TY - JOUR
T1 - 17β-estradiol attenuates breakdown of blood-brain barrier and hemorrhagic transformation induced by tissue plasminogen activator in cerebral ischemia
AU - Li, Mingchang
AU - Zhang, Zhan
AU - Sun, Weiyun
AU - Koehler, Raymond C.
AU - Huang, Judy
N1 - Funding Information:
This work was supported by the Clinician Scientist Award of the Johns Hopkins University School of Medicine to Dr. Judy Huang. Dr. Raymond C. Koehler was supported by grants from the National Institutes of Health ( NS038684 and NS067525 ). The authors would like to thank Dr. Ethan Shimony and Dr. Ning Lin of Harvard Medical School for editing the manuscript.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
KW - Cerebral ischemia
KW - Estrogen
KW - Matrix metalloproteinase
KW - Middle cerebral artery
KW - Thrombolysis
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U2 - 10.1016/j.nbd.2011.07.004
DO - 10.1016/j.nbd.2011.07.004
M3 - Article
C2 - 21816222
AN - SCOPUS:80053289143
SN - 0969-9961
VL - 44
SP - 277
EP - 283
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -