8-bromocyclic-gmp and arachidonyltrifluoromethane

Pathologic microglial activation is believed to contribute to progressive neuronal damage in neurodegenerative diseases by the release of potentially neurotoxic agents, such as pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-alpha). Using cultured N9 microglial cells, we have examined the regulation of TNF-alpha following endotoxic insult with lipopolysacharide (LPS), focusing on the role of the pro-inflammatory phospholipase A2/mitogen activated protein kinase/arachidonic acid/cyclo-oxygenase-2 cascade and the nitric oxide/cGMP pathway. Data show that various inhibitors of the PLA2 cascade markedly inhibit LPS-induced TNF-alpha release, supporting a key role of this pathway in the regulation of microglial activation. We also investigated the putative effects of cGMP-elevating agents on blocking microglial activation induced by LPS. Data show that each member of this class of cGMP-elevating compounds that we employed opposed microglial TNF-alpha release, suggesting that strengthening intracellular cGMP signaling mitigates against microglial activation. Taken together, our results suggest novel strategies for reducing microglial activation.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Cells, Cultured; Cyclic GMP; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dipyridamole; Enzyme Inhibitors; Flavonoids; Guanylate Cyclase; Imidazoles; Indazoles; Isoenzymes; Lipopolysaccharides; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mice; Microglia; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; p38 Mitogen-Activated Protein Kinases; Phospholipases A; Phospholipases A2; Phosphorylcholine; Prostaglandin-Endoperoxide Synthases; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyridines; Signal Transduction; Tumor Necrosis Factor-alpha