Smoothened agonist augments proliferation and survival of neural cells
Smoothened agonist augments proliferation and survival of neural cells
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DOI：
10.1016/j.neulet.2010.06.068
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发表时间：
2010-09-27
影响因子：
2.5
通讯作者：
Zarkovsky, Aleksandr
中科院分区：
文献类型：
--
作者：
Bragina, Olga;Sergejeva, Svetlana;Zarkovsky, Aleksandr
Sonic hedgehog信号通路在背腹神经管构型、神经干细胞增殖、神经元和神经胶质细胞存活等发育过程中起重要作用。Shh也参与了成年海马神经发生的调节。最近，Shh途径的非肽基平滑激活物已被发现。本研究的目的是探讨氯代苯并噻吩类分子Smo激动剂(SAG)在体内外模型中对神经发生和神经元存活的影响。我们的体外实验表明，SAG诱导Gill mRNA、转录靶标和Shh信号的介导物表达增加。体外实验还表明，低纳摩尔浓度的SAG可诱导神经元和神经胶质前体细胞的增殖，而不影响新生细胞的分化模式。与Shh相比，SAG在神经细胞培养中不产生神经毒性。SAG和Shh治疗也促进了成年大鼠侧脑室给药后齿状回新生神经细胞的存活。我们认为，SAG和类似的化合物代表着有吸引力的分子，可用于治疗疾病，在这些疾病中，刺激新神经细胞的生成和存活将是有益的。(C)2010爱思唯尔爱尔兰有限公司。保留所有权利。
Sonic hedgehog signaling pathway is important in developmental processes like dorsoventral neural tube patterning, neural stem cell proliferation and neuronal and glial cell survival. Shh is also implicated in the regulation of the adult hippocampal neurogenesis. Recently, nonpeptidyl Smoothened activators of the Shh pathway have been identified. The aim of this study was to investigate the effects of chlorobenzothiophene-containing molecule, Smo agonist (SAG), which has been shown to activate Shh signaling pathway, in neurogenesis and neuronal survival in in vitro and in vivo models. Our in vitro experiments showed that SAG induces increased expression of Gill mRNA, transcriptional target and mediator of Shh signal. In vitro experiments also demonstrated that SAG in low-nanomolar concentrations induces proliferation of neuronal and glial precursors without affecting the differentiation pattern of newly produced cells. In contrast to Shh, SAG did not induce neurotoxicity in neuronal cultures. The SAG and Shh treatment also promoted the survival of newly generated neural cells in the dentate gyrus after their intracerebroventricular administration to adult rats. We propose that SAG and similar compounds represent attractive molecules to be developed for treatment of disorders where stimulation of the generation and survival of new neural cells would be beneficial. (C) 2010 Elsevier Ireland Ltd. All rights reserved.