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 increased astrocytic nitric oxide synthase activity in the postmortem brain of multiple sclerosis patients supports this hypothesis. Interferon-beta is used for the treatment of multiple sclerosis, but currently little is known regarding its mode of action. Exposure of astrocytes in culture to interferon-gamma plus lipopolysaccharide results in stimulation of nitric oxide release. Using a coculture system, we have been able 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 activity causes significant damage to the mitochondrial activities of complexes II/III and IV of neighbouring neurones. This damage was prevented by a nitric oxide synthase inhibitor, suggesting that the damage was nitric oxide-mediated. Furthermore, interferon-alpha/beta also prevented this damage. In view of these results, we suggest that a possible mechanism of action of interferon-beta in the treatment of multiple sclerosis is that it prevents astrocytic nitric oxide production, thereby limiting damage to neighbouring cells, such as neurones.
Stewart
V C
VC
Department of Neurochemistry, Institute of Neurology, London, England, UK.
Land
J M
JM
Clark
J B
JB
Heales
S J
SJ
D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D018920:Coculture Techniques; D004338:Drug Combinations; D004579:Electron Transport / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D016899:Interferon-beta; D007371:Interferon-gamma; D019331:NG-Nitroarginine Methyl Ester