title: Regulation of rotenone-induced microglial activation by 5-lipoxygenase and cysteinyl leukotriene receptor 1.
abstract: The 5-lipoxygenase (5-LOX) products cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators. CysLTs mediate their biological actions through activating CysLT receptors (CysLT(1)R and CysLT(2)R). We have recently reported that 5-LOX and CysLT(1)R mediated PC12 cell injury induced by high concentrations of rotenone (0.3-10 μM), which was reduced by the selective 5-LOX inhibitor zileuton and CysLT(1)R antagonist montelukast. The purpose of this study was to examine the regulatory roles of the 5-LOX/CysLT(1)R pathway in microglial activation induced by low concentration rotenone. After mouse microglial BV2 cells were stimulated with rotenone (0.3-3 nM), phagocytosis and release of pro-inflammatory cytokine were assayed as indicators of microglial activation. We found that rotenone (1 and 3 nM) increased BV2 microglial phagocytosis and the release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Zileuton and montelukast prevented rotenone (3 nM)-induced phagocytosis and cytokine release. Furthermore, rotenone significantly up-regulated 5-LOX expression, induced 5-LOX translocation to the nuclear envelope, and increased the production of CysLTs. These responses were inhibited by zileuton. Rotenone also increased CysLT(1)R expression and induced nuclear translocation of CysLT(1)R. In primary rat microglia, rotenone (10 nM) increased release of IL-1β and TNF-α, whereas zileuton (0.1 μΜ) and montelukast (0.01 μΜ) significantly inhibited this response. These results indicated that 5-LOX and CysLT(1)R might be key regulators of microglial activation induced by low concentration of rotenone. Interference of 5-LOX/CysLT(1)R pathway may be an effective therapeutic strategy for microglial inflammation.
authors.affiliation: Department of Pharmacology, Hangzhou Key Laboratory of Medical Neurobiology, School of Medicine, Hangzhou Normal University, 16 Xue Lin Road, Hangzhou 310036, PR China. Electronic address: zxy19870910@126.com.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Hangzhou Key Laboratory of Medical Neurobiology, School of Medicine, Hangzhou Normal University, 16 Xue Lin Road, Hangzhou 310036, PR China. Electronic address: chenlu19891128@163.com.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Hangzhou Key Laboratory of Medical Neurobiology, School of Medicine, Hangzhou Normal University, 16 Xue Lin Road, Hangzhou 310036, PR China. Electronic address: yyang@hznu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, 388 Yu Hang Tang Road, Hangzhou 310058, PR China. Electronic address: 286993845@qq.com.
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, 388 Yu Hang Tang Road, Hangzhou 310058, PR China; Department of Clinical Medicine, School of Medicine, Zhejiang University, 388 Yu Hang Tang Road, Hangzhou 310058, PR China. Electronic address: 3100102379@zju.edu.cn.
authors.forename: Si-Ran
authors.initials: SR
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Hangzhou Key Laboratory of Medical Neurobiology, School of Medicine, Hangzhou Normal University, 16 Xue Lin Road, Hangzhou 310036, PR China. Electronic address: lct@hznu.edu.cn.
authors.forename: Chen-Tan
authors.initials: CT
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Hangzhou Key Laboratory of Medical Neurobiology, School of Medicine, Hangzhou Normal University, 16 Xue Lin Road, Hangzhou 310036, PR China. Electronic address: Wei.zheng@hznu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, 388 Yu Hang Tang Road, Hangzhou 310058, PR China. Electronic address: shuying.101@163.com.
authors.forename: Shu-Ying
authors.initials: SY
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, 388 Yu Hang Tang Road, Hangzhou 310058, PR China. Electronic address: weieq2006@zju.edu.cn.
authors.forename: Er-Qing
authors.initials: EQ
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, Hangzhou Key Laboratory of Medical Neurobiology, School of Medicine, Hangzhou Normal University, 16 Xue Lin Road, Hangzhou 310036, PR China. Electronic address: lhzhang@hznu.edu.cn.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018077:Receptors, Leukotriene / Q000378:metabolism*; D012402:Rotenone / Q000633:toxicity*
chemical_list: D016207:Cytokines; D018077:Receptors, Leukotriene; D012402:Rotenone; D001094:Arachidonate 5-Lipoxygenase; C083169:leukotriene D4 receptor
keywords: 5-lipoxygenase; Cysteinyl leukotriene receptor; Microglial activation; Neuroinflammation; Rotenone