Decreased iNOS synthesis mediates dexamethasone-induced protection of neurons from inflammatory injury in vitro

被引:70
作者
Golde, S
Coles, A
Lindquist, JA
Compston, A
机构
[1] Otto Von Guericke Univ, Dept Neurol, D-39120 Magdeburg, Germany
[2] Univ Cambridge, Cambridge Ctr Brain Repair, Cambridge CB2 2PY, England
[3] Addenbrookes Hosp, Dept Neurol, Cambridge CB2 2QQ, England
[4] Otto Von Guericke Univ, Inst Immunol, D-39120 Magdeburg, Germany
关键词
dexamethasone; microglia; multiple sclerosis; nitric oxide; rat;
D O I
10.1046/j.1460-9568.2003.02917.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Brain inflammation is accompanied by transection of axons and death of neurons in the acute lesions of multiple sclerosis. We explored mechanisms of inflammatory damage to neurons in vitro using cocultures of rat embryonal cortical neurons with microglia activated by interferon-gamma (IFNgamma) and lipopolysaccharide (LPS). Previously, we have demonstrated that microglia are highly toxic to neurons and that nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) is necessary and sufficient to mediate this toxicity. Here, we show that addition of dexamethasone (1 muM) to activated cocultures provides effective neuroprotection. We demonstrate that dexamethasone down-regulates NO production of primary microglia by approximate to 50% and reduces steady-state iNOS protein and mRNA expression by approximate to 70%. These changes were reversed by the glucocorticoid receptor blocker RU-486. Furthermore, we analysed the stability of iNOS protein and show that whilst inhibitors of the proteasome blocked iNOS degradation they did not reverse the dexamethasone effect. Our results indicate that the main mechanism of corticosteroid activity on iNOS is reduction in protein synthesis, not destabilization as previously suggested.
引用
收藏
页码:2527 / 2537
页数:11
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