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Pretreatment of Astrocytes with Interferon‐α/β Prevents Neuronal Mitochondrial Respiratory Chain Damage
Author(s) -
Stewart Victoria C.,
Land John M.,
Clark John B.,
Heales Simon J. R.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.70010432.x
Subject(s) - peroxynitrite , nitric oxide , nitric oxide synthase , multiple sclerosis , interferon , stimulation , mitochondrial respiratory chain , astrocyte , chemistry , pathogenesis , microglia , mitochondrion , biology , microbiology and biotechnology , immunology , biochemistry , neuroscience , inflammation , central nervous system , endocrinology , superoxide , enzyme
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‐β 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‐γ 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‐α/β also prevented this damage. In view of these results, we suggest that a possible mechanism of action of interferon‐β in the treatment of multiple sclerosis is that it prevents astrocytic nitric oxide production, thereby limiting damage to neighbouring cells, such as neurones.