_US |
dc.identifier.authority | Shen, J=rp00487 | en_US |
dc.identifier.authority | Chung, SK=rp00381 | en_US |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1186/1471-2202-14-131 | en_US |
dc.identifier.pmid | 24156724 | - |
dc.identifier.pmcid | PMC3815232 | - |
dc.identifier.scopus | eid_2-s2.0-84886160406 | - |
dc.identifier.hkuros | 228220 | en_US |
dc.identifier.volume | 14 | en_US |
dc.identifier.spage | article no. 131 | en_US |
dc.identifier.epage | article no. 131 | en_US |
dc.identifier.isi | WOS:000326576600001 | - |
dc.publisher.place | United Kingdom | - |
dc.identifier.issnl | 1471-2202 | - |