Poly(ADP-ribose) polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9-mediated neuron death.

摘要: Activated microglia contribute to cell death in ischemic and neurodegenerative disorders of the CNS. Microglial activation is regulated part by NF-κB, nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) enhances NF-κB binding DNA. In this study, role PARP-1 microglia-mediated neurotoxicity was assessed using from wild-type (wt) PARP-1−/− mice. Cultured were incubated with TNF-α, a cytokine that up-regulated many neurological disorders. When stimulated wt proliferated, underwent morphological changes characteristic activation, killed neurons placed coculture. The effects TNF-α markedly attenuated both treated PARP enzymatic inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2h)-isoquinolinone. These also blocked (E)-3-(4-methylphenylsulfonyl)-2-propenenenitrile, which inhibits translocation nucleus. microglial release matrix metalloproteinase-9 (MMP-9), an potential neurotoxic properties transcriptionally NF-κB. This up-regulation Microglia MMP-9−/− mice used evaluate contribution MMP-9 neurotoxicity. showed substantially reduced relative microglia. TNF-α-stimulated MMP ilomastat findings suggest required for TNF-α-induced resulting release.