Chen Po C, Gaisina Irina N, El-Khodor Bassem F, Ramboz Sylvie, Makhortova Nina R, Rubin Lee L, Kozikowski Alan P
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612.
ACS Chem Neurosci. 2012 Jan 18;3(1):5-11. doi: 10.1021/cn200085z.
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 Δ7 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.
在各种病理状况下发现糖原合酶激酶-3（GSK-3）上调，促使人们开发出许多化学结构各异的小分子GSK-3抑制剂，如BIP-135。当一些GSK-3抑制剂在体外显示能提高存活运动神经元（SMN）水平，并且当它们的内在SMN水平因SMN特异性短发夹RNA（shRNA）而降低时能挽救运动神经元时，GSK-3抑制作为治疗脊髓性肌萎缩症（SMA）的替代治疗靶点出现。尽管GSK-3抑制剂具有细胞活性，但其在SMA动物模型中的体内疗效尚未得到评估。在此，我们披露一种强效且具有合理选择性的GSK-3抑制剂，即BIP-135，在SMA的转基因Δ7 SMA KO小鼠模型中进行了测试，并发现其能延长这些动物的中位生存期。此外，通过蛋白质印迹法测定，该化合物在SMA患者来源的成纤维细胞中能提高SMN蛋白水平，并且在基于细胞的、与SMA相关的氧化应激诱导神经退行性变模型中具有神经保护作用。
