A novel IL-1RA-PEP fusion protein alleviates blood-brain barrier disruption after ischemia-reperfusion in male rats

Journal of Neuroinflammation

Chen Jin¹  Dong-Gang Xu¹  Wen-Liang Fu¹  Dong-Dong Zhang¹  Ya-Tao Zhang¹  Wei-Wei Xing¹  Wen-Ron Xia¹  Min-Ji Zou¹  Yuan-Yuan Wang¹  Tao Xu¹  Xiang-Dong Gan¹ 

[1] Beijing Institute of Basic Medical Sciences;

关键词: Ischemia-reperfusion injury;    Blood-brain barrier;    IL-1RA-PEP fusion protein;    Middle cerebral artery occlusion;    Angiogenesis;   

DOI  :  10.1186/s12974-018-1058-z

来源: DOAJ

【 摘 要 】

Abstract Background Current options to treat clinical relapse in inflammatory central nervous system (CNS) conditions such as cerebral ischemia-reperfusion injury are limited, and agents that are more effective are required. Disruption of the blood-brain barrier is an early feature of lesion formation that correlates with clinical exacerbation and facilitates the entry of inflammatory medium and inflammatory cells. Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring anti-inflammatory antagonist of the interleukin-1 (IL-1) family. The broad-spectrum anti-inflammatory effects of IL-1RA have been investigated against various forms of neuroinflammation. However, the effect of IL-1RA on blood-brain barrier disruption following ischemia-reperfusion has not been reported. Methods In this study, we investigated the effects of IL-1RA and a novel protein (IL-1RA-PEP) that was fused to IL-1RA with a cell penetrating peptide, on blood-brain barrier integrity, in male rats subjected to transient middle cerebral artery occlusion. Results After intravenous administration, IL-1RA-PEP (50 mg/kg) penetrated cerebral tissues more effectively than IL-1RA. Moreover, it preserved blood-brain barrier integrity, attenuated changes in expression and localization of tight junction proteins and matrix metalloproteinases, and enhanced angiogenesis in ischemic brain tissue. Further study suggested that the effects of IL-1RA-PEP on preserving blood-brain barrier integrity might be closely correlated with the p65/NF-κB pathway, as evidenced by the effects of the inhibitor JSH-23. Conclusions Collectively, our results demonstrated that IL-1RA-PEP could effectively penetrate the brain of rats with middle cerebral artery occlusion and ameliorate blood-brain barrier disruption. This finding might represent its novel therapeutic potential in the treatment of the cerebral ischemia-reperfusion injury.

【 授权许可】

Unknown