Camara Marie Lou, Corrigan Frances, Jaehne Emily J, Jawahar Magdalene C, Anscomb Helen, Baune Bernhard T
1] Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia [2] Discipline of Anatomy, School of Medicine, James Cook University, Townsville QLD, Australia.
Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, SA, Australia.
Neuropsychopharmacology. 2015 Jan;40(2):502-12. doi: 10.1038/npp.2014.199. Epub 2014 Aug 8.
Peripheral cytokines affect central nervous system (CNS) function, manifesting in symptoms of anxiety and cognitive decline. Although the peripheral blockage of tumor necrosis factor (TNF)-α has been effective in alleviating depression and rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune-challenged CNS function. This study investigated the effects of central etanercept administration following a peripheral immune challenge on anxiety-like and cognition-like behaviors and microglia and astrocyte numbers. Twelve-week-old C57BL/6 mice (n=40) were treated with either LPS or saline administered peripherally 24 h before being treated with either etanercept or artificial CSF (aCSF) by intracerebroventricular injection. Mice underwent behavioral analyses for locomotion, memory, and anxiety-like behavior 24 h post-etanercept/aCSF treatment, and tissue was collected to estimate the numbers of hippocampal microglia and astrocytes. Following peripheral immune challenge with LPS, mice showed increased anxiety-like behavior, which was significantly improved following treatment with etanercept (two-way ANOVA: Interaction: F(1,30)=0.60, P=0.44; Saline/LPS challenge: F(1,30)=23.92, P<0.0001, etanercept vs aCSF: F(1,30)=11.09, P=0.0023). For cognition, a significant interaction effect found by two-way ANOVA (Interaction: F(1,20)=4.96, P=0.037, Saline/LPS challenge: F(1,20)=4.966, P=0.31, aCSF/etanercept treatment: F(1,20)=0.06, P=0.80) and post-hoc analysis revealed a significant decrease in cognition in LPS-aCSF compared with Sal-aCSF mice (P=0.038), but no significant difference was noted between LPS-aCSF and LPS-Etan mice (P>0.9). A significant reduction in the number of microglia within the hippocampus of these mice was noted (two-way ANOVA: Interaction: F(1,15)=11.41, P=0.0041; Saline/LPS challenge: F(1,15)=50.13, P<0.0001, etanercept vs aCSF: F(1,15)=3.36, P=0.08). Centrally administered etanercept improved anxiety-like behavior but not spatial memory under a peripheral immune challenge and was associated with a decrease in the hippocampal microglia numbers. This suggests that etanercept recovers anxiety-like behavior possibly mediated by a reduction of TNF-α-related central inflammation.
外周细胞因子会影响中枢神经系统（CNS）功能，表现为焦虑和认知能力下降等症状。尽管肿瘤坏死因子（TNF）-α的外周阻断已有效减轻抑郁症和类风湿性关节炎，但TNF-α的中枢阻断对免疫应激的中枢神经系统功能是否有益尚不清楚。本研究调查了外周免疫应激后中枢给予依那西普对焦虑样和认知样行为以及小胶质细胞和星形胶质细胞数量的影响。12周龄的C57BL/6小鼠（n = 40）在通过脑室内注射依那西普或人工脑脊液（aCSF）进行治疗前24小时，接受外周注射LPS或生理盐水处理。在依那西普/aCSF治疗后24小时，对小鼠进行运动、记忆和焦虑样行为的行为分析，并收集组织以估计海马小胶质细胞和星形胶质细胞的数量。在外周给予LPS进行免疫应激后，小鼠表现出焦虑样行为增加，而依那西普治疗后这种行为得到显著改善（双向方差分析：交互作用：F(1,30)=0.60，P = 0.44；生理盐水/LPS应激：F(1,30)=23.92，P < 0.0001，依那西普与aCSF比较：F(1,30)=11.09，P = 0.0023）。对于认知，双向方差分析发现显著的交互作用（交互作用：F(1,20)=4.96，P = 0.037，生理盐水/LPS应激：F(1,20)=4.966，P = 0.31，aCSF/依那西普治疗：F(1,20)=0.06，P = 0.80），事后分析显示，与生理盐水-aCSF小鼠相比，LPS-aCSF小鼠的认知能力显著下降（P = 0.038），但LPS-aCSF小鼠与LPS-依那西普小鼠之间未发现显著差异（P > 0.9）。这些小鼠海马内小胶质细胞数量显著减少（双向方差分析：交互作用：F(1,15)=11.41，P = 0.0041；生理盐水/LPS应激：F(1,15)=50.13，P < 0.0001，依那西普与aCSF比较：F(1,15)=3.36，P = 0.08）。中枢给予依那西普可改善外周免疫应激下的焦虑样行为，但对空间记忆无改善作用，且与海马小胶质细胞数量减少有关。这表明依那西普可能通过减少TNF-α相关的中枢炎症来恢复焦虑样行为。
