Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

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)-alpha has been effective in alleviating depression and rheumatoid arthritis, it is yet unknown whether central blockade of TNF-alpha 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,F-30) = 0.60, P = 0.44; Saline/LPS challenge: F-(1,F-30) = 23.92, P<0.0001, etanercept vs aCSF: F-(1,F-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,F-20) = 4.966, P = 0.31, aCSF/etanercept treatment: F-(1,F-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,F-15) = 11.41, P = 0.0041; Saline/LPS challenge: F-(1,F-15) = 50.13, P<0.0001, etanercept vs aCSF: F-(1,F-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-alpha-related central inflammation.