A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons.
A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons.
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DOI：
10.1523/jneurosci.5045-09.2010
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发表时间：
2010-01-20
期刊：
影响因子：
--
通讯作者：
Li S
中科院分区：
文献类型：
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作者：
Dill J;Patel AR;Yang XL;Bachoo R;Powell CM;Li S
布洛芬是一种非甾体抗炎药，广泛用于通过抑制环氧合酶来缓解许多疾病的疼痛和炎症。最近，我们证明布洛芬可抑制 RhoA 的细胞内信号传导，并促进啮齿动物脊髓损伤后显着的轴突生长和功能恢复。此外，另一项研究表明，布洛芬通过 RhoA 信号传导失活来减少淀粉样蛋白 - β42 肽的生成，尽管它也可能通过直接抑制 γ 分泌酶复合物来调节淀粉样蛋白 - β42 的形成。然而，布洛芬抑制神经元 RhoA 信号的分子机制仍不清楚。在这里，我们报告转录因子过氧化物酶体增殖物激活受体γ（PPARγ）对于将布洛芬耦合到RhoA抑制以及随后促进神经元中的神经突生长至关重要。布洛芬激活神经元样 PC12 和 B104 细胞中的 PPARγ。用传统激动剂激活 PPARγ 模拟了 PC12 细胞中布洛芬的 RhoA 抑制特性，并且与布洛芬一样，可促进暴露于轴突生长抑制剂的原代培养神经元的神经突伸长。使用 PPARγ 特异性小干扰 RNA 进行蛋白质敲除可阻断 PC12 细胞中 RhoA 对 PPARγ 激动剂的抑制。此外，选择性 PPARγ 抑制可阻止布洛芬对神经元培养物中 RhoA 活性和神经突生长的影响。这些发现支持 PPARγ 在介导布洛芬的 RhoA 抑制作用中发挥重要作用。阐明布洛芬与 RhoA 抑制之间的新分子机制可能为以 RhoA 激活为特征的疾病（包括脊髓损伤和阿尔茨海默病）提供额外的治疗靶点。
Ibuprofen is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that ibuprofen inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that ibuprofen reduces generation of amyloid-β42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-β42 formation by direct inhibition of the γ-secretase complex. The molecular mechanisms by which ibuprofen inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptorγ (PPARγ) is essential for coupling ibuprofen to RhoA inhibition and subsequent neurite growth promotion in neurons. Ibuprofen activates PPARγ in neuron-like PC12 and B104 cells. Activation of PPARγ with traditional agonists mimics the RhoA-inhibiting properties of ibuprofen in PC12 cells and, like ibuprofen, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for PPARγ blocks RhoA suppression of PPARγ agonists in PC12 cells. Moreover, the effect of ibuprofen on RhoA activity and neurite growth in neuronal cultures is prevented by selective PPARγ inhibition. These findings support that PPARγ plays an essential role in mediating the RhoA-inhibiting effect of ibuprofen. Elucidation of the novel molecular mechanisms linking ibuprofen to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer’s disease.