Cyclooxygenase-2 mediates the sensitizing effects of systemic IL-1-beta on excitotoxic brain lesions in newborn mice

NEUROBIOLOGY OF DISEASE

卷:25

Article

Favrais, Geraldine ; Schwendimann, Leslie ; Gressens, Pierre ; Lelievre, Vincent

关键词: cerebral palsy;    pro-inflammatory cytokine;    excitotoxicity;    ibotenate;    nimesulide;    indomethacin;   

DOI  :  10.1016/j.nbd.2006.10.012

来源: Elsevier

【 摘 要 】

Epidemiological and experimental data implicate maternal-fetal infection and an associated increase in circulating cytokines in the etiology of cerebral palsy. We have previously shown that pretreatment of newborn mice with systemic interleukin-l-beta exacerbates ibotenate-induced excitotoxic brain lesions. Such lesions are consistent with those observed in cerebral palsy. The present study builds on this murine model to assess the role of cyclooxygenase in interleukin-1-beta-induced brain toxicity. Pups pretreated with interleukin-l-beta developed greater ibotenate-induced brain damage than controls, an effect blocked by the co-administration of nimesulide (cyclooxygenase-2 inhibitor) or indomethacin (cyclooxygenase-1 and -2 inhibitor). Cyclooxygenase inhibitor administration prevented the interleukin-1-beta-induced increase in the production of brain prostaglandin E-2 (a cyclooxygenase metabolite) and changes in the expression of brain interleukin-6, interleukin-18, tumor necrosis factor-alpha, and brain-derived neurotrophic factor. It also stimulated the expression of brain interleukin-10. Our data suggest that the sensitizing effects of circulating inflammatory cytokines on the brain are mediated by the inducible isoform cyclooxygenase-2, which generates excess prostaglandin E-2. Some of these deleterious effects could involve an autocrine/paracrine loop leading to a disruption of the balance between pro- and anti-inflammatory cytokines in the brain. (c) 2006 Elsevier Inc. All rights reserved.

【 授权许可】

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