Cyclooxygenase-2 mediates the sensitizing effects of systemic IL-1-beta on excitotoxic brain lesions in newborn mice.
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-1-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-1-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.
Favrais
Géraldine
G
Inserm, U676, Paris, France.
Schwendimann
Leslie
L
Gressens
Pierre
P
Lelièvre
Vincent
V
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D002547:Cerebral Palsy / Q000453:epidemiology / Q000276:immunology / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007051:Ibotenic Acid / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D053583:Interleukin-1beta / Q000097:blood / Q000494:pharmacology*; D051379:Mice; D009498:Neurotoxins / Q000378:metabolism*; D011247:Pregnancy; D012307:Risk Factors; D013449:Sulfonamides / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D018690:Excitatory Amino Acid Agonists; D053583:Interleukin-1beta; D009498:Neurotoxins; D013449:Sulfonamides; D007051:Ibotenic Acid; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C012655:nimesulide; D007213:Indomethacin