Stewart V C, Heslegrave A J, Brown G C, Clark J B, Heales S J R
Division of Neurochemistry, Molecular Pathogenesis, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK.
Eur J Neurosci. 2002 Feb;15(3):458-64. doi: 10.1046/j.0953-816x.2001.01878.x.
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.
细胞因子刺激的星形胶质细胞会产生一氧化氮，它能够抑制线粒体呼吸链的组成部分。我们之前已经证明，长时间（48小时）暴露于大鼠星形胶质细胞产生的一氧化氮会损害共培养的相邻大鼠神经元的复合物II - III和IV，导致神经元死亡。基于这些观察结果，我们现在表明，NMDA受体拮抗剂MK - 801可预防这种损伤，提示谷氨酸参与其中。我们推测星形胶质细胞衍生的一氧化氮会刺激神经元谷氨酸的释放。事实上，我们证明与产生一氧化氮的星形胶质细胞共同孵育的神经元显示出谷氨酸释放增强。此外，直接暴露于一氧化氮供体DETA - NONOate会导致所有神经元线粒体复合物的活性丧失，而MK - 801同样可预防这种情况。因此，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都会导致NMDA受体激活，从而损害神经元线粒体呼吸链。已知谷氨酸暴露会通过神经元型一氧化氮合酶损害神经元线粒体呼吸链。因此，我们提出星形胶质细胞衍生的一氧化氮能够引发神经元谷氨酸释放，进而激活神经元NMDA受体，并通过神经元型一氧化氮合酶刺激活性氮物质的进一步形成，导致线粒体损伤和神经元死亡。我们的研究结果支持这样一种假设，即谷氨酸、活性氮物质和线粒体功能障碍可能在神经退行性过程中起作用。
