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MEK1/2 inhibitor U0126, but not nimodipine, reduces upregulation of cerebrovascular contractile receptors after subarachnoid haemorrhage in rats

Christensen, Simon T. ; Johansson, Sara E. LU ; Radziwon-Balicka, Aneta ; Warfvinge, Karin LU ; Haanes, Kristian A. and Edvinsson, Lars LU (2019) In PLoS ONE 14(4).
Abstract


Vascular pathophysiological changes after haemorrhagic stroke, such as phenotypic modulation of the cerebral arteries and cerebral vasospasms, are associated with delayed cerebral ischemia (DCI) and poor outcome. The only currently approved drug treatment shown to reduce the risk of DCI and improve neurologic outcome after aneurysmal subarachnoid haemorrhage (SAH) is nimodipine, a dihydropyridine L-type voltage-gated Ca
2+
channel blocker. MEK1/2 mediated transcriptional upregulation of contractile receptors, including endothelin-1 (ET-1)... (More)


Vascular pathophysiological changes after haemorrhagic stroke, such as phenotypic modulation of the cerebral arteries and cerebral vasospasms, are associated with delayed cerebral ischemia (DCI) and poor outcome. The only currently approved drug treatment shown to reduce the risk of DCI and improve neurologic outcome after aneurysmal subarachnoid haemorrhage (SAH) is nimodipine, a dihydropyridine L-type voltage-gated Ca
2+
channel blocker. MEK1/2 mediated transcriptional upregulation of contractile receptors, including endothelin-1 (ET-1) receptors, has previously been shown to be a factor in the pathology of SAH. The aim of the study was to compare intrathecal and subcutaneous treatment regimens of nimodipine and intrathecal treatment regimens of U0126, a MEK1/2 inhibitor, in a single injection experimental rat SAH model with post 48 h endpoints consisting of wire myography of cerebral arteries, flow cytometry of cerebral arterial tissue and behavioural evaluation. Following ET-1 concentration-response curves, U0126 exposed arteries had a significantly lower ET-1
max
than vehicle arteries. Arteries from both the intrathecal- and subcutaneous nimodipine treated animals had significantly higher ET-1
max
contractions than the U0126 arteries. Furthermore, Ca
2+
concentration response curves (precontracted with ET-1 and in the presence of nimodipine) showed that nimodipine treatment could result in larger nimodipine insensitive contractions compared to U0126. Flow cytometry showed decreased protein expression of the ET
B
receptor in U0126 treated cerebral vascular smooth muscle cells compared to vehicle. Only U0126 treatment lowered ET-1
max
contractions and ET
B
receptor levels, as well as decreased the contractions involving nimodipine-insensitive Ca
2+
channels, when compared to both intrathecal and subcutaneous nimodipine treatment. This indicate that targeting gene expression might be a better strategy than blocking specific receptors or ion channels in future treatments of SAH.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
14
issue
4
article number
e0215398
publisher
Public Library of Science
external identifiers
  • pmid:30978262
  • scopus:85064344551
ISSN
1932-6203
DOI
10.1371/journal.pone.0215398
language
English
LU publication?
yes
id
2ebb1ab5-10d3-45c1-abed-7b0937704997
date added to LUP
2019-05-03 12:59:12
date last changed
2020-07-08 04:49:30
@article{2ebb1ab5-10d3-45c1-abed-7b0937704997,
  abstract     = {<p><br>
                                                         Vascular pathophysiological changes after haemorrhagic stroke, such as phenotypic modulation of the cerebral arteries and cerebral vasospasms, are associated with delayed cerebral ischemia (DCI) and poor outcome. The only currently approved drug treatment shown to reduce the risk of DCI and improve neurologic outcome after aneurysmal subarachnoid haemorrhage (SAH) is nimodipine, a dihydropyridine L-type voltage-gated Ca                             <br>
                            <sup>2+</sup><br>
                                                          channel blocker. MEK1/2 mediated transcriptional upregulation of contractile receptors, including endothelin-1 (ET-1) receptors, has previously been shown to be a factor in the pathology of SAH. The aim of the study was to compare intrathecal and subcutaneous treatment regimens of nimodipine and intrathecal treatment regimens of U0126, a MEK1/2 inhibitor, in a single injection experimental rat SAH model with post 48 h endpoints consisting of wire myography of cerebral arteries, flow cytometry of cerebral arterial tissue and behavioural evaluation. Following ET-1 concentration-response curves, U0126 exposed arteries had a significantly lower ET-1                             <br>
                            <sub>max</sub><br>
                                                          than vehicle arteries. Arteries from both the intrathecal- and subcutaneous nimodipine treated animals had significantly higher ET-1                             <br>
                            <sub>max</sub><br>
                                                          contractions than the U0126 arteries. Furthermore, Ca                             <br>
                            <sup>2+</sup><br>
                                                          concentration response curves (precontracted with ET-1 and in the presence of nimodipine) showed that nimodipine treatment could result in larger nimodipine insensitive contractions compared to U0126. Flow cytometry showed decreased protein expression of the ET                             <br>
                            <sub>B</sub><br>
                                                          receptor in U0126 treated cerebral vascular smooth muscle cells compared to vehicle. Only U0126 treatment lowered ET-1                             <br>
                            <sub>max</sub><br>
                                                          contractions and ET                             <br>
                            <sub>B</sub><br>
                                                          receptor levels, as well as decreased the contractions involving nimodipine-insensitive Ca                             <br>
                            <sup>2+</sup><br>
                                                          channels, when compared to both intrathecal and subcutaneous nimodipine treatment. This indicate that targeting gene expression might be a better strategy than blocking specific receptors or ion channels in future treatments of SAH.                         <br>
                        </p>},
  author       = {Christensen, Simon T. and Johansson, Sara E. and Radziwon-Balicka, Aneta and Warfvinge, Karin and Haanes, Kristian A. and Edvinsson, Lars},
  issn         = {1932-6203},
  language     = {eng},
  month        = {04},
  number       = {4},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {MEK1/2 inhibitor U0126, but not nimodipine, reduces upregulation of cerebrovascular contractile receptors after subarachnoid haemorrhage in rats},
  url          = {http://dx.doi.org/10.1371/journal.pone.0215398},
  doi          = {10.1371/journal.pone.0215398},
  volume       = {14},
  year         = {2019},
}