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首页> 外文期刊>The European Journal of Neuroscience >Nitric oxide-dependent damage to neuronal mitochondria involves the NMDA receptor.
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Nitric oxide-dependent damage to neuronal mitochondria involves the NMDA receptor.

机译：一氧化氮依赖性神经元线粒体损伤涉及NMDA受体。

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摘要

Cytokine-stimulated astrocytes produce nitric oxide, which can inhibit components of the mitochondrial respiratory chain. We have previously demonstrated that prolonged exposure (48 h) to rat astrocytic nitric oxide damages complexes II--III and IV of neighbouring rat neurons in coculture, resulting in neuronal death. Expanding on these observations, we have now shown that the NMDA receptor antagonist, MK-801, prevents this damage, suggesting involvement of glutamate. We postulate that astrocyte-derived nitric oxide stimulates release of neuronal glutamate. Indeed we demonstrate that neurons incubated with nitric oxide-generating astrocytes display enhanced glutamate release. Furthermore, direct exposure to the nitric oxide donor, DETA-NONOate resulted in a loss of activity of all the neuronal mitochondrial complexes, which was again prevented by MK-801. Thus, nitric oxide, generated by both cytokine-stimulated astrocytes and by a nitric oxide donor, causes activation of the NMDA receptor leading to damage to the neuronal mitochondrial respiratory chain. Glutamate exposure is known to damage the neuronal mitochondrial respiratory chain via neuronal nitric oxide synthase. Therefore, we propose that astrocyte-derived nitric oxide is capable of eliciting neuronal glutamate release, which in turn activates the neuronal NMDA receptor and stimulates further formation of reactive nitrogen species via neuronal nitric oxide synthases, leading to mitochondrial damage and neuronal death. Our findings support the hypothesis that glutamate, reactive nitrogen species and mitochondrial dysfunction may have a role in the neurodegenerative process.
机译：细胞因子刺激的星形胶质细胞产生一氧化氮，可以抑制线粒体呼吸链的成分。我们以前已经证明，长时间暴露于大鼠星形细胞一氧化氮（48小时）会破坏共培养中邻近大鼠神经元的复合物II-III和IV，从而导致神经元死亡。扩展这些观察结果，我们现在已经表明NMDA受体拮抗剂MK-801可以防止这种损害，提示谷氨酸的参与。我们假设星形胶质细胞源性一氧化氮刺激神经元谷氨酸的释放。实际上，我们证明了与产生一氧化氮的星形胶质细胞孵育的神经元显示出增强的谷氨酸释放。此外，直接暴露于一氧化氮供体DETA-NONOate导致所有神经元线粒体复合物的活性丧失，这又被MK-801阻止。因此，由细胞因子刺激的星形胶质细胞和一氧化氮供体产生的一氧化氮引起NMDA受体的活化，从而导致神经元线粒体呼吸链的损伤。已知谷氨酸的暴露通过神经元一氧化氮合酶破坏神经元线粒体呼吸链。因此，我们提出星形胶质细胞源性一氧化氮能够引起神经元谷氨酸释放，进而激活神经元NMDA受体并通过神经元一氧化氮合酶刺激反应性氮物种的进一步形成，从而导致线粒体损伤和神经元死亡。我们的发现支持以下假设：谷氨酸，反应性氮和线粒体功能障碍可能在神经变性过程中起作用。

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