EAP 2017 Congress and MasterCourse, October 12-15, 2017, Ljubljana, Slovenia

Pathogen Specific Changes in Core Temperature and Neuro-Inflammation in The Neonatal Rat

Mari Falck 1 Damjan Osredkar 1,2 Elke Maes 1 Torun Flatebo 1 Thomas Wood 1 Hemmen Sabir 1,3 Marianne Thoresen 1,4
1Department of Physiology, University of Oslo, Institute of Basic Medical Sciences, Norway
2Department of Paediatric Neurology, University Children’s Hospital, Slovenia
3Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine University, Germany
4School of Clinical Sciences, University of Bristol, UK

Background: Perinatal infections increase vulnerability of the neonatal brain to hypoxic-ischemic (HI) injury. We recently demonstrated experimentally how inflammatory pre-sensitisation through TLR-4 (LPS) abolished the effect of therapeutic hypothermia (TH) after HI. Remarkably, when inflammation is induced through TLR-2 (PAM3CSK4), TH provides 80% neuroprotection1,2. A sepsis-like condition is induced in both situations, but how they differ with respect to neuro-inflammatory responses in the newborn is unknown.

Objective: To examine physiological and neuro-immunological changes induced in the neonatal rat by triggering inflammation systemically using LPS or PAM3CSK4 (PAM), compared to saline.

Methods: After a systemic injection of 0.9% NaCl (Veh), LPS, (0.1mg/kg) or PAM (1 mg/kg) in P7 rats, core temperature was measured 2-hourly for 24h. Brain tissue was analyzed for pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, and IL-10) (PCR) and apoptosis (cCas3) and microglial activation (Iba1) (WB).

Results: LPS induced a significant drop in core temperature after injection compared to Veh (p=0.01) and PAM (p=0.01) (Fig 1). Temporal expression of IL-6, IL-1β, TNFα and IL-10 differed significantly after injection of LPS and PAM, with expression peaks after different incubation lengths (Fig 2, A: PAM, B: Veh, C: LPS). cCas3 was significantly increased 24-48 hours after LPS injection compared to PAM and Veh (p=0.0002) which were similar. Iba1 was increased by systemic LPS and PAM compared to Veh (p=0.07).

Conclusion: Experimental induction of a sepsis-like condition through TLR-2 and TLR-4 induced neuro-inflammation. The gram-positive pathway (PAM) creates a neuro-inflammatory state very different from that of the gram-negative pathway (LPS). The difference in core temperature preservation indicates a role of metabolic demands during infection that might be pathogen specific. These results highlight the need for more research on inflammatory cross-talk between blood and brain, and the importance of pre-clinical models being carefully tailored to their clinical scenario.

1. Osredkar, D. et al. Resuscitation 85, 567–572 (2014).
2. Falck, M. et al. http://www.abstracts2view.com/pas/view.php?nu=PAS16L1_4615.4 (2016).

Fig 1 Core temperature after an i.p. injection of LPS, PAM or Vehicle

Fig 2 Cytokine expression changes in brain after an i.p. injection of vehicle (A), PAM (B) or LPS (C)

Mari Falck
Mari Falck
UIO








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