title: Effects of centrally administered etanercept on behavior, microglia, and astrocytes in mice following a peripheral immune challenge.
abstract: 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.
authors.affiliation: 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.
authors.forename: Marie Lou
authors.initials: ML
authors.lastname: Camara
authors.affiliation: Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, SA, Australia.
authors.forename: Frances
authors.initials: F
authors.lastname: Corrigan
authors.affiliation: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Jaehne
authors.affiliation: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Magdalene C
authors.initials: MC
authors.lastname: Jawahar
authors.affiliation: Discipline of Anatomy, School of Medicine, James Cook University, Townsville QLD, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Anscomb
authors.affiliation: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Bernhard T
authors.initials: BT
authors.lastname: Baune
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000276:immunology; D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology; D002452:Cell Count; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D000068800:Etanercept; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D008070:Lipopolysaccharides; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000276:immunology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept
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