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MEK1/2 inhibition attenuates vascular ET(A) and ET (B) receptor alterations after cerebral ischaemia.

Henriksson, Marie LU ; Stenman, Emelie LU ; Vikman, Petter LU and Edvinsson, Lars LU (2007) In Experimental Brain Research 178(4). p.470-476
Abstract
Cerebral ischaemia is associated with elevated levels of endothelin B (ETB) receptors in the ipsilateral middle cerebral artery (MCA). This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases (MAPK). The aim of this study was to examine the effect of inhibition of the MAP kinase/ERK kinase (MEK)1/2 on ET receptor alteration, brain damage, and neurology in experimental cerebral ischaemia. Transient middle cerebral artery occlusion (MCAO) was induced in male Wistar rats by the intraluminal filament technique. The animals received 100 mg/kg intraperitoneally of the MEK1/2 inhibitor U0126 or vehicle in conjunction with the occlusion. After 24 h, the rats were decapitated and the brains... (More)
Cerebral ischaemia is associated with elevated levels of endothelin B (ETB) receptors in the ipsilateral middle cerebral artery (MCA). This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases (MAPK). The aim of this study was to examine the effect of inhibition of the MAP kinase/ERK kinase (MEK)1/2 on ET receptor alteration, brain damage, and neurology in experimental cerebral ischaemia. Transient middle cerebral artery occlusion (MCAO) was induced in male Wistar rats by the intraluminal filament technique. The animals received 100 mg/kg intraperitoneally of the MEK1/2 inhibitor U0126 or vehicle in conjunction with the occlusion. After 24 h, the rats were decapitated and the brains removed. The middle cerebral arteries were dissected out and examined with myographs or immunohistochemistry. The ischaemic areas of the brains were compared. After the MCAO, the contractile responses of the ETA and ETB receptors were augmented in the ipsilateral MCA. U0126 decreased this alteration in ET receptor response. Furthermore, treatment with U0126 significantly decreased the brain damage and improved neurological scores. Immunohistochemistry showed that there were lower protein levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated transcription factor Elk-1 in the U0126-treated rats compared to control. The results show that treatment with the MEK1/2 inhibitor U0126 in ischaemic stroke decreases brain damage, neurological symptoms, and ET receptor alteration. The vascular effects of U0126 provide new perspective on possible mechanisms of actions of MAPK inhibition in cerebral ischaemia. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ET, ischaemia, MCAO, MEK1/2, ERK1/2, receptor, Elk-1
in
Experimental Brain Research
volume
178
issue
4
pages
470 - 476
publisher
Springer
external identifiers
  • wos:000245429100005
  • scopus:34147181750
ISSN
0014-4819
DOI
10.1007/s00221-006-0753-7
language
English
LU publication?
yes
id
570f5da1-da13-480f-9d64-c4ffd6d4149f (old id 163372)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17091294&dopt=Abstract
date added to LUP
2007-07-09 15:51:30
date last changed
2017-04-02 03:31:46
@article{570f5da1-da13-480f-9d64-c4ffd6d4149f,
  abstract     = {Cerebral ischaemia is associated with elevated levels of endothelin B (ETB) receptors in the ipsilateral middle cerebral artery (MCA). This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases (MAPK). The aim of this study was to examine the effect of inhibition of the MAP kinase/ERK kinase (MEK)1/2 on ET receptor alteration, brain damage, and neurology in experimental cerebral ischaemia. Transient middle cerebral artery occlusion (MCAO) was induced in male Wistar rats by the intraluminal filament technique. The animals received 100 mg/kg intraperitoneally of the MEK1/2 inhibitor U0126 or vehicle in conjunction with the occlusion. After 24 h, the rats were decapitated and the brains removed. The middle cerebral arteries were dissected out and examined with myographs or immunohistochemistry. The ischaemic areas of the brains were compared. After the MCAO, the contractile responses of the ETA and ETB receptors were augmented in the ipsilateral MCA. U0126 decreased this alteration in ET receptor response. Furthermore, treatment with U0126 significantly decreased the brain damage and improved neurological scores. Immunohistochemistry showed that there were lower protein levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated transcription factor Elk-1 in the U0126-treated rats compared to control. The results show that treatment with the MEK1/2 inhibitor U0126 in ischaemic stroke decreases brain damage, neurological symptoms, and ET receptor alteration. The vascular effects of U0126 provide new perspective on possible mechanisms of actions of MAPK inhibition in cerebral ischaemia.},
  author       = {Henriksson, Marie and Stenman, Emelie and Vikman, Petter and Edvinsson, Lars},
  issn         = {0014-4819},
  keyword      = {ET,ischaemia,MCAO,MEK1/2,ERK1/2,receptor,Elk-1},
  language     = {eng},
  number       = {4},
  pages        = {470--476},
  publisher    = {Springer},
  series       = {Experimental Brain Research},
  title        = {MEK1/2 inhibition attenuates vascular ET(A) and ET (B) receptor alterations after cerebral ischaemia.},
  url          = {http://dx.doi.org/10.1007/s00221-006-0753-7},
  volume       = {178},
  year         = {2007},
}