丙戊酸钠通过上调Wnt/β-catenin信号通路促进培养神经元的生长(英文)  

Valproate promotes cultured neuronal growth partly through upregulating Wnt/β-catenin pathway

作　　者：王中平[1] 熊小琴[1] 孙燕[2] 彭裕文[2] 李瑞锡[2,3] 

机构地区：[1]九江学院基础医学院,九江332000 [2]复旦大学上海医学院人体解剖与组织胚胎学系 [3]复旦大学脑科学研究院,上海200032

出　　处：《神经解剖学杂志》2011年第3期235-241,共7页Chinese Journal of Neuroanatomy

基　　金：Specialized Research Fund for the Doctoral Program of Higher Education(SRFDP)sponsored by the Ministry of Education of China (20070246184);Opened Fund sponsored by Institute of Brain Science,Fudan University(2007);Basic-clinic Cross Research Fund sponsored by Shanghai Medical College,Fudan University(2007-09)~~

摘　　要：目的：丙戊酸盐（丙戊酸valproic acid,VPA）在过去数十年应用于临床治疗癫痫和偏头痛。然而,母亲怀孕早期使用VPA将大大增加子代罹患孤独症群谱障碍的易感性。鉴于Wnt/β-catenin信号通路对神经元增殖、分化、突起生长及凋亡的重要作用,本文旨在研究VPA在原代培养神经元中对Wnt/β-catenin信号通路的影响。方法：用VPA处理原代培养神经元,以生理盐水处理为对照,运用Western Blot检测Wnt/β-catenin通路相关信号分子Wnt1,Wnt2,WIF-1,Dickkopf 1及效应分子β-catenin的表达变化,同时运用免疫荧光技术观察神经元形态变化。结果：与对照组比较,VPA处理显著增加Wnt1及Wnt2的表达（P〈0.05~0.01）,而未增加WIF-1及Dickkopf 1的表达（P〉0.05）;VPA处理也导致Wnt/β-catenin通路活性上调,表现为神经元内β-catenin含量显著上升。此外,与对照组比较,VPA处理促进神经元生长,表现为神经元突起数目（P〈0.05~0.01）及总长度显著增加（P〈0.05~0.01）;Wnt/β-catenin通路抑制剂能部分抑制VPA引起的Wnt/β-catenin通路活性上调及神经元生长。结论：VPA通过上调Wnt/β-catenin信号通路促进神经元生长,可能是VPA增加子代罹患孤独症群谱障碍易感性的原因。Objective： Valproate（valproic acid,VPA） has been used for decades in the treatment of epilepsy and migraine.However,maternal administration of VPA in early pregnancy will remarkably increase susceptibility in the offspring to autism spectrum disorders（ASDs）.The aim of this study was to investigate the effect of VPA on Wnt/β-catenin pathway,which plays an important role in the neuronal proliferation,differentiation,process outgrowth and apoptosis.Methods： Primary cultured neurons were exposed to VPA or control.Western Blot was used to test the expression of Wnt/β-catenin pathway related molecules Wnt1,Wnt2,Wnt inhibitory factor-1（WIF-1）,Dickkopf 1 DKK1 and β-catenin,then the morphological changes of neurons were observed by immunofluorescence staining.Results： We found that VPA exposure,in comparison with control,induced overexpression of Wnt1 and Wnt2（P0.05-0.01）,but not of WIF-1 and Dickkopf 1（P0.05）.It also upregulated the activity of Wnt/β-catenin pathway,as indicated by the increased levels of β-catenin.We also observed that VPA treatment,in comparison with control,promoted neuronal growth,which showed significant increase of number of neurite branches（P0.05-0.01） and total neurite length（P0.05-0.01）.Furthermore,the increased activity of Wnt/β-catenin pathway,as well as the promotion of neurite complexity induced by VPA could be partly suppressed by the inhibitor of Wnt/β-catenin pathway.Conclusion：VPA promotes primary cultured neuronal growth partly through upregulating Wnt/β-catenin pathway,thus increasing susceptibility in the offspring to ASDs.

关 键 词：丙戊酸盐 WNT/Β-CATENIN通路 WNT1 Wnt2 神经元生长 

分 类 号：R965[医药卫生—药理学]