期刊
EXPERIMENTAL NEUROLOGY
卷 297, 期 -, 页码 1-13出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2017.06.012
关键词
Ischemia-reperfusion injury; IL-1RA-PEP fusion protein; Cell penetrating peptide (CPP); Blood-brain barrier (BBB); Inflammation; Oxidative stress
资金
- National Natural Science Foundation of China [81170255]
- National Science and Technology Major Project [2012ZX09102301-017]
Neuroinflammation and oxidative stress are involved in cerebral ischemia-reperfusion, in which Interleukin 1 (IL-1), as an effective intervention target, is implicated. Interleukin-1 receptor antagonist (IL-1RA) is the natural inhibitor of IL-1, but blood-brain barrier (BBB) limits the brain penetration of intravenously administered IL-1RA, thereby restricting its therapeutic effect against neuroinflammation. In this study, we evaluated the potential effects of anti-inflammation and anti-oxidative stress of a novel protein IL-1RA-PEP, which fused IL-1RA with a cell penetrating peptide (CPP). Studies were carried out in transient middle cerebral artery occlusion (MCAO) in rats and oxygen glucose deprivation/reoxygenation (OGD/R) in primary cortical neurons. In MCAO rat model, IL-1RA-PEP (50 mg/kg) injected i.v., penetrated BBB effectively, and alleviated brain infarction, cerebral edema, neurological deficit score and motor performance as well as inhibited the inflammatory cytokines expression. Furthermore, our results firstly showed that IL-1RA-PEP also regulated the oxidases expression, decreased the levels of NO, MDA and ROS. In addition, the inhibitory effects of IL-1RA-PEP on oxidative stress and inflammation were confirmed in rat cortical neurons induced by OGD/R, it reduced ROS, IL-6 and TNF-alpha. Further study showed that the effects of IL-1RA-PEP were closely associated with the NF-kappa B and p38 pathways which were proved respectively by their inhibitors JSH-23 and SB203580. Our results indicated that IL-1RA-PEP could effectively penetrate the brain of MCAO rats, alleviated the cerebral ischemia reperfusion injury by inhibiting neuroinflammation and oxidative stress, showing a great clinical potential for stroke. (C) 2017 Published by Elsevier Inc.
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