CYTOKINE-MEDIATED NEURONAL APOPTOSIS

Cytokines have been reported to induce neuronal injury via the free ra dical nitric oxide (NO); however, the precise mechanism underlying cyt okine-mediated neurotoxicity is unclear. We investigated the hypothesi s that cytokine-mediated neurotoxicity in primary cultures of human fe tal neurons occurs via an apoptotic mechanism triggered by NO. Treatme nt of mixed neuronal/glial cell cultures with interferon (IFN)-gamma p lus interleukin (IL)-1 beta for 13 days induced a high output of NO ac companied by marked neuronal loss. The NO synthase inhibitor N-monomet hyl-L-arginine (NMMA) significantly attenuated cytokine-induced neuron al loss, confirming the involvement of NO. Cytokine-mediated neuronal injury was accompanied by morphologic changes and a DNA fragmentation pattern consistent with apoptosis. Treatment of neuronal cell cultures with NMMA protected against cytokine-mediated apoptotic death. These findings, using primary human neuronal cell cultures, support the hypo thesis that cytokine-mediated neurotoxicity involving NO proceeds via an apoptotic mechanism. These findings could lead to the development o f new therapies for neurodegenerative diseases involving glia, cytokin es, and NO. (C) 1997 Elsevier Science Ltd.