title: Influence of extracellular zinc on M1 microglial activation.
abstract: Extracellular zinc, which is released from hippocampal neurons in response to brain ischaemia, triggers morphological changes in microglia. Under ischaemic conditions, microglia exhibit two opposite activation states (M1 and M2 activation), which may be further regulated by the microenvironment. We examined the role of extracellular zinc on M1 activation of microglia. Pre-treatment of microglia with 30-60 μM ZnCl2resulted in dose-dependent increases in interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNFα) secretion when M1 activation was induced by lipopolysaccharide administration. In contrast, the cell-permeable zinc chelator TPEN, the radical scavenger Trolox, and the P2X7 receptor antagonist A438079 suppressed the effects of zinc pre-treatment on microglia. Furthermore, endogenous zinc release was induced by cerebral ischaemia-reperfusion, resulting in increased expression of IL-1β, IL-6, TNFα, and the microglial M1 surface marker CD16/32, without hippocampal neuronal cell loss, in addition to impairments in object recognition memory. However, these effects were suppressed by the zinc chelator CaEDTA. These findings suggest that extracellular zinc may prime microglia to enhance production of pro-inflammatory cytokines via P2X7 receptor activation followed by reactive oxygen species generation in response to stimuli that trigger M1 activation, and that these inflammatory processes may result in deficits in object recognition memory.
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan.
authors.forename: Youichirou
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Aratake
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Institute for Laboratory Animal Research, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Neurosurgery, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Yawata
authors.affiliation: Department of Neurosurgery, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan.
authors.forename: Tetuya
authors.initials: T
authors.lastname: Ueba
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan.
authors.forename: Motoaki
authors.initials: M
authors.lastname: Saito
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002712:Chlorides / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015032:Zinc / Q000378:metabolism; D017967:Zinc Compounds / Q000494:pharmacology*
chemical_list: D002712:Chlorides; D016207:Cytokines; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D017967:Zinc Compounds; C016837:zinc chloride; D015032:Zinc