Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism

被引：139

作者：

Zhao, WH ^{[1
]}

Xie, WJ ^{[1
]}

Le, WD ^{[1
]}

Beers, DR ^{[1
]}

He, Y ^{[1
]}

Henkel, JS ^{[1
]}

Simpson, EP ^{[1
]}

Yen, AA ^{[1
]}

Xiao, Q ^{[1
]}

Appel, SH ^{[1
]}

机构：

[1] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA

来源：

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY | 2004年 / 63卷 / 09期

关键词：

amyotrophic lateral sclerosis (ALS); AMPA/kainate receptors; Astrocytes; microglia; motor neurons; peroxynitrite;

D O I：

10.1093/jnen/63.9.964

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：964 / 977

页数：14

共 66 条

[31] Minocycline slows disease progression in a mouse model of arnyotrophic lateral sclerosis [J].