Zhao Weihua, Xie Wenjie, Le Weidong, Beers David R, He Yi, Henkel Jenny S, Simpson Ericka P, Yen Albert A, Xiao Qin, Appel Stanley H
Department of Neurology, Baylor College of Medicine, One Baylor Plaza, NB 302, Houston, TX, 77030, USA.
J Neuropathol Exp Neurol. 2004 Sep;63(9):964-77. doi: 10.1093/jnen/63.9.964.
Recent studies suggest that motor neuron (MN) death may be non-cell autonomous, with cell injury mediated by interactions involving non-neuronal cells, such as microglia and astrocytes. To help define these interactions, we used primary MN cultures to investigate the effects of microglia activated by lipopolysaccharide or IgG immune complexes from patients with amyotrophic lateral sclerosis. Following activation, microglia induced MN injury, which was prevented by a microglial iNOS inhibitor as well as by catalase or glutathione. Glutamate was also required since inhibition of the MN AMPA/kainate receptor by CNQX prevented the toxic effects of activated microglia. Peroxynitrite and glutamate were synergistic in producing MN injury. Their toxic effects were also blocked by CNQX and prevented by calcium removal from the media. The addition of astrocytes to cocultures of MN and activated microglia prevented MN injury by removing glutamate from the media. The protective effects could be reversed by inhibiting astrocytic glutamate transport with dihydrokainic acid or pretreating astrocytes with H2O2. Astrocytic glutamate uptake was also decreased by activated microglia or by added peroxynitrite. These data suggest that free radicals released from activated microglia may initiate MN injury by increasing the susceptibility of the MN AMPA/kainate receptor to the toxic effects of glutamate.
最近的研究表明，运动神经元（MN）死亡可能是非细胞自主性的，细胞损伤是由涉及非神经元细胞（如小胶质细胞和星形胶质细胞）的相互作用介导的。为了帮助确定这些相互作用，我们使用原代MN培养物来研究脂多糖或来自肌萎缩侧索硬化症患者的IgG免疫复合物激活的小胶质细胞的作用。激活后，小胶质细胞诱导MN损伤，小胶质细胞诱导型一氧化氮合酶抑制剂以及过氧化氢酶或谷胱甘肽可预防这种损伤。谷氨酸也是必需的，因为CNQX抑制MN的AMPA/海人藻酸受体可预防激活的小胶质细胞的毒性作用。过氧亚硝酸盐和谷氨酸在产生MN损伤方面具有协同作用。它们的毒性作用也被CNQX阻断，并通过从培养基中去除钙来预防。在MN与激活的小胶质细胞的共培养物中添加星形胶质细胞可通过从培养基中去除谷氨酸来预防MN损伤。用二氢海人藻酸抑制星形胶质细胞的谷氨酸转运或用过氧化氢预处理星形胶质细胞可逆转这种保护作用。激活的小胶质细胞或添加的过氧亚硝酸盐也会降低星形胶质细胞的谷氨酸摄取。这些数据表明，激活的小胶质细胞释放的自由基可能通过增加MN的AMPA/海人藻酸受体对谷氨酸毒性作用的敏感性来引发MN损伤。
