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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.

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Western blot analysis of PKC-α and p-PKC-α in Ntg and GET-1 brain after SAH. Representative blots show PKC-α and p-PKC-α expression in the sham and SAH groups of Ntg and GET-1 brain. Histogram below shows the quantification (relative percentage) of the Western blot. (*P < 0.05, **P < 0.01, Mann-Whitey test; n = 4 for Ntg and GET-1 mice).
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Figure 4: Western blot analysis of PKC-α and p-PKC-α in Ntg and GET-1 brain after SAH. Representative blots show PKC-α and p-PKC-α expression in the sham and SAH groups of Ntg and GET-1 brain. Histogram below shows the quantification (relative percentage) of the Western blot. (*P < 0.05, **P < 0.01, Mann-Whitey test; n = 4 for Ntg and GET-1 mice).

Mentions: In SAH, ET-1 induces the development of vasospasm through enhancement of PKC-α activity, and the increased-PKC-α activity inhibits eNOS production [42,43]. To investigate whether PKC-α mediates astrocytic ET-1 induced downregulation of NOS, Western blot analysis was performed. Significant upregulation of PKC-α and p-PKC-α was observed in the brain of both Ntg and GET-1 mice after SAH when compared to their sham groups (Ntg Sham: 100 ± 3.7% vs Ntg SAH: 119.7 ± 4.6%, P < 0.05; GET-1 Sham: 100.5 ± 3.7% vs GET-1 SAH: 135.8 ± 1.6% P < 0.01, Mann–Whitney test; n = 4). Significant difference was observed between Ntg and GET-1 mice brain after SAH (Ntg SAH; 119.7 ± 4.6% vs GET-1 SAH 135.8 ± 1.6% P < 0.05, Mann–Whitney test; n = 4) (Figure 4).


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)

Western blot analysis of PKC-α and p-PKC-α in Ntg and GET-1 brain after SAH. Representative blots show PKC-α and p-PKC-α expression in the sham and SAH groups of Ntg and GET-1 brain. Histogram below shows the quantification (relative percentage) of the Western blot. (*P < 0.05, **P < 0.01, Mann-Whitey test; n = 4 for Ntg and GET-1 mice).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 4: Western blot analysis of PKC-α and p-PKC-α in Ntg and GET-1 brain after SAH. Representative blots show PKC-α and p-PKC-α expression in the sham and SAH groups of Ntg and GET-1 brain. Histogram below shows the quantification (relative percentage) of the Western blot. (*P < 0.05, **P < 0.01, Mann-Whitey test; n = 4 for Ntg and GET-1 mice).
Mentions: In SAH, ET-1 induces the development of vasospasm through enhancement of PKC-α activity, and the increased-PKC-α activity inhibits eNOS production [42,43]. To investigate whether PKC-α mediates astrocytic ET-1 induced downregulation of NOS, Western blot analysis was performed. Significant upregulation of PKC-α and p-PKC-α was observed in the brain of both Ntg and GET-1 mice after SAH when compared to their sham groups (Ntg Sham: 100 ± 3.7% vs Ntg SAH: 119.7 ± 4.6%, P < 0.05; GET-1 Sham: 100.5 ± 3.7% vs GET-1 SAH: 135.8 ± 1.6% P < 0.01, Mann–Whitney test; n = 4). Significant difference was observed between Ntg and GET-1 mice brain after SAH (Ntg SAH; 119.7 ± 4.6% vs GET-1 SAH 135.8 ± 1.6% P < 0.05, Mann–Whitney test; n = 4) (Figure 4).

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