Novel strategies for opposing murine microglial activation

Pathologic microglial activation is believed to contribute to progressive n euronal damage in neurodegenerative diseases by the release of potentially neurotoxic agents, such as pro-inflammatory cytokines including tumor necro sis factor alpha (TNF-alpha). Using cultured N9 microglial cells, we have e xamined the regulation of TNF-alpha following endotoxic insult with lipopol ysaccharide (LPS), focusing on the role of the pro-inflammatory phospholipa se A(2)/mitogen activated protein kinase/arachidonic acid/cyclo-oxygenase-2 cascade and the nitric oxide/cGMP pathway. Data show that various inhibito rs of the PLA(2) cascade markedly inhibit LPS-induced TNF-alpha release, su pporting a key role of this pathway in the regulation of microglial activat ion, We also investigated the putative effects of cGMP-elevating agents on blocking microglial activation induced by LPS. Data show that each member o f this class of cGMP-elevating compounds that we employed opposed microglia l TNF-alpha release, suggesting that strengthening intracellular cGMP signa ling mitigates against microglial activation. Taken together, our results s uggest novel strategies for reducing microglial activation. (C) 2000 Elsevi er Science Ireland Ltd. All rights reserved.