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Journal of Chinese Pharmaceutical Sciences ›› 2019, Vol. 28 ›› Issue (11): 760-769.DOI: 10.5246/jcps.2019.11.072

• Original articles • Previous Articles     Next Articles

Engineering the protein targeting two pathways of cerebral ischemia reperfusion injury provides better neuroprotective effect than targeting one pathway

Kuai Yu, Ruyi Li, Yuanjun Zhu*, Xiaoyan Liu, Yinye Wang*   

  1. Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China
  • Received:2019-08-23 Revised:2019-09-15 Online:2019-12-01 Published:2019-10-25
  • Contact: Tel.: +86-10-82802652, E-mail: zhuyuanjun@bjmu.edu.cn; wangyinye@bjmu.edu.cn
  • Supported by:

    National Natural Science Foundation of China (Grant No. 81573333, 81503060).

Abstract:

We hypothesized that neuroprotective agents targeting various pathways involved in cerebral ischemia/reperfusion (I/R) injury might be superior to that targeting single pathway. Here, we prepared a fusion protein (B-I) by combining anti-apoptotic Bcl-xL (B) and anti-inflammatory IL-10 (I). B-I could cross blood brain barrier by its N-terminal TAT domain, and be cleaved into separate B and I by Caspase-1. B-I treatment significantly reduced the cerebral infarct volume, better than B or I treatment alone, and equivalent to B and I treatment (B+I). Treatment with B or B-I significantly attenuated I/R-induced neuronal apoptosis as shown by the decrease in apoptotic rate and the inhibition of caspase-3 activity. Moreover, all recombinant proteins, especially B-I, remarkably attenuated I/R-induced up-regulation of TNF-α. These results suggested that fusion protein B-I inhibiting both inflammation and apoptosis provided better neuroprotective effects than inhibiting either one alone. Our study suggested that multiple pathways targeting brain I-R injury could enhance the neuroprotective effect, and it provided a new idea for the study of neuroprotective drugs for ischemic stroke.

Key words: Cerebral ischemia reperfusion, Bifunction, Apoptosis, Inflammation, Neuroprotection

CLC Number: 

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