The hypnotic bromovalerylurea ameliorates 6-hydroxydopamine-induced dopaminergic neuron loss while suppressing expression of interferon regulatory factors by microglia
The hypnotic bromovalerylurea ameliorates 6-hydroxydopamine-induced dopaminergic neuron loss while suppressing expression of interferon regulatory factors by microglia
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DOI：
10.1016/j.neuint.2016.06.013
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发表时间：
2016-10-01
影响因子：
4.2
通讯作者：
Tanaka, Junya
中科院分区：
文献类型：
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作者：
Higaki, Hiromi;Choudhury, Mohammed Emamussalehin;Tanaka, Junya
低分子量有机化合物溴valerylurea （BU）长期以来被用作催眠/镇静药物。在本研究中，我们发现，在脂多糖（LPS）处理的大鼠原代小胶质细胞培养中，BU抑制促炎因子mRNA表达和一氧化氮释放。在lps处理的神经元-小胶质细胞共培养中，BU阻止了神经元变性。布鲁里溃疡的抗炎作用与合成糖皮质激素地塞米松一样强。右纹状体注射6-羟多巴胺制备半帕金森大鼠模型。大鼠连续7天口服BU可改善黑质致密部（SNpc）多巴胺能神经元变性，减轻运动障碍。BU抑制右脑（受损）腹侧中脑干扰素调节因子（IRFs） 1、7和8 mrna的表达以及促炎介质mrna的表达。BU增加了各种神经保护因子的mRNA表达，包括血小板源性生长因子和肝细胞生长因子，但未增加替代激活（M2）标志物的表达。在小胶质细胞培养中，BU抑制了lps诱导的IRFs 1和8表达的增加，并降低了lps诱导的JAK1和STATs 1和3的磷酸化。敲低irf1和8抑制lps诱导的小胶质细胞释放NO。这些结果表明，BU对小胶质细胞IRF表达的抑制可以防止发生小胶质细胞激活的损伤脑区域的神经元细胞死亡。由于许多帕金森患者患有睡眠障碍，睡前给药布鲁里菌可有效改善神经系统症状，减轻睡眠功能障碍。(C) 2016 Elsevier Ltd.版权所有。
The low molecular weight organic compound bromovalerylurea (BU) has long been used as a hypnotic/sedative. In the present study, we found that BU suppressed mRNA expression of proinflammatory factors and nitric oxide release in lipopolysaccharide (LPS)-treated rat primary microglial cell cultures. BU prevented neuronal degeneration in LPS-treated neuron-microglia cocultures. The anti-inflammatory effects of BU were as strong as those of a synthetic glucocorticoid, dexamethasone. A rat hemi-Parkinsonian model was prepared by injecting 6-hydroxydopamine into the right striatum. BU was orally administered to these rats for 7 days, which ameliorated the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and alleviated motor deficits. BU suppressed the expression of mRNAs for interferon regulatory factors (IRFs) 1, 7 and 8 in the right (lesioned) ventral midbrain as well as those for proinflammatory mediators. BU increased mRNA expression of various neuroprotective factors, including platelet-derived growth factor and hepatocyte growth factor, but it did not increase expression of alternative activation (M2) markers. In microglial culture, BU suppressed the LPS-induced increase in expression of IRFs 1 and 8, and it reduced LPS-induced phosphorylation of JAK1 and STATs 1 and 3. Knockdown of IRFs 1 and 8 suppressed LPS-induced NO release by microglial cells. These results suggest that suppression of microglial IRF expression by BU prevents neuronal cell death in the injured brain region, where microglial activation occurs. Because many Parkinsonian patients suffer from sleep disorders, BU administration before sleep may effectively ameliorate neurological symptoms and alleviate sleep dysfunction. (C) 2016 Elsevier Ltd. All rights reserved.