Combination therapy of 17beta-estradiol and recombinant tissue plasminogen activator for experimental ischemic stroke.
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 17beta-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.
Liu
Ran
R
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.
Liu
Qing
Q
He
Shaoqing
S
Simpkins
James W
JW
Yang
Shao-Hua
SH
D000818:Animals; D004359:Drug Therapy, Combination; D004789:Enzyme Activation; D004958:Estradiol / Q000627:therapeutic use*; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D011994:Recombinant Proteins; D004958:Estradiol; D010959:Tissue Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9