期刊
JOURNAL OF NEUROCHEMISTRY
卷 134, 期 5, 页码 904-914出版社
WILEY-BLACKWELL
DOI: 10.1111/jnc.13182
关键词
allosteric modulation; dehydroepiandrosterone; microglia; neuroinflammation; sigma-1 receptor; SKF83959
资金
- National Science Foundation of China [81402905, 81130023, 30825042]
- National Basic Research Plan (973) of the Ministry of Science and Technology of China [2011CB5C4403]
- Ministry of Education [20133201110017]
- Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD)
- Jiangsu Key Laboratory grant [BM2013003]
Recent studies have shown that sigma-1 receptor orthodox agonists can inhibit neuroinflammation. SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 agonist, has been recently identified as a potent allosteric modulator of sigma-1 receptor. Here, we investigated the anti-inflammatory effects of SKF83959 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Our results indicated that SKF83959 significantly suppressed the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor- (TNF-), interleukin-1 (IL-1), inducible nitric oxide synthase (iNOS), and inhibited the generation of reactive oxygen species. All of these responses were blocked by selective sigma-1 receptor antagonists (BD1047 or BD1063) and by ketoconazole (an inhibitor of enzyme cytochrome c(17) to inhibit the synthesis of endogenous dehydroepiandrosterone, DHEA). Additionally, we found that SKF83959 promoted the binding activity of DHEA with sigma-1 receptors, and enhanced the inhibitory effects of DHEA on LPS-induced microglia activation in a synergic manner. Furthermore, in a microglia-conditioned media system, SKF83959 inhibited the cytotoxicity of conditioned medium generated by LPS-activated microglia toward HT-22 neuroblastoma cells. Taken together, our study provides the first evidence that allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据