Modulation of the Purinergic P2X7 Receptor Attenuates Lipopolysaccharide-Mediated Microglial Activation and Neuronal Damage in Inflamed Brain

摘要: We investigated the involvement and roles of ionotropic purinergic receptor P2X(7)R in microglia mediating lipopolysaccharide (LPS)-induced inflammatory responses neuronal damage rat striatum. A detailed vivo study showed that LPS injection into striatum markedly increased expression compared with control (saline)-injected animals. Additionally, upregulated a broad spectrum proinflammatory mediators, including inducible nitric oxide synthase (nitric production marker), 3-nitrotyrosine (peroxynitrite-mediated nitration 4-hydroxynonenal (lipid peroxidation 8-hydroxy-2'-deoxyguanosine (oxidative DNA reduced viability. The antagonist oxidized ATP (oxATP) was effective attenuating expressions all mediators addition inhibited LPS-induced activation cellular signaling factors p38 mitogen-activated protein kinase transcriptional factor nuclear kappaB. Most importantly, vivo, oxATP blockade also numbers caspase-3-positive neurons survival LPS-injected brain. In vitro, stimulation cultured human enhanced host factors, cyclooxygenase-2, interleukin-1beta (IL-1beta), IL-6, IL-12, tumor necrosis factor-alpha; were by oxATP. novel finding potentiated intracellular [Ca(2+)](i) mobilization induced ligand 2',3'-O-(4-benzoyl-benzoyl) ATP, which could serve as mechanistic link for amplification responses. Our results suggest critical inflammation inhibition this subtype therapeutic approach to reduce microglial confer neuroprotection inflamed diseased