title: Involvement of neuronal IL-1β in acquired brain lesions in a rat model of neonatal encephalopathy.
abstract: BACKGROUND
  Infection-inflammation combined with hypoxia-ischemia (HI) is the most prevalent pathological scenario involved in perinatal brain damage leading to life-long neurological disabilities. Following lipopolysaccharide (LPS) and/or HI aggression, different patterns of inflammatory responses have been uncovered according to the brain differentiation stage. In fact, LPS pre-exposure has been reported to aggravate HI brain lesions in post-natal day 1 (P1) and P7 rat models that are respectively equivalent - in terms of brain development - to early and late human preterm newborns. However, little is known about the innate immune response in LPS plus HI-induced lesions of the full-term newborn forebrain and the associated neuropathological and neurobehavioral outcomes.
  
  
  METHODS
  An original preclinical rat model has been previously documented for the innate neuroimmune response at different post-natal ages. It was used in the present study to investigate the neuroinflammatory mechanisms that underline neurological impairments after pathogen-induced inflammation and HI in term newborns.
  
  
  RESULTS
  LPS and HI exerted a synergistic detrimental effect on rat brain. Their effect led to a peculiar pattern of parasagittal cortical-subcortical infarcts mimicking those in the human full-term newborn with subsequent severe neurodevelopmental impairments. An increased IL-1β response in neocortical and basal gray neurons was demonstrated at 4 h after LPS + HI-exposure and preceded other neuroinflammatory responses such as microglial and astroglial cell activation. Neurological deficits were observed during the acute phase of injury followed by a recovery, then by a delayed onset of profound motor behavior impairment, reminiscent of the delayed clinical onset of motor system impairments observed in humans. Interleukin-1 receptor antagonist (IL-1ra) reduced the extent of brain lesions confirming the involvement of IL-1β response in their pathophysiology.
  
  
  CONCLUSIONS
  In rat pups at a neurodevelopmental age corresponding to full-term human newborns, a systemic pre-exposure to a pathogen component amplified HI-induced mortality and morbidities that are relevant to human pathology. Neuronal cells were the first cells to produce IL-1β in LPS + HI-exposed full-term brains. Such IL-1β production might be responsible for neuronal self-injuries via well-described neurotoxic mechanisms such as IL-1β-induced nitric oxide production, or IL-1β-dependent exacerbation of excitotoxic damage.
authors.affiliation: Laboratoire de Neurologie Pédiatrique, Université de Sherbrooke, 3001 12e Avenue Nord, J1H 5N4 Sherbrooke, Québec, Canada. guillaume.sebire@usherbrooke.ca.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Savard
authors.forename: Karine
authors.initials: K
authors.lastname: Lavoie
authors.forename: Marie-Elsa
authors.initials: ME
authors.lastname: Brochu
authors.forename: Djordje
authors.initials: D
authors.lastname: Grbic
authors.forename: Martin
authors.initials: M
authors.lastname: Lepage
authors.forename: Denis
authors.initials: D
authors.lastname: Gris
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sebire
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008279:Magnetic Resonance Imaging; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides