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

Yeung PK, Shen J, Chung SS, Chung SK - BMC Neurosci (2013)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. skchung@hkucc.hku.hk.

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-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.

Show MeSH

Related in: MedlinePlus

Immunocytochemical analysis of Ca2+-activated K+ channel and ETAR expressions in Ntg and GET-1 MCA after SAH. (A) Representative micrograph shows the localization and expression of Ca2+-activated K+ channel in the MCA of the Ntg and GET-1 after SAH. (n = 3 from each group of mice). Histogram shows the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ***P < 0.005, ANOVA followed by Bonferroni’s test; n = 3 for each group of mice). (B) Representative micrograph shows the localization and expression of ETAR in the smooth muscle cells (arrows) of MCA in Ntg and GET-1 mice. Histogram shows the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ANOVA followed by Bonferroni’s test; n = 3 for each group of mice). (C) Representative micrograph shows the immunocytochemical expressions of PKC-α and the diameters of MCA after treating with ETAR antagonist ABT-627. Histogram below shows the measurements of MCA diameter. (*P < 0.05, **P < 0.01, Mann-Whitey test; n = 3 for Ntg and GET-1 mice).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3815232&req=5

Figure 5: Immunocytochemical analysis of Ca2+-activated K+ channel and ETAR expressions in Ntg and GET-1 MCA after SAH. (A) Representative micrograph shows the localization and expression of Ca2+-activated K+ channel in the MCA of the Ntg and GET-1 after SAH. (n = 3 from each group of mice). Histogram shows the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ***P < 0.005, ANOVA followed by Bonferroni’s test; n = 3 for each group of mice). (B) Representative micrograph shows the localization and expression of ETAR in the smooth muscle cells (arrows) of MCA in Ntg and GET-1 mice. Histogram shows the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ANOVA followed by Bonferroni’s test; n = 3 for each group of mice). (C) Representative micrograph shows the immunocytochemical expressions of PKC-α and the diameters of MCA after treating with ETAR antagonist ABT-627. Histogram below shows the measurements of MCA diameter. (*P < 0.05, **P < 0.01, Mann-Whitey test; n = 3 for Ntg and GET-1 mice).

Mentions: The vascular tone of the smooth muscle is regulated by the K+ membrance conductance and studies have shown that reduced expression of the potassium channels might contribute to vasospasm after SAH [44,45]. To investigate the expression of the Ca2+-activated K+ channel in the MCA after SAH, immunocytochemical analysis was performed. Significant downregulation of Ca2+-activated K+ channel expression was observed in both Ntg and GET-1 MCA after SAH compared to their sham groups. GET-1 MCA after SAH showed a significant reduction of Ca2+-activated K+ channel expression compared to the Ntg MCA (Figure 5A), suggesting that astrocytic ET-1 mediated-SAH induces a more severe dysfunction of K+ channel that might lead to cerebral vasospasm.


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

Yeung PK, Shen J, Chung SS, Chung SK - BMC Neurosci (2013)

Immunocytochemical analysis of Ca2+-activated K+ channel and ETAR expressions in Ntg and GET-1 MCA after SAH. (A) Representative micrograph shows the localization and expression of Ca2+-activated K+ channel in the MCA of the Ntg and GET-1 after SAH. (n = 3 from each group of mice). Histogram shows the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ***P < 0.005, ANOVA followed by Bonferroni’s test; n = 3 for each group of mice). (B) Representative micrograph shows the localization and expression of ETAR in the smooth muscle cells (arrows) of MCA in Ntg and GET-1 mice. Histogram shows the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ANOVA followed by Bonferroni’s test; n = 3 for each group of mice). (C) Representative micrograph shows the immunocytochemical expressions of PKC-α and the diameters of MCA after treating with ETAR antagonist ABT-627. Histogram below shows the measurements of MCA diameter. (*P < 0.05, **P < 0.01, Mann-Whitey test; n = 3 for Ntg and GET-1 mice).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815232&req=5

Figure 5: Immunocytochemical analysis of Ca2+-activated K+ channel and ETAR expressions in Ntg and GET-1 MCA after SAH. (A) Representative micrograph shows the localization and expression of Ca2+-activated K+ channel in the MCA of the Ntg and GET-1 after SAH. (n = 3 from each group of mice). Histogram shows the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ***P < 0.005, ANOVA followed by Bonferroni’s test; n = 3 for each group of mice). (B) Representative micrograph shows the localization and expression of ETAR in the smooth muscle cells (arrows) of MCA in Ntg and GET-1 mice. Histogram shows the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ANOVA followed by Bonferroni’s test; n = 3 for each group of mice). (C) Representative micrograph shows the immunocytochemical expressions of PKC-α and the diameters of MCA after treating with ETAR antagonist ABT-627. Histogram below shows the measurements of MCA diameter. (*P < 0.05, **P < 0.01, Mann-Whitey test; n = 3 for Ntg and GET-1 mice).
Mentions: The vascular tone of the smooth muscle is regulated by the K+ membrance conductance and studies have shown that reduced expression of the potassium channels might contribute to vasospasm after SAH [44,45]. To investigate the expression of the Ca2+-activated K+ channel in the MCA after SAH, immunocytochemical analysis was performed. Significant downregulation of Ca2+-activated K+ channel expression was observed in both Ntg and GET-1 MCA after SAH compared to their sham groups. GET-1 MCA after SAH showed a significant reduction of Ca2+-activated K+ channel expression compared to the Ntg MCA (Figure 5A), suggesting that astrocytic ET-1 mediated-SAH induces a more severe dysfunction of K+ channel that might lead to cerebral vasospasm.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. skchung@hkucc.hku.hk.

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-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.

Show MeSH
Related in: MedlinePlus