Combination therapy of 17β-estradiol and recombinant tissue plasminogen activator for experimental ischemic stroke

Ran Liu, Qing Liu, Shaoqing He, James W. Simpkins, Shaohua Yang

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36 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1006-1012
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume332
Issue number3
DOIs
StatePublished - 1 Mar 2010

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Tissue Plasminogen Activator
Estradiol
Stroke
Middle Cerebral Artery Infarction
Transient Ischemic Attack
Therapeutics
Plasminogen
Urokinase-Type Plasminogen Activator
Embolism
Blood-Brain Barrier
Matrix Metalloproteinases
Sutures
Estrogens
Hemorrhage

Cite this

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title = "Combination therapy of 17β-estradiol and recombinant tissue plasminogen activator for experimental ischemic stroke",
abstract = "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.",
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T1 - Combination therapy of 17β-estradiol and recombinant tissue plasminogen activator for experimental ischemic stroke

AU - Liu, Ran

AU - Liu, Qing

AU - He, Shaoqing

AU - Simpkins, James W.

AU - Yang, Shaohua

PY - 2010/3/1

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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.

AB - 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.

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