TY - JOUR T1 - Combination Therapy of 17β-Estradiol and Recombinant Tissue Plasminogen Activator for Experimental Ischemic Stroke JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1006 LP - 1012 DO - 10.1124/jpet.109.160937 VL - 332 IS - 3 AU - Ran Liu AU - Qing Liu AU - Shaoqing He AU - James W. Simpkins AU - Shao-Hua Yang Y1 - 2010/03/01 UR - http://jpet.aspetjournals.org/content/332/3/1006.abstract N2 - Thrombolysis with recombinant tissue plasminogen activator (rtPA) in ischemic stroke is limited by the increased risk of hemorrhage transformation due to blood-brain barrier breakdown. We determined the interaction of 17β-estradiol (E2) and rtPA on activation of plasminogen system and matrix metalloproteinases (MMPs) in a transient middle cerebral artery occlusion (MCAO) model. Ovariectomized female rats were subjected to 1-h transient focal cerebral ischemia using a suture MCAO model. Ischemic lesion volume was significantly reduced with acute treatment of E2 despite of exogenous administration of rtPA. The expression and activation of urokinase (uPA), MMP2, and MMP9 were significantly increased in ischemic hemisphere after transient cerebral ischemia. Exogenous rtPA administration further enhanced expression and activation of uPA, MMP2, and MMP9, which was blocked by E2 treatment. We further determined the effect of combination therapy of E2 and rtPA in an embolic MCAO model. Although no protection was indicated upon acute treatment of E2 alone, combination treatment of E2 and rtPA provided protective action at 3 h after embolism. Collectively, the present study suggests that estrogen could be a candidate for combination therapy with rtPA to attenuate its side effect and hence expand its short therapeutic window for treatment of ischemic stroke.Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -