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Epigallocatechin gallate Extends Acute Therapeutic Window for Ischemic Stroke

5/29/2017 2:51:24 PM
Brain injury after ischemic stroke can cause both short-term and long-term debilities. The injurious effects of ischemic stroke can be mitigated by immediate treatment with recombinant tissue plasminogen activator (rt-PA), a serine protease that degrades fibrin clots. The treatment window for rt-PA is narrow, however, and administration after 3 hours of stroke onset can have severe adverse effects, including cerebral edema, disruption of the blood-brain barrier, and intracerebral hemorrhage.
 
Researchers at the Wuxi Hospital in China have previously shown epigallocatechin gallate (EGCG) to extend the therapeutic window and reduce the adverse effects of delayed rt-PA treatment in ischemic rats. One of the mechanisms they identified to mediate this effect was downregulation of matrix metalloproteinases, MMP-2 and MMP-9. In a randomized, placebo-controlled trial published in Clinical Neuropharmacology (2017), these same researchers evaluated the ability of EGCG to extend the therapeutic window for rt-PA in human stroke patients.
 
A total of 371 patients receiving treatment for ischemic stroke at the Wuxi Hospital received intravenous rt-PA therapy per the standard protocol. In addition, patients were randomized to receive EGCG or placebo. EGCG (500mg, provided by Sigma-Aldrich) was administered intravenously at the same time as rt-PA, with 10% as a bolus followed by the remaining 90% as a constant infusion over 1 hour. Patients were then administered EGCG (500mg/d) or placebo intravenously for the next 7 days.
 
The primary outcome was the National Institutes of Health Stroke Scale (NIHSS) score, which ranges from 0 to 25, with 0 indicating no sign of neurological deficit.
 
One day after initial treatment, NIHSS scores were similar for all participants receiving rt-PA therapy within 0-3 hours of stroke onset and for those in the EGCG group receiving treatment at 3-5 hours after stroke onset (40%-43% in all 3 groups had NIHSS scores 0-10). However, patients in the placebo group receiving treatment at 3-5 hours after stroke onset fared significantly worse, with only 27% achieving NIHSS scores of 0-10. Scores tested after 7 days showed a similar pattern. Strong linear correlations were observed between NIHSS scores and levels of both MMP-2 and MMP-9, suggesting that the clinical effect was likely mediated by this mechanism.
 
The results of this study provide the first human clinical evidence that supplementing rt-PA therapy with EGCG could extend its therapeutic window to at least 5 hours in patients being treated for ischemic stroke.  
 
Reference: Wang XH, You YP. Epigallocatechin Gallate Extends Therapeutic Window of Recombinant Tissue Plasminogen Activator Treatment for Brain Ischemic Stroke: A Randomized Double-Blind and Placebo-Controlled Trial. Clin Neuropharmacol. 2017;40(1):24-28.