PRETREATMENT OF ASTROCYTES WITH INTERFERON-ALPHA BETA PREVENTS NEURONAL MITOCHONDRIAL RESPIRATORY-CHAIN DAMAGE/

Excessive nitric oxide/peroxynitrite generation has been implicated in the pathogenesis of multiple sclerosis, and the demonstration of incr eased astrocytic nitric oxide synthase activity in the postmortem brai n of multiple sclerosis patients supports this hypothesis. Interferon- beta is used for the treatment of multiple sclerosis, but currently li ttle is known regarding its mode of action. Exposure of astrocytes in culture to interferon-gamma plus lipopolysaccharide results in stimula tion of nitric oxide release. Using a coculture system, we have been a ble to use astrocytes as a source of nitric oxide/peroxynitrite in an attempt to ''model'' the effects of raised cytokine levels observed in multiple sclerosis and to monitor the effect on neurones. Our results indicate that stimulation of astrocytic nitric oxide synthase activit y causes significant damage to the mitochondrial activities of complex es II/III and IV of neighbouring neurones. This damage was prevented b y a nitric oxide synthase inhibitor, suggesting that the damage was ni tric oxide-mediated. Furthermore, interferon-alpha/beta also prevented this damage. In view of these results, we suggest that a possible mec hanism of action of interferon-beta in the treatment of multiple scler osis is that it prevents astrocytic nitric oxide production, thereby l imiting damage to neighbouring cells, such as neurones.