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The MEK Inhibitor Trametinib Improves Outcomes following Subarachnoid Haemorrhage in Female Rats

Bömers, Jesper Peter ; Grell, Anne Sofie LU ; Edvinsson, Lars LU ; Johansson, Sara Ellinor LU and Haanes, Kristian Agmund (2022) In Pharmaceuticals 15(12).
Abstract

Aneurysmal subarachnoid haemorrhage (SAH) is a haemorrhagic stroke that causes approximately 5% of all stroke incidents. We have been working on a treatment strategy that targets changes in cerebrovascular contractile receptors, by blocking the MEK/ERK1/2 signalling pathway. Recently, a positive effect of trametinib was found in male rats, but investigations of both sexes in pre-clinical studies are an important necessity. In the current study, a SAH was induced in female rats, by autologous blood-injection into the pre-chiasmatic cistern. This produces a dramatic, transient increase in intracranial pressure (ICP) and an acute and prolonged decrease in cerebral blood flow. Rats were then treated with either vehicle or three doses of 0.5... (More)

Aneurysmal subarachnoid haemorrhage (SAH) is a haemorrhagic stroke that causes approximately 5% of all stroke incidents. We have been working on a treatment strategy that targets changes in cerebrovascular contractile receptors, by blocking the MEK/ERK1/2 signalling pathway. Recently, a positive effect of trametinib was found in male rats, but investigations of both sexes in pre-clinical studies are an important necessity. In the current study, a SAH was induced in female rats, by autologous blood-injection into the pre-chiasmatic cistern. This produces a dramatic, transient increase in intracranial pressure (ICP) and an acute and prolonged decrease in cerebral blood flow. Rats were then treated with either vehicle or three doses of 0.5 mg/kg trametinib (specific MEK/ERK1/2 inhibitor) intraperitoneally at 3, 9, and 24 h after the SAH. The outcome was assessed by a panel of tests, including intracranial pressure (ICP), sensorimotor tests, a neurological outcome score, and myography. We observed a significant difference in arterial contractility and a reduction in subacute increases in ICP when the rats were treated with trametinib. The sensory motor and neurological outcomes in trametinib-treated rats were significantly improved, suggesting that the improved outcome in females is similar to that of males treated with trametinib.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cerebral artery, ET-1, rat, SAH, subarachnoid haemorrhage, trametinib
in
Pharmaceuticals
volume
15
issue
12
article number
1446
publisher
MDPI AG
external identifiers
  • pmid:36558896
  • scopus:85144734252
ISSN
1424-8247
DOI
10.3390/ph15121446
language
English
LU publication?
yes
id
ce1499a2-fe65-449e-9803-64ec02695320
date added to LUP
2023-01-05 12:00:04
date last changed
2025-02-07 23:28:06
@article{ce1499a2-fe65-449e-9803-64ec02695320,
  abstract     = {{<p>Aneurysmal subarachnoid haemorrhage (SAH) is a haemorrhagic stroke that causes approximately 5% of all stroke incidents. We have been working on a treatment strategy that targets changes in cerebrovascular contractile receptors, by blocking the MEK/ERK1/2 signalling pathway. Recently, a positive effect of trametinib was found in male rats, but investigations of both sexes in pre-clinical studies are an important necessity. In the current study, a SAH was induced in female rats, by autologous blood-injection into the pre-chiasmatic cistern. This produces a dramatic, transient increase in intracranial pressure (ICP) and an acute and prolonged decrease in cerebral blood flow. Rats were then treated with either vehicle or three doses of 0.5 mg/kg trametinib (specific MEK/ERK1/2 inhibitor) intraperitoneally at 3, 9, and 24 h after the SAH. The outcome was assessed by a panel of tests, including intracranial pressure (ICP), sensorimotor tests, a neurological outcome score, and myography. We observed a significant difference in arterial contractility and a reduction in subacute increases in ICP when the rats were treated with trametinib. The sensory motor and neurological outcomes in trametinib-treated rats were significantly improved, suggesting that the improved outcome in females is similar to that of males treated with trametinib.</p>}},
  author       = {{Bömers, Jesper Peter and Grell, Anne Sofie and Edvinsson, Lars and Johansson, Sara Ellinor and Haanes, Kristian Agmund}},
  issn         = {{1424-8247}},
  keywords     = {{cerebral artery; ET-1; rat; SAH; subarachnoid haemorrhage; trametinib}},
  language     = {{eng}},
  number       = {{12}},
  publisher    = {{MDPI AG}},
  series       = {{Pharmaceuticals}},
  title        = {{The MEK Inhibitor Trametinib Improves Outcomes following Subarachnoid Haemorrhage in Female Rats}},
  url          = {{http://dx.doi.org/10.3390/ph15121446}},
  doi          = {{10.3390/ph15121446}},
  volume       = {{15}},
  year         = {{2022}},
}