the impact of il-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunctionil - 1的影响调制lipopolysaccharide-induced认知功能障碍的发展.pdf

Terrando et al. Critical Care 2010, 14:R88 /content/14/3/R88 R E S E A R C H Open Access Research The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction 1,2 1 1 1,4 1 3 Niccolò Terrando* , António Rei Fidalgo , Marcela Vizcaychipi , Mario Cibelli , Daqing Ma , Claudia Monaco , Marc Feldmann3 and Mervyn Maze* 1,2 Abstract Introduction: The impact of pro-inflammatory cytokines on neuroinflammation and cognitive function after lipopolysaccharide (LPS) challenge remains elusive. Herein we provide evidence that there is a temporal correlation between high-mobility group box 1 (HMGB-1), microglial activation, and cognitive dysfunction. Disabling the interleukin (IL)-1 signaling pathway is sufficient to reduce inflammation and ameliorate the disability. Methods: Endotoxemia was induced in wild-type and IL-1R-/- mice by intra peritoneal injection of E. Coli LPS (1 mg/kg). Markers of inflammation were assessed both peripherally and centrally, and correlated to behavioral outcome using trace fear conditioning. Results: Increase in plasma tumor necrosis factor-α (TNFα) peaked at 30 minutes after LPS challenge. Up-regulation of IL-1β, IL-6 and HMGB-1 was more persistent, with detectable levels up to day three. A 15-fold increase in IL-6 and a 6.5- fold increase in IL-1β mRNA at 6 hours post intervention (P 0.001 respectively) was found in the hippocampus. Reactive microgliosis was observed both at days one and three, and was associated with elevated HMGB-1 and impaired memory retention (P 0.005). Preemptive administration of IL-1 receptor antagonist (IL-1Ra) significantly reduced plasma cytokines and hippocampal microgliosis an