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Mechanism of Microglia Neuroprotection: Involvement of P2X7, TNF alpha, and Valproic Acid

Masuch, A., Shieh, C-H., van Rooijen, N., van Calker, D. & Biber, K., Jan-2016, In : Glia. 64, 1, p. 76-89 14 p.

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  • Mechanism of Microglia Neuroprotection Involvement of P2X7, TNF alpha

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DOI

  • Annette Masuch
  • Chu-Hsin Shieh
  • Nico van Rooijen
  • Dietrich van Calker
  • Knut Biber

Recently, we have demonstrated that ramified microglia are neuroprotective in N-methyl-D-aspartate (NMDA)-induced excitotoxicity in organotypic hippocampal slice cultures (OHSCs). The present study aimed to elucidate the underlying neuron-glia communication mechanism. It is shown here that pretreatment of OHSC with high concentrations of adenosine 5'-triphosphate (ATP) reduced NMDA-induced neuronal death only in presence of microglia. Specific agonists and antagonists identified the P2X7 receptor as neuroprotective receptor which was confirmed by absence of ATP-dependent neuroprotection in P2X7-deficient OHSC. Microglia replenished chimeric OHSC consisting of wild-type tissue replenished with P2X7-deficient microglia confirmed the involvement of microglial P2X7 receptor in neuroprotection. Stimulation of P2X7 in primary microglia induced tumor necrosis factor alpha (TNF alpha) release and blocking TNF alpha by a neutralizing antibody in OHSC abolished neuroprotection by ATP. OHSC from TNF alpha-deficient mice show increased exicitoxicity and activation of P2X7 did not rescue neuronal survival in the absence of TNF alpha. The neuroprotective effect of valproic acid (VPA) was strictly dependent on the presence of microglia and was mediated by upregulation of P2X7 in the cells. The present study demonstrates that microglia-mediated neuroprotection depends on ATP-activated purine receptor P2X7 and induction of TNF alpha release. This neuroprotective pathway was strengthened by VPA elucidating a novel mechanism for the neuroprotective function of VPA.

Original languageEnglish
Pages (from-to)76-89
Number of pages14
JournalGlia
Volume64
Issue number1
Publication statusPublished - Jan-2016

    Keywords

  • ATP, purine receptor, excitotoxicity, NMDA, OHSC, hippocampus, glia, cytokine, TUMOR-NECROSIS-FACTOR, HIPPOCAMPAL SLICE CULTURES, CEREBELLAR GRANULE NEURONS, NERVOUS-SYSTEM, P2X(7) RECEPTOR, DNA DEMETHYLATION, IN-VITRO, ACTIVATED MICROGLIA, SPINAL-CORD, EXPRESSION

ID: 37951053