title: U0126 attenuates cerebral vasoconstriction and improves long-term neurologic outcome after stroke in female rats.
abstract: 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.
authors.affiliation: Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Hilda
authors.initials: H
authors.lastname: Ahnstedt
authors.affiliation: Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Maryam
authors.initials: M
authors.lastname: Mostajeran
authors.affiliation: Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Blixt
authors.affiliation: Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Warfvinge
authors.affiliation: Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Saema
authors.initials: S
authors.lastname: Ansar
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Irvine, California, USA.
authors.forename: Diana N
authors.initials: DN
authors.lastname: Krause
authors.affiliation: Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects*; D020521:Stroke / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009570:Nitriles; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C113580:U 0126