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U0126 attenuates cerebral vasoconstriction and improves long-term neurologic outcome after stroke in female rats.

Ahnstedt, Hilda LU ; Mostajeran, Maryam LU ; Blixt, Frank LU ; Warfvinge, Karin LU ; Ansar, Saema LU ; Krause, Diana N and Edvinsson, Lars LU (2015) In Journal of Cerebral Blood Flow and Metabolism 35(3). p.454-460
Abstract
Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours... (More)
Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 December 2014; doi:10.1038/jcbfm.2014.217. (Less)
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Contribution to journal
publication status
published
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in
Journal of Cerebral Blood Flow and Metabolism
volume
35
issue
3
pages
454 - 460
publisher
Nature Publishing Group
external identifiers
  • pmid:25492115
  • wos:000350393600014
  • scopus:84938527442
ISSN
1559-7016
DOI
10.1038/jcbfm.2014.217
language
English
LU publication?
yes
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aba6058c-293f-42a0-ab2f-35d8f163e22a (old id 4908697)
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http://www.ncbi.nlm.nih.gov/pubmed/25492115?dopt=Abstract
date added to LUP
2015-01-10 15:13:29
date last changed
2017-10-01 03:06:11
@article{aba6058c-293f-42a0-ab2f-35d8f163e22a,
  abstract     = {Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 December 2014; doi:10.1038/jcbfm.2014.217.},
  author       = {Ahnstedt, Hilda and Mostajeran, Maryam and Blixt, Frank and Warfvinge, Karin and Ansar, Saema and Krause, Diana N and Edvinsson, Lars},
  issn         = {1559-7016},
  language     = {eng},
  number       = {3},
  pages        = {454--460},
  publisher    = {Nature Publishing Group},
  series       = {Journal of Cerebral Blood Flow and Metabolism},
  title        = {U0126 attenuates cerebral vasoconstriction and improves long-term neurologic outcome after stroke in female rats.},
  url          = {http://dx.doi.org/10.1038/jcbfm.2014.217},
  volume       = {35},
  year         = {2015},
}