Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia.
Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia.
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DOI：
10.1186/1742-2094-5-15
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发表时间：
2008-05-13
影响因子：
9.3
通讯作者：
Godbout JP
中科院分区：
文献类型：
--
作者：
Henry CJ;Huang Y;Wynne A;Hanke M;Himler J;Bailey MT;Sheridan JF;Godbout JP
外周先天免疫系统的激活刺激调节疾病的行为症状的CNS细胞因子的分泌。然而，小胶质细胞过度产生细胞因子可能会导致长期的行为和认知并发症。本研究的目的是确定米诺环素，一种抗炎剂和所谓的小胶质细胞抑制剂，是否能减弱脂多糖（LPS）诱导的神经炎症，病态行为和快感缺乏。在第一组实验中，在BV-2小胶质细胞培养物中评估米诺环素预处理对LPS诱导的小胶质细胞活化的影响。在第二项研究中，成年（3-6 m）BALB/c小鼠接受腹膜内（i. p.）注射媒介物或米诺环素（50 mg/kg）连续三天。在第三天，还将小鼠注射（i. p.）用盐水或大肠杆菌LPS（0.33mg/kg）和行为（即，疾病和快感缺乏）和神经炎症的标志物（即，小胶质细胞活化和炎性细胞因子）。在最后的研究中，用相同的米诺环素和LPS注射方案处理成年和老年BALB/c小鼠，并测定神经炎症的标志物。使用统计分析系统一般线性模型程序分析所有数据，并进行单因素、双因素或三因素ANOVA，以确定显著的主效应和相互作用。米诺环素阻断BV-2小胶质细胞衍生细胞系中LPS刺激的炎性细胞因子分泌，并降低LPS诱导的脑小胶质细胞上Toll样受体2（TLR 2）表面表达。此外，米诺环素有助于从疾病行为中恢复（即，厌食、体重减轻和社交退缩）并防止用LPS攻击的成年小鼠的快感缺乏。此外，二甲胺四环素相关的从LPS诱导的疾病行为的恢复被皮质和海马中白细胞介素（IL）-1β、IL-6和吲哚胺2，3双加氧酶（IDO）的mRNA水平降低所阻碍。最后，在老年小鼠中，其中由LPS引起的过度神经炎症，米诺环素预处理仍然有效地显著降低海马中IL-1β、TLR 2和IDO的mRNA水平。这些数据表明，米诺环素减轻成人和老年人大脑中的神经炎症，并调节动机和行为中与二甲胺有关的变化。
Activation of the peripheral innate immune system stimulates the secretion of CNS cytokines that modulate the behavioral symptoms of sickness. Excessive production of cytokines by microglia, however, may cause long-lasting behavioral and cognitive complications. The purpose of this study was to determine if minocycline, an anti-inflammatory agent and purported microglial inhibitor, attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. In the first set of experiments the effect of minocycline pretreatment on LPS-induced microglia activation was assessed in BV-2 microglia cell cultures. In the second study, adult (3–6 m) BALB/c mice received an intraperitoneal (i.p.) injection of vehicle or minocycline (50 mg/kg) for three consecutive days. On the third day, mice were also injected (i.p.) with saline or Escherichia coli LPS (0.33 mg/kg) and behavior (i.e., sickness and anhedonia) and markers of neuroinflammation (i.e., microglia activation and inflammatory cytokines) were determined. In the final study, adult and aged BALB/c mice were treated with the same minocycline and LPS injection regimen and markers of neuroinflammation were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions. Minocycline blocked LPS-stimulated inflammatory cytokine secretion in the BV-2 microglia-derived cell line and reduced LPS-induced Toll-like-receptor-2 (TLR2) surface expression on brain microglia. Moreover, minocycline facilitated the recovery from sickness behavior (i.e., anorexia, weight loss, and social withdrawal) and prevented anhedonia in adult mice challenged with LPS. Furthermore, the minocycline associated recovery from LPS-induced sickness behavior was paralleled by reduced mRNA levels of Interleukin (IL)-1β, IL-6, and indoleamine 2, 3 dioxygenase (IDO) in the cortex and hippocampus. Finally, in aged mice, where exaggerated neuroinflammation was elicited by LPS, minocycline pretreatment was still effective in markedly reducing mRNA levels of IL-1β, TLR2 and IDO in the hippocampus. These data indicate that minocycline mitigates neuroinflammation in the adult and aged brain and modulates the cytokine-associated changes in motivation and behavior.
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影响因子：
15.1
作者：
Chen, Jing;Buchanan, Jessica B.;Johnson, Rodney W.
通讯作者：
Johnson, Rodney W.
DOI：
10.2165/00129785-200404050-00005
发表时间：
2004-01-01
期刊：
American journal of pharmacogenomics : genomics-related research in drug development and clinical practice
影响因子：
--
作者：
Carson, Monica J;Thrash, J Cameron;Lo, David
通讯作者：
Lo, David
影响因子：
3.7
作者：
Frenois, Francois;Moreau, Maite;Castanon, Nathalie
通讯作者：
Castanon, Nathalie
影响因子：
5.3
作者：
Ching, San;Zhang, Hao;Quan, Ning
通讯作者：
Quan, Ning
DOI：
10.1152/ajpregu.1997.272.6.r1880
发表时间：
1997-06-01
影响因子：
2.8
作者：
Finck, BN;Dantzer, R;Johnson, RW
通讯作者：
Johnson, RW