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Pre-clinical effects of highly potent MEK1/2 inhibitors on rat cerebral vasculature after organ culture and subarachnoid haemorrhage

Christensen, Simon T.; Haanes, Kristian A.; Spray, Stine; Grell, Anne Sofie LU ; Warfvinge, Karin LU ; Edvinsson, Lars LU and Johansson, Sara E. LU (2019) In Clinical Science 133(16). p.1797-1811
Abstract

Background: Aneurysmal subarachnoid haemorrhage (SAH) is a variant of haemorrhagic stroke with a striking 50% mortality rate. In addition to the initial insult, secondary delayed brain injury may occur days after the initial ischemic insult and is associated with vasospasms leading to delayed cerebral ischemia. We have previously shown that the MEK1/2 inhibitor U0126 improves neurological assessment after SAH in rats. Aim: The purpose of the present study was to analyse the impact of a broad selection of high potency MEK1/2 inhibitors in an organ culture model and use the IC50 values obtained from the organ culture to select highly potent inhibitors for pre-clinical in vivo studies. Results: Nine highly potent mitogen... (More)

Background: Aneurysmal subarachnoid haemorrhage (SAH) is a variant of haemorrhagic stroke with a striking 50% mortality rate. In addition to the initial insult, secondary delayed brain injury may occur days after the initial ischemic insult and is associated with vasospasms leading to delayed cerebral ischemia. We have previously shown that the MEK1/2 inhibitor U0126 improves neurological assessment after SAH in rats. Aim: The purpose of the present study was to analyse the impact of a broad selection of high potency MEK1/2 inhibitors in an organ culture model and use the IC50 values obtained from the organ culture to select highly potent inhibitors for pre-clinical in vivo studies. Results: Nine highly potent mitogen activated protein kinase kinase (MEK1/2) inhibitors were screened and the two most potent inhibitors from the organ culture screening, trametinib and PD0325901, were tested in an in vivo experimental rat SAH model with intrathecal injections. Subsequently, the successful inhibitor trametinib was administered intraperitoneally in a second in vivo study. In both regimens, trametinib treatment caused significant reductions in the endothelin-1 induced contractility after SAH, which is believed to be associated with endothelin B receptor up-regulation. Trametinib treated rats showed improved neurological scores, evaluated by the ability to traverse a rotating pole, after induced SAH. Conclusion: The PD0325901 treatment did not improve the neurological score after SAH, nor showed any beneficial therapeutic effect on the contractility, contrasting with the reduction in neurological deficits seen after trametinib treatment. These data show that trametinib might be a potential candidate for treatment of SAH.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Science
volume
133
issue
16
pages
15 pages
publisher
Portland Press
external identifiers
  • scopus:85071654383
ISSN
0143-5221
DOI
10.1042/CS20190636
language
English
LU publication?
yes
id
a5a0bb43-cf67-41b8-b89a-1710b617ff73
date added to LUP
2019-09-27 12:50:05
date last changed
2019-10-08 03:59:14
@article{a5a0bb43-cf67-41b8-b89a-1710b617ff73,
  abstract     = {<p>Background: Aneurysmal subarachnoid haemorrhage (SAH) is a variant of haemorrhagic stroke with a striking 50% mortality rate. In addition to the initial insult, secondary delayed brain injury may occur days after the initial ischemic insult and is associated with vasospasms leading to delayed cerebral ischemia. We have previously shown that the MEK1/2 inhibitor U0126 improves neurological assessment after SAH in rats. Aim: The purpose of the present study was to analyse the impact of a broad selection of high potency MEK1/2 inhibitors in an organ culture model and use the IC<sub>50</sub> values obtained from the organ culture to select highly potent inhibitors for pre-clinical in vivo studies. Results: Nine highly potent mitogen activated protein kinase kinase (MEK1/2) inhibitors were screened and the two most potent inhibitors from the organ culture screening, trametinib and PD0325901, were tested in an in vivo experimental rat SAH model with intrathecal injections. Subsequently, the successful inhibitor trametinib was administered intraperitoneally in a second in vivo study. In both regimens, trametinib treatment caused significant reductions in the endothelin-1 induced contractility after SAH, which is believed to be associated with endothelin B receptor up-regulation. Trametinib treated rats showed improved neurological scores, evaluated by the ability to traverse a rotating pole, after induced SAH. Conclusion: The PD0325901 treatment did not improve the neurological score after SAH, nor showed any beneficial therapeutic effect on the contractility, contrasting with the reduction in neurological deficits seen after trametinib treatment. These data show that trametinib might be a potential candidate for treatment of SAH.</p>},
  author       = {Christensen, Simon T. and Haanes, Kristian A. and Spray, Stine and Grell, Anne Sofie and Warfvinge, Karin and Edvinsson, Lars and Johansson, Sara E.},
  issn         = {0143-5221},
  language     = {eng},
  number       = {16},
  pages        = {1797--1811},
  publisher    = {Portland Press},
  series       = {Clinical Science},
  title        = {Pre-clinical effects of highly potent MEK1/2 inhibitors on rat cerebral vasculature after organ culture and subarachnoid haemorrhage},
  url          = {http://dx.doi.org/10.1042/CS20190636},
  volume       = {133},
  year         = {2019},
}