期刊
BRAIN BEHAVIOR AND IMMUNITY
卷 67, 期 -, 页码 101-117出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2017.08.006
关键词
Balasubramide; Stroke; Microglia; Neuroinflammation; AMPK; PGC-1 alpha
资金
- National Natural Science Foundation of China [21402241]
- Natural Science Foundation of Jiangsu Province [BK20160032]
- Guangdong Science and Technology Plan Project [2015A020211031, 2016A020217022]
- Six Talent Peaks Project of Jiangsu Province
- Program for Jiangsu Province Shuang Chuang Team
- Postgraduate Research & Practice Innovation Program of Jiangsu Province
- Georgetown University Medical Center
Neuroinflammation plays a vital role in the pathological process of cerebral ischemic stroke, but currently there is no effective treatment. After ischemia, microglia-produced proinflammatory mediator expression contributes to the aggravation of neuroinflammation, while anti-inflammatory activation of microglia develops an anti-neuroinflammatory effect via secretion of anti-inflammatory factor. Promoting the anti-inflammatory activation of microglia might be an effective treatment of stroke. Previously, we discovered one derivative of the natural product (+)-balasubramide, compound 3C, that exhibits a remarkably anti-neuroinflammatory effect in vitro with unknown mechanisms. Thus in this study, we aimed to clarify its molecular mechanisms and determine whether compound 3C has a neuroprotective effect after ischemia via regulation on microglial inflammation. We found that compound 3C promoted the anti-inflammatory mediator expression and reduced the proinflammatory mediator expression in LPS-stimulated BV2 cells and mouse primary microglia cells, which were reversed by AMP-activated protein kinase (AMPK) inhibition or AMPK upstream calmodulin-dependent protein kinase kinase beta (CaMKK beta) inhibition. Compound 3C also prevented LPS-stimulated JNK activation and enhanced PGC-1 alpha activation in microglia, which was attenuated by AMPK inhibition. Additionally, compound 3C ameliorated depressive behaviors in LPS-induced neuroinflammatory mice by promoting the anti-inflammatory activation of microglia. Furthermore, we found that compound 3C markedly reduced brain infarct volume, improved the neurological deficit in rats with ischemia and reduced the activated microglia/macrophage cells in the ischemic area, which concomitantly enhanced the anti-inflammatory mediator expression. A mechanistic study showed that the compound 3C-mediated activation of CaMKK beta, AMPK and PGC-1 alpha is involved in the anti-neuroinflammatory and neuroprotective effects of 3C in the brain of LPS-treated mice and ischemic rats. Taken together, our results show that compound 3C could suppress neuroinflammation in vitro and in vivo by modulating microglial activation state through the CaMKK beta-dependent AMPK/PGC-1 alpha signaling pathway, and maybe further be developed as a promising new drug candidate for the treatment of brain disorders such as stroke associated with brain inflammation. (C) 2017 Elsevier Inc. All rights reserved.
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