Effects of centrally administered etanercept on behaviour, histology and TNF-α expression in mice following a peripheral immune challenge

Background: Peripheral cytokines affect central nervous system (CNS) function, triggering anxiety and cognitive decline. Although peripheral blockade of tumor necrosis factor (TNF-α) by etanercept, has been effective in alleviating rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune-challenged CNS function. This study investigated effects of central etanercept administration post-peripheral immune challenge, on behaviour and histology. Methods: 12-week-old C57BL/6 mice (n=40) were challenged with either LPS or saline, administered peripherally 24hr before being treated with etanercept or artificial CSF (aCSF), via intracerebroventricular injection. Mice underwent behavioural analyses for locomotion (open field test: OFT), memory (Y maze) and anxiety (elevated zero maze: EZM) 24hr post etanercept/aCSF treatment. Brain tissue was then collected to estimate number of hippocampal microglia and expression of Tnfa. Results: Acute systemic challenge with LPS decreased weight in mice at 24hr, and impaired locomotor activity. LPS significantly increased anxiety-like behaviour (2-way ANOVA: Interaction: P=0.096; Saline/LPS challenge: P=0.0006, aCSF/etanercept treatment: P=0.0008), which was reversed by etanercept and significantly reduced cognition in the Y Maze (Interaction: P=0.037, Saline/LPS challenge: P=0.31, aCSF/etanercept treatment: P=0.80), which was not reversed by etanercept. LPS challenge also increased Tnfa expression in the hippocampus (Interaction: F(1,13)=28.04, P=0.0001, Saline/LPS challenge: P=0.0003, aCSF/etanercept treatment: P=0.021) and etanercept treatment was effective in reducing this Tnfa expression (P=0.001). Etanercept also significantly reduced microglial numbers within the hippocampus, which were increased following LPS administration (2-way ANOVA: Interaction: P= 0.0041; Saline/LPS challenge: P<0.0001, etanercept/aCSF: P=0.08,). Conclusion: A single dose of etanercept was found to be effective in significantly decreasing anxiety, Tnfa expression and microglia numbers 48hr post-peripheral immune challenge. The present study suggests that there is effective cross-talk between peripheral and central immune systems. Additionally behavioural and biological changes caused by LPS challenge which may be mediated by TNF-α related central inflammation, were reversed by etanercept treatment

Reviewing and improving the value of a viva assessment

INTRODUCTION: The anatomy viva is an oral examination format allowing in-depth assessment of knowledge. There are many valuable aspects to this assessment: it is quick, effective, and tests the higher cognitive thinking of students. Assessment drives learning so this type of assessment is also valuable for promoting the integration of anatomical knowledge with clinical applications. However, implementing a successful viva assessment to large student groups is challenging. MATERIALS AND METHODS: This report describes studies into the design and development of an anatomy viva framework for Year 3 MBBS students studying anatomy by dissection. The aim of the framework was to allow the viva assessment to remain a reliable, appropriate, and valid exam despite rapid growth in student numbers between 2016 (n = 19) and 2017 (n = 40). Student feedback on the subject and assessment experience was also reviewed and compared to the smaller 2016 cohort. RESULTS: Use of the new framework demonstrated a significant increase in reliability (marking consistency) when compared to 2016 data, and review of the examination data sheets indicated that the newly structured framework to the viva did not diminish the appropriateness of the viva (i.e., higher levels of cognitive thinking were still able to be assessed). Student feedback demonstrated no change to satisfaction in the subject or the assessment methods. CONCLUSION: The implementation of the new framework allowed a valuable assessment method to be updated, improved and applied to a significantly larger student cohort, thus providing an opportunity for students to develop skills in applying, integrating, and evaluating anatomical knowledge

Effects of centrally administered etanercept on behaviour, histology and TNF-α expression in mice following a peripheral immune challenge

Background: Peripheral cytokines affect central nervous system (CNS) function, triggering anxiety and cognitive decline. Although peripheral blockade of tumor necrosis factor (TNF-α) by etanercept, has been effective in alleviating rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune-challenged CNS function. This study investigated effects of central etanercept administration post-peripheral immune challenge, on behaviour and histology. \ud \ud Methods: 12-week-old C57BL/6 mice (n=40) were challenged with either LPS or saline, administered peripherally 24hr before being treated with etanercept or artificial CSF (aCSF), via intracerebroventricular injection. Mice underwent behavioural analyses for locomotion (open field test: OFT), memory (Y maze) and anxiety (elevated zero maze: EZM) 24hr post etanercept/aCSF treatment. Brain tissue was then collected to estimate number of hippocampal microglia and expression of Tnfa.\ud \ud Results: Acute systemic challenge with LPS decreased weight in mice at 24hr, and impaired locomotor activity. LPS significantly increased anxiety-like behaviour (2-way ANOVA: Interaction: P=0.096; Saline/LPS challenge: P=0.0006, aCSF/etanercept treatment: P=0.0008), which was reversed by etanercept and significantly reduced cognition in the Y Maze (Interaction: P=0.037, Saline/LPS challenge: P=0.31, aCSF/etanercept treatment: P=0.80), which was not reversed by etanercept. LPS challenge also increased Tnfa expression in the hippocampus (Interaction: F(1,13)=28.04, P=0.0001, Saline/LPS challenge: P=0.0003, aCSF/etanercept treatment: P=0.021) and etanercept treatment was effective in reducing this Tnfa expression (P=0.001). Etanercept also significantly reduced microglial numbers within the hippocampus, which were increased following LPS administration (2-way ANOVA: Interaction: P= 0.0041; Saline/LPS challenge: P<0.0001, etanercept/aCSF: P=0.08,). \ud \ud Conclusion: A single dose of etanercept was found to be effective in significantly decreasing anxiety, Tnfa expression and microglia numbers 48hr post-peripheral immune challenge. The present study suggests that there is effective cross-talk between peripheral and central immune systems. Additionally behavioural and biological changes caused by LPS challenge which may be mediated by TNF-α related central inflammation, were reversed by etanercept treatment

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)-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