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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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Effects of subarachnoid hemorrhage induction in Ntg and GET-1 mice after subarachnoid hemorrhage. (A) Kaplan-Meier curves show the survival data of the Ntg (solid line, n = 10) and the GET-1 (broken line, n = 13) mice after subarachnoid hemorrhage. (B) Line graph shows the cerebral blood flow of Ntg and GET-1 mice during SAH. (C) Histogram comparing the neurological deficit scores for the Ntg (white bar) and GET-1 (black bar) mice after SAH for 3 days. (*P < 0.05, Mann-Whitey test; n = 10 for Ntg and GET-1 mice).
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Figure 1: Effects of subarachnoid hemorrhage induction in Ntg and GET-1 mice after subarachnoid hemorrhage. (A) Kaplan-Meier curves show the survival data of the Ntg (solid line, n = 10) and the GET-1 (broken line, n = 13) mice after subarachnoid hemorrhage. (B) Line graph shows the cerebral blood flow of Ntg and GET-1 mice during SAH. (C) Histogram comparing the neurological deficit scores for the Ntg (white bar) and GET-1 (black bar) mice after SAH for 3 days. (*P < 0.05, Mann-Whitey test; n = 10 for Ntg and GET-1 mice).

Mentions: The survival rate of Ntg, and GET-1 mice was 100% and 77%, respectively, 24 hours after SAH. The survival rate of Ntg mice decreased steadily on Day 2 (90%) and Day 3 (80%) after SAH. However, GET-1 mice showed a substantial drop in the survival rate, 61% and 54% on Day 2 and Day 3, respectively. GET-1 mice were more susceptible to SAH damage with a death rate of about 50% three days after SAH (Figure 1A).


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)

Effects of subarachnoid hemorrhage induction in Ntg and GET-1 mice after subarachnoid hemorrhage. (A) Kaplan-Meier curves show the survival data of the Ntg (solid line, n = 10) and the GET-1 (broken line, n = 13) mice after subarachnoid hemorrhage. (B) Line graph shows the cerebral blood flow of Ntg and GET-1 mice during SAH. (C) Histogram comparing the neurological deficit scores for the Ntg (white bar) and GET-1 (black bar) mice after SAH for 3 days. (*P < 0.05, Mann-Whitey test; n = 10 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 1: Effects of subarachnoid hemorrhage induction in Ntg and GET-1 mice after subarachnoid hemorrhage. (A) Kaplan-Meier curves show the survival data of the Ntg (solid line, n = 10) and the GET-1 (broken line, n = 13) mice after subarachnoid hemorrhage. (B) Line graph shows the cerebral blood flow of Ntg and GET-1 mice during SAH. (C) Histogram comparing the neurological deficit scores for the Ntg (white bar) and GET-1 (black bar) mice after SAH for 3 days. (*P < 0.05, Mann-Whitey test; n = 10 for Ntg and GET-1 mice).
Mentions: The survival rate of Ntg, and GET-1 mice was 100% and 77%, respectively, 24 hours after SAH. The survival rate of Ntg mice decreased steadily on Day 2 (90%) and Day 3 (80%) after SAH. However, GET-1 mice showed a substantial drop in the survival rate, 61% and 54% on Day 2 and Day 3, respectively. GET-1 mice were more susceptible to SAH damage with a death rate of about 50% three days after SAH (Figure 1A).

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