| Abstract No.: | A-C1099 |
| Country: | Canada |
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| Title: | IL-1 AND IL-18 EXPRESSION BY THE NEONATAL BRAIN IN RESPONSE TO ANTENATAL EXPOSURE TO LPS AND/OR POST-NATAL HYPOXIA-ISCHEMIA: CONTRIBUTION OF MATERNALLY PRODUCED CYTOKINES ? |
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| Authors/Affiliations: | 1 Sylvie Girard*; 1 Luc Tremblay; 1 Martin Lepage; 1 Guillaume Sébire;
1 University of Sherbrooke, QC, Canada
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| Content: | Objectives: Neonatal hypoxia-ischemia and/or infections are the main etiopathogenic factors leading to perinatal cerebral palsy. Both are suspected to mediate part of their deleterious effects through the activation of inflammatory pathways and cytokines production. These pro-inflammatory cytokines, especially interleukin (IL)-1 and IL-18, might have some neurotoxic effects. We are interested in finding out whether these cytokines are expressed in the perinatal brain exposed to LPS and/or H/I and whether such cytokine’s expression is purely from fetal/neonatal origin or if the maternal innate immune system provides an additional contribution.
Material and Methods: We used an animal model of prenatal infection/inflammation and early postnatal hypoxia-ischemia (H/I), known to mediate the development of brain damages and further leading to motor impairments characteristic of what is observed in human cerebral palsy.
Results: First, members of the IL-1 family (namely, IL-1β, IL-18 and IL-1 converting enzyme (ICE)/caspase-1) were studied in the neonatal brain. At the mRNA levels, both IL-1β and IL-18 were elevated in the brain of rats pups exposed to LPS and/or H/I. The IL-1β mRNA level was increased as early as 4h following H/I; IL-18 mRNA level was increased only at a later time point (18h after H/I). No change was observed in the ICE levels at any time point. Second, magnetic resonance imaging (MRI) was used to study if maternally produced cytokines could be transferred to the fetal system. We studied the in vivo distribution of contrast agents of molecular weight similar to cytokines (19000 Da) or lower (700 Da) in both saline or lipopolysaccharide (LPS) treated pregnant rat. In saline-treated animals, the agent was rapidly seen throughout the placenta but no signal was detected in the fetus, including the brain. In the LPS-treated rat, the agent was also distributed in the placenta but with lower intensity as compared to saline treated rats. Third, additional experiences are under process, using radiolabeled IL-1β, injected to the pregnant rat, to further study the placental permeability to IL-1.
Conclusion: In summary, these experiments show that IL-1 and IL-18 synthesis are induced within the brain exposed to LPS and/or H/I. However, an additional contribution from maternal innate immunity transferred to the fetus remains possible, even in the absence of visible permeability to the contrast agent as detected by MRI. This point will be clarified by experiments using radiolabeled IL-1. These data will help to better target the use of potential neuroprotective treatment (eg anti-inflammatory molecule) by determining the optimal therapeutic window and subsequently minimizing the deleterious effect on the developing brain.
Funded by CIHR, FRSQ, Fondation des Etoiles pour la Recherche sur les Maladies Infantiles, Centre de Neurosciences de l’Université de Sherbrooke.
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