title: Inhibition of glycogen synthase kinase-3β by lithium chloride suppresses 6-hydroxydopamine-induced inflammatory response in primary cultured astrocytes.
abstract: An increasing amount of evidence has emerged to suggest that neuroinflammatory process is involved in the pathogenesis of Parkinson's disease (PD). Activated microglia and astrocytes are found in the substantia nigra (SN) of Parkinson's disease brains as well as in animal models of Parkinson's disease. Although reactive astrocytes are involved in the progression of PD, the role of reactive astrocytes in neuroinflammation of PD has received limited attention to date. Recently, Glycogen synthase kinase-3β (GSK-3β) was identified as a crucial regulator of the inflammatory response. The purpose of this study was to explore the mechanism by which 6-hydroxydopamine (6-OHDA) induces inflammatory response in astrocytes and observe the anti-inflammatory effect of lithium chloride (LiCl) on 6-OHDA-treated astrocytes. In the present study, we found that glial fibrillary acidic protein (GFAP) was markedly upregulated in the presence of 6-OHDA. Moreover, our results revealed that proinflammatory molecules including inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase-2(COX-2), prostaglandins E2 (PGE2), and tumor necrosis factor-α (TNF-α) were obviously increased in astrocytes exposed to 6-OHDA. Western blot analysis revealed that 6-OHDA significantly increased dephosphorylation/activation of GSK-3β as well as the nuclear translocation of nuclear factor-κB (NF-κB) p65. Besides, GSK-3β inhibitor LiCl and SB415286 inhibited the GSK-3β/NF-κB signaling pathway, leading to the reduction of proinflammatory molecules in 6-OHDA-activated astrocytes. These results confirmed that GSK-3β inhibitor LiCl and SB415286 provide protection against neuroinflammation in 6-OHDA-treated astrocytes. Therefore, GSK-3β may be a potential therapeutic target for the treatment of PD.
authors.affiliation: Department of Neurology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Wang
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Huang
authors.forename: Rong-Fu
authors.initials: RF
authors.lastname: Chen
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Sun
mesh_terms: D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D007249:Inflammation / Q000139:chemically induced*; D018021:Lithium Chloride / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D005904:Glial Fibrillary Acidic Protein; D008301:Maleimides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D016627:Oxidopamine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D015232:Dinoprostone
keywords: 4′,6-diamidino-2-phenylindole, dihydrochloride; 6-OHDA; 6-hydroxydopamine; COX-2; DAPI; GFAP; GSK; Glycogen synthase kinase-3β; IL-6; LPS; LiCl; Lithium chloride; NF-κB; NO; Nuclear factor kappa B; PD; PGE2; Parkinson’s disease; Proinflammatory molecules; SN; SNpc; TNF-α; cyclooxygenase-2; glial fibrillary acidic protein; glycogen synthase kinase; iNOS; inducible nitric oxide synthase; interleukin-6; lipopolysaccharide; lithium chloride; nitric oxide; nuclear factor kappa B; prostaglandins E2; substantia nigra; substantia nigra pars compacta; tumor necrosis factor-α