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-a (TNF-a), interleukin-1b (IL-1b), 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.

Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia

“…Both S1R and BDNF were present in BV-2 microglial cells, yet treating these cells with an S1R agonist did not facilitate BDNF secretion. Although activated microglia (Nakajima et al, 2001; Sun et al, 2014), including a murine N9 microglial cell line (Gomes et al, 2013), are capable of secreting BDNF, our finding is in agreement with numerous studies indicating that the S1R is present in microglia and can modulate injury or toxicant-induced microgliosis by various mechanisms not involving BDNF (Behensky et al, 2013; Cuevas et al, 2011; Dong et al, 2015; Gekker et al, 2006; Hall et al, 2009; Mancuso et al, 2012; Moritz et al, 2015; Robson et al, 2013; Wegleiter et al, 2014; Wu et al, 2015; Zhao et al, 2014). Alternatively, the BV-2 cell line may lack the necessary machinery for investigating S1R-BDNF interactions in microglia or the microglia may need to be activated in order to study the effect.…”

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection

“…Associated with this reduction in M1 microglia was an obviation of IL-6 and oncostatin M, showing protection against neuroinflammation [98]. In lipopolysaccharide (LPS)-stimulated murine microglial BV2 cells, the sigma-1 agonist SKF83959 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1-(3-methylphenyl)-1H-3-benzazepine-7,8-diol) prevented M1 microglial activation and decreased pro-inflammatory cytokines, including tumor necrosis factor alpha, IL-1 beta, and inducible NOS [99]. The sigma agonists DTG (1,3-di-(2-tolyl)guanidine) and afobazole have also been shown to suppress microglial activation and migration and the release of inflammatory cytokines in response to not only LPS, but also other microglial activators such as ATP, uridine triphosphate and monocyte chemoattractant protein-1 [100].…”

Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation‐induced cell death

“…All drugs were freshly prepared before each experiment. LPS was dissolved in sterile phosphate-buffered saline as previously described (Wu et al 2015), primary microglia or BV2 microglia both were exposed to LPS (200 ng/mL) in this experiment for designed time point. CsnB was initially dissolved in dimethylsulfoxide (DMSO), and then diluted with culture medium.…”