In:
European Journal of Neuroscience, Wiley, Vol. 39, No. 12 ( 2014-06), p. 2107-2118
Abstract:
Ischemic stroke is currently treated with thrombolytic therapy with a drawback to induce hemorrhagic transformation ( HT ) if applied beyond its relatively narrow treatment time window. The present study was designed to examine the role of IMM ‐ H 004, a derivative of coumarin, in recombinant tissue plasminogen activator (t PA )‐induced HT . Rats subjected to 6 h of thromboembolic occlusion or middle cerebral artery occlusion received t PA with or without IMM ‐ H 004. Delayed t PA intervention drastically increased the risk of HT and exaggerated the ischemic injury. To assess the effect of IMM ‐ H 004 on delayed treatment of t PA ‐induced toxicity after ischemia and reperfusion, various approaches were used, including a behavior test, TTC ‐staining, determination of cerebral hemorrhage, laser speckle imaging, Western blot, gelatin zymogram, immunohistochemistry and immunofluorescence staining. Experiments were also conducted in vitro in human brain microvascular endothelial cells ( HBMEC s) and PC 12 cells to explore the mechanism for the role of IMM ‐ H 004. Combination therapy of t PA and IMM ‐ H 004 prevented the development of HT , and reduced the mortality rate, infarct volume and brain edema. IMM ‐ H 004 also exerted a protective role by decreasing matrix metalloproteinases, the co‐localization of matrix metalloproteinase‐2 with astrocytes and increasing occludin. Experiments in HBMEC s and PC 12 revealed an elevation in ATP level and a protein kinase A ‐ and PI 3 K ‐dependent activation of A kt by IMM ‐ H 004 after t PA administration. These results suggest IMM ‐ H 004 as a promising adjuvant to alleviate the detrimental side effects of t PA in clinical therapy of ischemic stroke, and contribute to better understand the mechanism for the beneficial role of this novel remedy.
Type of Medium:
Online Resource
ISSN:
0953-816X
,
1460-9568
DOI:
10.1111/ejn.2014.39.issue-12
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2005178-5
SSG:
12
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