Inhibition of glycogen synthase kinase 30 attenuates neurocognitive dysfunction resulting from cranial irradiation
Inhibition of glycogen synthase kinase 30 attenuates neurocognitive dysfunction resulting from cranial irradiation
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DOI：
10.1158/0008-5472.can-07-6327
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Yazlovitskaya, Eugenia M.
中科院分区：
文献类型：
--
作者：
Thotala, Dinesh K.;Hallahan, Dennis E.;Yazlovitskaya, Eugenia M.
目前，美国有超过1000万癌症幸存者。随着这些数字，癌症治疗引起的慢性后遗症已成为一个主要的卫生保健问题。虽然脑部放射治疗提高了癌症治愈率，但学习障碍和记忆缺陷是这种治疗的常见后果。在这里，我们表明，糖原合成酶激酶30（GSK-3）是辐射诱导的海马神经元凋亡和随后的神经认知能力下降所必需的。通过小分子（SB 216763或S13415286）或通过在照射前异位表达激酶失活的GSK-30抑制GSK-30显著减弱了海马神经元中的辐射诱导的凋亡。用SB 216763或SB 415286抑制GSK-3也减少了辐射小鼠海马颗粒下区的细胞凋亡，从而改善了辐射动物的认知功能。细胞保护作用的分子机制的研究表明，GSK-30的活性在海马神经元辐射没有显着改变，指出这种酶在辐射诱导的细胞凋亡的间接参与。同时，辐射导致p53积累增加，而在辐射前抑制GSK-3活性的基础水平可阻止p53积累，这表明GSK-30抑制剂可能具有细胞保护作用。这些发现确定GSK-30信号传导是海马神经元辐射诱导损伤的关键调节因子，并表明GSK-3抑制剂可能在保护儿童和成人癌症患者方面具有治疗作用，并可能有助于改善癌症幸存者的生活质量。
There are now more than 10 million cancer survivors in the United States. With these numbers, chronic sequelae that result from cancer therapy have become a major health care problem. Although radiation therapy of the brain has improved cancer cure rates, learning disorders and memory deficits are a common consequence of this therapy. Here we show that glycogen synthase kinase 30 (GSK-3) is required for radiation-induced hippocampal neuronal apoptosis and subsequent neurocognitive decline. Inhibition of GSK-30 either by small molecules (SB216763 or S13415286) or by ectopic expression of kinase-inactive GSK-30 before irradiation significantly attenuated radiation-induced apoptosis in hippocampal neurons. GSK-3 inhibition with SB216763 or SB415286 also decreased apoptosis in the subgranular zone of the hippocampus in irradiated mice, leading to improved cognitive function in irradiated animals. Studies of the molecular mechanisms of the cytoprotective effect showed that GSK-30 activity in hippocampal neurons was not significantly altered by radiation, pointing to the indirect involvement of this enzyme in radiation-induced apoptosis. At the same time, radiation led to increased accumulation of p53, whereas inhibition of the basal level of GSK-3 activity before radiation prevented p53 accumulation, suggesting a possible mechanism of cytoprotection by GSK-30 inhibitors. These findings identify GSK-30 signaling as a key regulator of radiation-induced damage in hippocampal neurons and suggest that GSK-3 inhibitors may have a therapeutic role in protecting both pediatric and adult cancer patients and may help to improve quality of life in cancer survivors.