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

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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.
OriginalsprogEngelsk
Artikelnummer1446
TidsskriftPharmaceuticals
Vol/bind15
Udgave nummer12
Antal sider15
ISSN1424-8247
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
This work was supported by the Lundbeck Foundation, Lundbeck Grant of Excellence (no. R59-A5404), the KA Wallenberg Foundation (KAW 2016.0081), and the Heart-Lung Foundation (no. 20130271). The APC was funded by the institution. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2022 by the authors.

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