title: Gx-50 Inhibits Neuroinflammation via α7 nAChR Activation of the JAK2/STAT3 and PI3K/AKT Pathways.
abstract: Recent studies have revealed that the α7 nicotinic acetylcholine receptor (α7 nAChR) is a critical link between inflammation and neurodegeneration, which is closely associated with Alzheimer's disease (AD). The JAK2/STAT3 and PI3K/AKT signaling pathways contribute to the neuroprotective and anti-inflammatory effects of α7nAChR. Our previous studies have shown that treatment with gx-50 improves cognitive function and is neuroprotective. Here, we investigated the effect of gx-50 on α7 nAChR and Aβ-induced inflammation in microglia. First, the binding affinity of gx-50 to α7 nAChR was examined using the fluorescence-based Octet RED system, and the expression of α7 nAChR was detected using real-time PCR and western blotting. We also investigated downstream events of α7 nAChR activity, including the translocation of p-STAT3 and the phosphorylation of JAK2, STAT3, PI3K, and AKT. Finally, the effect of gx-50 on Aβ-induced inflammation via α7 nAChR-mediated signaling pathways was investigated using cytokine assays. The results showed that gx-50 is able to act as a specific ligand to activate α7 nAChR, which then upregulates the JAK2/STAT3 and PI3K/AKT signaling pathways to inhibit the secretions of pro-inflammatory cytokines, such as IL-1β. In conclusion, the results suggest that gx-50 could inhibit the Aβ-induced inflammatory response in microglia via α7 nAChR activity, which might be a successful therapeutic target against AD.
authors.forename: Shi
authors.initials: S
authors.lastname: Shi
authors.forename: Dongli
authors.initials: D
authors.lastname: Liang
authors.forename: Min
authors.initials: M
authors.lastname: Bao
authors.forename: Yilin
authors.initials: Y
authors.lastname: Xie
authors.forename: Wangjie
authors.initials: W
authors.lastname: Xu
authors.forename: Lianyun
authors.initials: L
authors.lastname: Wang
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Wang
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Qiao
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000178:Acrylamides; D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D053614:Janus Kinase 2; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D064569:alpha7 Nicotinic Acetylcholine Receptor; C583359:lemairamin; C507926:Jak2 protein, mouse
keywords: Alzheimer’s disease; JAK2/STAT3; PI3K/AKT; gx-50; inflammation; α7 nAChR