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

doi:10.5246/jcps.2019.11.072

Abstract

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:

R965

Supporting:

Kuai Yu, Ruyi Li, Yuanjun Zhu, Xiaoyan Liu, Yinye Wang. Engineering the protein targeting two pathways of cerebral ischemia reperfusion injury provides better neuroprotective effect than targeting one pathway[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(11): 760-769.

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