Stewart V C, Land J M, Clark J B, Heales S J
Department of Neurochemistry, Institute of Neurology, London, England, UK.
J Neurochem. 1998 Jan;70(1):432-4. doi: 10.1046/j.1471-4159.1998.70010432.x.
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.
过量一氧化氮/过氧亚硝酸盐的产生与多发性硬化症的发病机制有关，多发性硬化症患者死后大脑中星形胶质细胞一氧化氮合酶活性增加的证据支持了这一假说。β-干扰素用于治疗多发性硬化症，但目前对其作用方式知之甚少。培养中的星形胶质细胞暴露于γ-干扰素加脂多糖会导致一氧化氮释放增加。利用共培养系统，我们能够将星形胶质细胞作为一氧化氮/过氧亚硝酸盐的来源，试图“模拟”在多发性硬化症中观察到的细胞因子水平升高的影响，并监测对神经元的作用。我们的结果表明，星形胶质细胞一氧化氮合酶活性的刺激会对相邻神经元的复合物II/III和IV的线粒体活性造成显著损害。一氧化氮合酶抑制剂可预防这种损害，表明这种损害是由一氧化氮介导的。此外，α/β-干扰素也可预防这种损害。鉴于这些结果，我们认为β-干扰素治疗多发性硬化症的一种可能作用机制是它可阻止星形胶质细胞产生一氧化氮，从而限制对相邻细胞（如神经元）的损害。
