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Article: Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage

TitleTargeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage
Authors
Issue Date2013
PublisherBioMed 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?
AbstractBACKGROUND: 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 Identifierhttp://hdl.handle.net/10722/195658
ISSN
2015 Impact Factor: 2.304
2015 SCImago Journal Rankings: 1.318
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYeung, PKKen_US
dc.contributor.authorShen, Jen_US
dc.contributor.authorChung, SSen_US
dc.contributor.authorChung, SKen_US
dc.date.accessioned2014-03-07T04:20:58Z-
dc.date.available2014-03-07T04:20:58Z-
dc.date.issued2013en_US
dc.identifier.citationB M C Neuroscience, 2013, v. 14, p. article no. 131en_US
dc.identifier.issn1471-2202en_US
dc.identifier.urihttp://hdl.handle.net/10722/195658-
dc.description.abstractBACKGROUND: 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.languageengen_US
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.biomedcentral.com/bmcneurosci/-
dc.relation.ispartofB M C Neuroscienceen_US
dc.rightsB M C Neuroscience. Copyright © BioMed Central Ltd.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleTargeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhageen_US
dc.typeArticleen_US
dc.identifier.emailYeung, PKK: ykkp@hkucc.hku.hken_US
dc.identifier.emailShen, J: shenjg@hku.hken_US
dc.identifier.emailChung, SK: skchung@hkucc.hku.hken_US
dc.identifier.authorityShen, J=rp00487en_US
dc.identifier.authorityChung, SK=rp00381en_US
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/1471-2202-14-131en_US
dc.identifier.pmid24156724-
dc.identifier.pmcidPMC3815232-
dc.identifier.hkuros228220en_US
dc.identifier.volume14en_US
dc.identifier.spagearticle no. 131en_US
dc.identifier.epagearticle no. 131en_US
dc.identifier.isiWOS:000326576600001-
dc.publisher.placeUnited Kingdom-

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