Henry Christopher J, Huang Yan, Wynne Angela, Hanke Mark, Himler Justin, Bailey Michael T, Sheridan John F, Godbout Jonathan P
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, 333 W, 10th Ave, Columbus, OH 43210, USA.
J Neuroinflammation. 2008 May 13;5:15. doi: 10.1186/1742-2094-5-15.
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)-1beta, 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-1beta, 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.
外周固有免疫系统的激活会刺激中枢神经系统细胞因子的分泌，这些细胞因子可调节疾病的行为症状。然而，小胶质细胞过度产生细胞因子可能会导致持久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）是否能减轻脂多糖（LPS）诱导的神经炎症、疾病行为和快感缺失。
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诱导的小胶质细胞激活的影响。在第二项研究中，成年（3 - 6个月）BALB/c小鼠连续三天腹腔注射载体或米诺环素（50 mg/kg）。在第三天，小鼠还腹腔注射生理盐水或大肠杆菌LPS（0.33 mg/kg），并测定行为（即疾病行为和快感缺失）以及神经炎症标志物（即小胶质细胞激活和炎性细胞因子）。在最后一项研究中，成年和老年BALB/c小鼠接受相同的米诺环素和LPS注射方案，并测定神经炎症标志物。所有数据使用统计分析系统通用线性模型程序进行分析，并进行单因素、双因素或三因素方差分析以确定显著的主效应和相互作用。
米诺环素可阻断LPS刺激的BV-2小胶质细胞系炎性细胞因子的分泌，并降低LPS诱导的脑小胶质细胞上Toll样受体2（TLR2）的表面表达。此外，米诺环素促进成年小鼠从疾病行为（即厌食、体重减轻和社交退缩）中恢复，并预防LPS攻击后的快感缺失。此外，米诺环素使成年小鼠从LPS诱导的疾病行为中恢复的同时，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。最后，在老年小鼠中，LPS引发了过度的神经炎症，米诺环素预处理仍能显著降低海马中IL-1β、TLR2和IDO的mRNA水平。
这些数据表明，米诺环素可减轻成年和老年大脑中的神经炎症，并调节与细胞因子相关的动机和行为变化。
