Involvement of neuronal IL-1β in acquired brain lesions in a rat model of neonatal encephalopathy

• Published in: Journal of neuroinflammation 2013-09, Vol.10 (1), p.110-110, Article 880
• Main Authors: Savard, Alexandre, Lavoie, Karine, Brochu, Marie-Elsa, Grbic, Djordje, Lepage, Martin, Gris, Denis, Sebire, Guillaume
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain Diseases - etiology; Brain Diseases - metabolism; Brain Diseases - pathology; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - pathology; Immunohistochemistry; In Situ Hybridization; Inflammation - metabolism; Inflammation - pathology; Interleukin-1beta - metabolism; Lipopolysaccharides - toxicity; Magnetic Resonance Imaging; Neurons - metabolism; Neurons - pathology; Rats; Rats, Inbred Lew
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/1742-2094-10-110

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. 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. 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. 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.