title: Allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation.
abstract: 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-α (TNF-α), interleukin-1β (IL-1β), 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 c17 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. SKF83959 is a potent allosteric modulator of sigma-1 receptor. Our results indicated that SKF83959 enhanced the activity of endogenous dehydroepiandrosterone (DHEA) in a synergic manner, and inhibited the activation of BV2 microglia and the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS).
authors.affiliation: Jiangsu Key laboratory of Translational Research and Therapy for Neuropsychiatric-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Jiangsu Key laboratory of Translational Research and Therapy for Neuropsychiatric-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Linlang
authors.initials: L
authors.lastname: Li
authors.affiliation: Jiangsu Key laboratory of Translational Research and Therapy for Neuropsychiatric-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Long-Tai
authors.initials: LT
authors.lastname: Zheng
authors.affiliation: Jiangsu Huayi Technology Co, Changshu, Jiangsu, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Jiangsu Key laboratory of Translational Research and Therapy for Neuropsychiatric-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Jiangsu Key laboratory of Translational Research and Therapy for Neuropsychiatric-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005029:Ethylenediamines / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000473:pathology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D015213:Neuroimmunomodulation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000893:Anti-Inflammatory Agents; D017077:Culture Media, Conditioned; D003687:Dehydroepiandrosterone; D005029:Ethylenediamines; D016753:Interleukin-10; D007654:Ketoconazole; D008070:Lipopolysaccharides; D009292:Narcotic Antagonists; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D010879:Piperazines; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; D014409:Tumor Necrosis Factor-alpha; D000097605:Sigma-1 Receptor; C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; C556062:IL10 protein, mouse; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C080703:SK&F 83959; C496317:Nos2 protein, mouse
keywords: SKF83959; allosteric modulation; dehydroepiandrosterone; microglia; neuroinflammation; sigma-1 receptor