The MEK Inhibitor Trametinib Improves Outcomes following Subarachnoid Haemorrhage in Female Rats
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The MEK Inhibitor Trametinib Improves Outcomes following Subarachnoid Haemorrhage in Female Rats. / Bömers, Jesper Peter; Grell, Anne Sofie; Edvinsson, Lars; Johansson, Sara Ellinor; Haanes, Kristian Agmund.
I: Pharmaceuticals, Bind 15, Nr. 12, 1446, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - The MEK Inhibitor Trametinib Improves Outcomes following Subarachnoid Haemorrhage in Female Rats
AU - Bömers, Jesper Peter
AU - Grell, Anne Sofie
AU - Edvinsson, Lars
AU - Johansson, Sara Ellinor
AU - Haanes, Kristian Agmund
N1 - Publisher Copyright: © 2022 by the authors.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - cerebral artery
KW - ET-1
KW - rat
KW - SAH
KW - subarachnoid haemorrhage
KW - trametinib
U2 - 10.3390/ph15121446
DO - 10.3390/ph15121446
M3 - Journal article
C2 - 36558896
AN - SCOPUS:85144734252
VL - 15
JO - Pharmaceuticals
JF - Pharmaceuticals
SN - 1424-8247
IS - 12
M1 - 1446
ER -
ID: 346410177