Glycogen Synthase Kinase 3 Inhibition Promotes Adult Hippocampal Neurogenesis in Vitro and in Vivo
Glycogen Synthase Kinase 3 Inhibition Promotes Adult Hippocampal Neurogenesis in Vitro and in Vivo
复制标题
DOI：
10.1021/cn300110c
复制
发表时间：
2012-11-01
影响因子：
5
通讯作者：
Perez-Castillo, Ana
中科院分区：
文献类型：
--
作者：
Morales-Garcia, Jose A.;Luna-Medina, Rosario;Perez-Castillo, Ana
糖原合成酶激酶 3 (GSK-3) 是一种丝氨酸/苏氨酸激酶，最初被认为是糖原代谢的调节剂，但它也在许多细胞功能中发挥着关键作用，包括分化、细胞周期调节和增殖。海马齿状回和侧脑室的室下区是成人大脑中发生神经发生的区域之一。在这里，我们使用化学遗传学方法，使用几种不同的 GSK-3 抑制剂作为药理学工具，在体外研究中表明，GSK-3 的抑制可诱导神经干细胞向神经元表型增殖、迁移和分化。此外，我们还证明，用称为 tidglusib 的小分子 NP03112 抑制 GSK-3 会诱导成年大鼠海马齿状回的神经发生。综上所述，我们的结果表明，GSK-3 应被视为调节海马中新神经元的产生和整合的新靶分子，作为神经退行性疾病或脑损伤的治疗方法，因此，其抑制剂可能代表神经再生医学中新的潜在治疗药物。
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase originally identified as a regulator of glycogen metabolism but it also plays a pivotal role in numerous cellular functions, including differentiation, cell cycle regulation, and proliferation. The dentate gyrus of the hippocampus, together with the subventricular zone of the lateral ventricles, is one of the regions in which neurogenesis takes place in the adult brain. Here, using a chemical genetic approach that involves the use of several diverse inhibitors of GSK-3 as pharmacological tools, we show that inhibition of GSK-3 induces proliferation, migration, and differentiation of neural stem cells toward a neuronal phenotype in in vitro-studies. Also, we demonstrate that inhibition of GSK-3 with the small molecule NP03112, called tideglusib, induces neurogenesis in the dentate gyrus of the hippocampus of adult rats. Taken together, our results suggest that GSK-3 should be considered as a new target molecule for modulating the production and integration of new neurons in the hippocampus as a treatment for neurodegenerative diseases or brain injury and, consequently, its inhibitors may represent new potential therapeutic dugs in neuroregenerative medicine.