Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation
Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation
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DOI：
10.1093/hmg/ddt191
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发表时间：
2013-09-01
影响因子：
3.5
通讯作者：
MacKenzie, Alex
中科院分区：
文献类型：
--
作者：
Farooq, Faraz;Abadia-Molina, Francisco;MacKenzie, Alex
由于 SMN1 基因突变或缺失，功能性运动神经元生存 (SMN) 蛋白的丧失会导致常染色体隐性神经退行性脊髓肌萎缩 (SMA)。 SMA 的一种潜在治疗策略是上调源自高度同源的 SMN2 基因的 SMN 蛋白量，部分补偿功能性 SMN1 基因的缺失。我们之前已经证明，p38 通路的体外激活可以稳定并增加 SMN mRNA 水平，从而导致 SMN 蛋白水平增加。在本报告中，我们探讨了 FDA 批准的 p38 激活、血脑屏障渗透化合物塞来昔布对体外和 SMA 小鼠模型中 SMN 水平的影响。我们证明，塞来昔布治疗后可显着诱导人类和小鼠神经元细胞中的 SMN 蛋白水平。我们发现，低剂量塞来昔布激活 p38 通路会以 HuR 蛋白依赖性方式增加 SMN 蛋白。此外，塞来昔布治疗可诱导野生型小鼠体内脑和脊髓样本中 SMN 的表达。至关重要的是，塞来昔布治疗可提高严重 SMA 小鼠模型的 SMN 水平、改善运动功能并提高生存率。我们的结果表明低剂量塞来昔布是 SMA 治疗药物的潜在新成员。
The loss of functional Survival Motor Neuron (SMN) protein due to mutations or deletion in the SMN1 gene causes autosomal recessive neurodegenerative spinal muscle atrophy (SMA). A potential treatment strategy for SMA is to upregulate the amount of SMN protein originating from the highly homologous SMN2 gene, compensating in part for the absence of the functional SMN1 gene. We have previously shown that in vitro activation of the p38 pathway stabilizes and increases SMN mRNA levels leading to increased SMN protein levels. In this report, we explore the impact of the p38 activating, FDA-approved, blood brain barrier permeating compound celecoxib on SMN levels in vitro and in a mouse model of SMA. We demonstrate a significant induction of SMN protein levels in human and mouse neuronal cells upon treatment with celecoxib. We show that activation of the p38 pathway by low doses celecoxib increases SMN protein in a HuR protein-dependent manner. Furthermore, celecoxib treatment induces SMN expression in brain and spinal cord samples of wild-type mice in vivo. Critically, celecoxib treatment increased SMN levels, improved motor function and enhanced survival in a severe SMA mouse model. Our results identify low dose celecoxib as a potential new member of the SMA therapeutic armamentarium.