17β-estradiol attenuates breakdown of blood–brain barrier and hemorrhagic transformation induced by tissue plasminogen activator in cerebral ischemia

Tissue plasminogen activator (tPA) remains the only approved thrombolytic agent for the early treatment of ischemic stroke. However, treatment with tPA may lead to disruption of the blood–brain barrier and hemorrhagic transformation. 17β-estradiol (E2) has demonstrated efficacy in reduction of infarct volume in ischemic stroke models. The effects of acute administration of E2 on permeability of the blood–brain barrier and its ability to prevent hemorrhagic transformation in ischemic rats treated with tPA have not previously been studied. Here, we show that neurological deficits, brain water content, and Evan's blue extravasation were increased in ovariectomized female Wistar rats treated with tPA and attenuated in rats receiving E2 + tPA. We also show that intracerebral hemoglobin and matrix metalloproteinase-9 activity were elevated with tPA treatment, and these increases were reduced by E2 treatment. Taken together, these data demonstrate that acute administration of E2 is capable of ameliorating some of the adverse effects of tPA administration, including the increase of matrix metalloproteinase-9 activity, blood–brain barrier permeability, and hemorrhagic transformation. These findings suggest a potential role for estrogen in thrombolytic treatment for ischemic stroke.

► Neurological deficits and edema increased in ovariectomized rats with tPA but not with E2 + tPA.
► Intracerebral hemoglobin and matrix metalloproteinase-9 activity were elevated with tPA.
► E2 reduces tPA's adverse effects of increased MMP-9 activity, BBB permeability, and hemorrhage.