Novel Para-Phenyl Substituted Diindolylmethanes Protect Against MPTP Neurotoxicity and Suppress Glial Activation in a Mouse Model of Parkinson's Disease
Novel Para-Phenyl Substituted Diindolylmethanes Protect Against MPTP Neurotoxicity and Suppress Glial Activation in a Mouse Model of Parkinson's Disease
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DOI：
10.1093/toxsci/kfu236
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发表时间：
2015-02-01
影响因子：
3.8
通讯作者：
Tjalkens, Ronald B.
中科院分区：
文献类型：
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作者：
De Miranda, Briana R.;Popichak, Katriana A.;Tjalkens, Ronald B.
孤儿核受体NR4A2 （Nurr1）通过抑制NF-kappa b的DNA结合活性，组成性地调节神经胶质细胞中的炎症基因表达。我们最近报道了新的1,1-二（3'-吲哚基）-1-（对取代苯基）甲烷（C-DIM）化合物在癌细胞中激活NR4A家族核受体，也抑制了初级星形胶质细胞中的炎症基因表达，并防止暴露于1-甲基-4-苯基-1,2,3,6-四氢吡啶和苯基的小鼠的多巴胺能神经元的损失丙磺舒(MPTPp)。在这项研究中，我们假设这种神经保护的基础包括阻断胶质细胞激活和随后nf - κ b调节的炎症基因的表达。为了研究这一机制，我们用MPTPp处理转基因NF-kappa B/EGFP报告小鼠7天（MPTPp7d），然后每天用载药（玉米油；MPTPp14d）或含有对甲氧基苯基（C-DIM5）、对羟基苯基（C-DIM8）或对氯苯基（C-DIM12）组的c - dim灌胃。每种化合物都对黑质致密部（SNpc）中多巴胺能神经元的进行性损失具有显著的保护作用，即使在MPTPp给药7天后也如此。在mptp处理的小鼠中，C-DIM12具有最大的神经保护活性，并且在定量聚合酶链反应（qPCR）阵列研究中，C-DIM12也是抑制小胶质细胞和星形胶质细胞活化、细胞因子和趋化因子表达以及降低SN中NF-kappa B/EGFP表达的最有效化合物。C-DIM12阻止Nurr1在多巴胺能神经元中的核输出，并增强Nurr1调节蛋白酪氨酸羟化酶和多巴胺转运蛋白的表达。这些数据表明，nr4a活性C-DIM化合物通过防止神经胶质介导的神经元损伤和支持SNpc中th阳性神经元的多巴胺能表型，保护MPTPp模型PD中多巴胺神经元的损失。
The orphan nuclear receptor NR4A2 (Nurr1) constitutively regulates inflammatory gene expression in glial cells by suppressing DNA binding activity of NF-kappa B. We recently reported that novel 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methane (C-DIM) compounds that activate NR4A family nuclear receptors in cancer lines also suppress inflammatory gene expression in primary astrocytes and prevent loss of dopaminergic neurons in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp). In this study, we postulated that the basis for this neuroprotection involves blockade of glial activation and subsequent expression of NF-kappa B-regulated inflammatory genes. To examine this mechanism, we treated transgenic NF-kappa B/EGFP reporter mice with MPTPp for 7 days (MPTPp7d) followed by daily oral gavage with either vehicle (corn oil; MPTPp14d) or C-DIMs containing p-methoxyphenyl (C-DIM5), p-hydroxyphenyl (C-DIM8), or p-chlorophenyl (C-DIM12) groups. Each compound conferred significant protection against progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), even when given after 7 days of dosing with MPTPp. C-DIM12 had the greatest neuroprotective activity in MPTPp-treated mice, and was also the most potent compound in suppressing activation of microglia and astrocytes, expression of cytokines and chemokines in quantitative polymerase chain reaction (qPCR) array studies, and in reducing expression of NF-kappa B/EGFP in the SN. C-DIM12 prevented nuclear export of Nurr1 in dopaminergic neurons and enhanced expression of the Nurr1-regulated proteins tyrosine hydroxylase and the dopamine transporter. These data indicate that NR4A-active C-DIM compounds protect against loss of dopamine neurons in the MPTPp model of PD by preventing glial-mediated neuronal injury and by supporting a dopaminergic phenotype in TH-positive neurons in the SNpc.