Cyclooxygenase-2 mediates the sensitizing effects of systemic IL-1-beta on excitotoxic brain lesions in newborn mice
Cyclooxygenase-2 mediates the sensitizing effects of systemic IL-1-beta on excitotoxic brain lesions in newborn mice
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DOI：
10.1016/j.nbd.2006.10.012
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发表时间：
2007-03-01
影响因子：
6.1
通讯作者：
Lelievre, Vincent
中科院分区：
文献类型：
--
作者：
Favrais, Geraldine;Schwendimann, Leslie;Lelievre, Vincent
流行病学和实验数据表明，母婴感染和循环中细胞因子的相关增加与脑性瘫痪的病因有关。我们之前已经证明，用系统白介素L-β预处理新生小鼠会加剧鹅膏所致的兴奋性毒性脑损伤。这种损害与脑性瘫痪时观察到的一致。本研究建立在这个小鼠模型的基础上，评估环氧合酶在白介素1-β诱导的脑毒性中的作用。与对照组相比，经白细胞介素化L-β预处理的幼鼠出现了更严重的鹅膏所致的脑损伤，这种作用可被尼美舒利(环氧合酶-2抑制剂)或吲哚美辛(环氧合酶-1和环氧合酶-2抑制剂)所阻断。给予环氧合酶抑制剂可抑制IL-1-β诱导的脑内前列腺素E-2(一种环氧合酶代谢物)的产生增加以及脑内IL-6、IL-18、肿瘤坏死因子-α和脑源性神经营养因子表达的变化。它还能刺激脑白介素10的表达。我们的数据表明，循环炎症细胞因子对大脑的增敏作用是由可诱导的同型环氧合酶-2介导的，该酶产生过量的前列腺素E-2。其中一些有害影响可能涉及自分泌/旁分泌循环，导致大脑中促炎和抗炎细胞因子之间的平衡被破坏。(C)2006 Elsevier Inc.保留所有权利。
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.