U0126 attenuates cerebral vasoconstriction and improves long-term neurologic outcome after stroke in female rats

作者：Ahnstedt Hilda^*; Mostajeran Maryam; Blixt Frank W; Warfvinge Karin; Ansar Saema; Krause Diana N; Edvinsson Lars

来源：Journal of Cerebral Blood Flow and Metabolism, 2015, 35(3): 454-460.

DOI：10.1038/jcbfm.2014.217

• cerebral ischemia
• endothelin receptors
• extracellular signal regulated kinase 1 and 2
• female
• middle cerebral artery occlusion
• U0126

Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24?hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome

• 出版日期2015-3