Long term protection in brain trauma by Lipopolysaccharide preconditioning

Objectives: We tested the hypothesis that a low dose of lipopolysaccharide (LPS) could act as a preconditioning stimulus and attenuate the neurobehavioral and histological sequelae induced by a subsequent traumatic brain injury (TBI). We investigated the time window of LPS effects, its persistence and the associated molecular mechanisms. Methods: C57/Bl6 mice received 0.1 mg/Kg LPS or saline intraperitoneally and subsequently TBI at various time intervals. Outcome measures included motor (Neuroscore and Beam walk test) and cognitive (Morris water maze) function, contusion volume and mRNA expression of genes known to be modulated by preconditioning and/or acute brain injury. Results: Mice receiving LPS 3, 5 or 7 days prior to TBI showed a significant attenuation of motor deficits at 1 week postinjury compared to mice receiving saline. Those receiving LPS 5 days before injury had also a significant reduction in contusion volume (7.9±1.3 vs. 12±2.3 mm3). One month after TBI, the protective effect of LPS on contusion volume was still present (14.5±1.2 vs. 18.2±1.2 mm3) together with an improvement in neurological function. Traumatic brain injury significantly increased GFAP, CD11b, CD68, TNF-α, IL-10 and IL-6 mRNA expression 24 hours postinjury. Lipopolysaccharide induced a persistent increase in the expression of CD11b (233%) and IFNβ (500%) in uninjured mice. In preconditioned injured mice, the expression of CD68 was dampened (by 46%) while that of IL-6 was increased (by 52%) compared to non preconditioned mice. Conclusions: Lipopolysaccharide preconditioning conferred a long lasting neuroprotection following TBI, which was associated with an early modulation of microglia/macrophages activity and cytokine production