Oral treatment with rofecoxib reduces hippocampal excitotoxic neurodegeneration
Oral treatment with rofecoxib reduces hippocampal excitotoxic neurodegeneration
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DOI：
10.1124/jpet.106.109876
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发表时间：
2006-12-01
影响因子：
3.5
通讯作者：
Hewett, James A.
中科院分区：
文献类型：
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作者：
Hewett, Sandra J.;Silakova, Janna M.;Hewett, James A.
本研究的目的是确定选择性环氧化酶 - 2（COX - 2）抑制剂罗非昔布[4 - [4 -（甲磺酰基）苯基] - 3 - 苯基 - 2（5H）- 呋喃酮]在兴奋性神经毒性神经变性的动物模型中是否能有效预防海马神经元损伤。在左侧海马CA1区注射N - 甲基 - D - 天冬氨酸（NMDA；18 nmol）后，COX - 2蛋白水平在3至6小时之间升高，在12小时达到峰值，并在24小时下降至接近基线水平。在注射NMDA之前4天和之后3天随意喂食对照啮齿动物饲料的小鼠，在同侧CA1、CA3和齿状回的主要细胞层显示出明显的神经元丢失（分别为50%、30%和20%的细胞丢失）。通过给动物喂食标准化为每天提供15或30 mg/kg罗非昔布的饲料，这种损伤得到了有效且呈剂量依赖性的减轻。CA1区的神经变性分别减少了30.1±5.6%和51.5±9.0%；CA3区分别减少了64.6±12.4%和69.0±14.1%；齿状回分别减少了47.8±15.2%和58.0±18.2%。此外，罗非昔布饲料略微但显著地减轻了损伤诱导的脑水肿。这些发现表明，罗非昔布在体内能够改善兴奋性神经毒性神经元损伤，因此，它可能是一种特别有前景的用于治疗与NMDA受体过度激活相关的神经系统疾病的药物。
The purpose of this study was to determine whether the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib [ 4-[ 4-(methylsulfonyl) phenyl]-3-phenyl-2(5H)-furanone] could effectively prevent hippocampal neuronal injury in an animal model of excitotoxic neurodegeneration. COX-2 protein levels increased between 3 and 6 h, peaked at 12 h, and declined to near baseline levels 24 h after injection of N-methyl-D-aspartate (NMDA; 18 nmol) into the CA1 region of the left hippocampus. Mice that were fed ad libitum a control rodent diet for 4 days before and 3 days after injection of NMDA demonstrated marked neuronal loss in the primary cell layers of the ipsilateral CA1, CA3, and dentate gyrus (50, 30, and 20% cell loss, respectively). This injury was potently and dose-dependently reduced by feeding animals a diet standardized to deliver 15 or 30 mg/ kg rofecoxib per day. Neurodegeneration in the CA1 region was reduced by 30.1 +/- 5.6 and 51.5 +/- 9.0%, respectively; in the CA3 by 64.6 +/- 12.4 and 69.0 +/- 14.1%, respectively; and in the dentate gyrus by 47.8 +/- 15.2 and 58.0 +/- 18.2%, respectively. Moreover, rofecoxib chow slightly but significantly reduced injury-induced brain edema. These findings demonstrate that rofecoxib can ameliorate excitotoxic neuronal injury in vivo and, as such, may be a particularly promising pharmaceutical for the treatment of neurological diseases associated with overactivation of NMDA receptors.