Identification of a Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitor, BIP-135, That Prolongs the Median Survival Time of Δ7 SMA KO Mouse Model of Spinal Muscular Atrophy
Identification of a Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitor, BIP-135, That Prolongs the Median Survival Time of Δ7 SMA KO Mouse Model of Spinal Muscular Atrophy
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DOI：
10.1021/cn200085z
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发表时间：
2012-01-01
影响因子：
5
通讯作者：
Kozikowski, Alan P.
中科院分区：
文献类型：
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作者：
Chen, Po C.;Gaisina, Irina N.;Kozikowski, Alan P.
在各种病理条件下发现上调的糖原合成酶激酶-3（GSK-3）已经导致开发了许多化学上不同的小分子GSK-3抑制剂，例如BIP-135。GSK-3抑制剂成为治疗脊髓性肌萎缩症（SMA）的替代治疗靶点，因为许多GSK-3抑制剂在体外显示可提高运动神经元（SMN）存活水平，并在运动神经元的固有SMN水平被SMN特异性短发夹RNA（shRNA）降低时拯救运动神经元。尽管它们具有细胞效力，但GSK-3抑制剂的体内功效尚未在SMA动物模型中进行评价。本文中，我们公开了在SMA的转基因Delta 7 SMA KO小鼠模型中测试有效且合理选择性的GSK-3抑制剂，即BIP-135，并发现其延长这些动物的中值存活。此外，如通过蛋白质印迹测定的，该化合物显示提高SMA患者来源的成纤维细胞中的SMN蛋白水平，并且在基于细胞的神经保护性研究中具有神经保护性。氧化应激诱导的神经变性的SMA相关模型。
The discovery of upregulated glycogen synthase kinase-3 (GSK-3) in various pathological conditions has led to the development of a host of chemically diverse small molecule GSK-3 inhibitors, such as BIP-135. GSK-3 inhibition emerged as an alternative therapeutic target for treating spinal muscular atrophy (SMA) when a number of GSK-3 inhibitors were shown to elevate survival motor neuron (SMN) levels in vitro and to rescue motor neurons when their intrinsic SMN level was diminished by SMN-specific short hairpin RNA (shRNA). Despite their cellular potency, the in vivo efficacy of GSK-3 inhibitors has yet to be evaluated in an animal model of SMA. Herein, we disclose that a potent and reasonably selective GSK-3 inhibitor, namely BIP-135, was tested in a transgenic Delta 7 SMA KO mouse model of SMA and found to prolong the median survival of these animals, In addition, this compound was shown to elevate the SMN protein level in SMA patient-derived fibroblast cells as determined by Western blot, and was neuroprotective in a cell-based, SMA-related model of oxidative stress-induced neurodegeneration.