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IMM-H004 reduced okadaic acid-induced neurotoxicity by inhibiting Tau pathology in vitro and in vivo.
NeuroToxicology ( IF 3.4 ) Pub Date : 2019-09-25 , DOI: 10.1016/j.neuro.2019.09.012 Yingying Wang 1 , Xiuyun Song 2 , Dandan Liu 3 , Yu-Xia Lou 3 , Piao Luo 4 , Tianbi Zhu 4 , Qi Wang 5 , Naihong Chen 6
NeuroToxicology ( IF 3.4 ) Pub Date : 2019-09-25 , DOI: 10.1016/j.neuro.2019.09.012 Yingying Wang 1 , Xiuyun Song 2 , Dandan Liu 3 , Yu-Xia Lou 3 , Piao Luo 4 , Tianbi Zhu 4 , Qi Wang 5 , Naihong Chen 6
Affiliation
This study aimed to explore effects and mechanisms of 004 (IMM-H004), a novel coumarin derivative, in OKA (okadaic acid)-induced AD (Alzheimer's disease)-like model. In vitro, MTT, LDH, and Annexin V/FITC flow cytometry assay were used to test cell survival. In vivo, OKA microinjection was conducted to simulate AD-like neuropathology. Morris water maze and Nissl staining were used to detect spatial memory function and neuronal damage respectively. Western blot and immunohistochemistry were used to study the mechanisms of 004 in Tau pathology. The results showed that 004 reduced cell death and increased survival in PC12 cells, and decreased neuronal injury in the hippocampus in rats. 004 improved learning and memory functions in OKA-treated rats. The mechanistic studies indicated that 004 inhibited phosphorylation of Tau protein by down-regulating the activity of protein kinases CDK5 and GSK3β and increasing PP2A activity. Overall, 004 improved spatial memory impairments and neuron cells injury induced by OKA; on the other hand, 004 inhibited Tau hyperphosphorylation by regulating CDK5, GSK3β and PP2A.
中文翻译:
IMM-H004通过在体内外抑制Tau病理学来降低冈田酸诱导的神经毒性。
这项研究旨在探讨新型香豆素衍生物004(IMM-H004)在OKA(冈田酸)诱导的AD(阿尔茨海默氏病)样模型中的作用和机制。在体外,MTT,LDH和Annexin V / FITC流式细胞仪检测细胞存活率。在体内,进行OKA显微注射以模拟AD样神经病理。莫里斯水迷宫和Nissl染色分别用于检测空间记忆功能和神经元损伤。免疫印迹和免疫组化被用来研究004在Tau病理中的机制。结果表明,004可以降低大鼠PC12细胞的细胞死亡并提高其存活率,并减少海马神经元损伤。004改善了经OKA治疗的大鼠的学习和记忆功能。机理研究表明004通过下调蛋白激酶CDK5和GSK3β的活性并增加PP2A的活性来抑制Tau蛋白的磷酸化。总体而言,004改善了OKA引起的空间记忆障碍和神经元细胞损伤。另一方面,004通过调节CDK5,GSK3β和PP2A抑制Tau过度磷酸化。
更新日期:2019-09-25
中文翻译:
IMM-H004通过在体内外抑制Tau病理学来降低冈田酸诱导的神经毒性。
这项研究旨在探讨新型香豆素衍生物004(IMM-H004)在OKA(冈田酸)诱导的AD(阿尔茨海默氏病)样模型中的作用和机制。在体外,MTT,LDH和Annexin V / FITC流式细胞仪检测细胞存活率。在体内,进行OKA显微注射以模拟AD样神经病理。莫里斯水迷宫和Nissl染色分别用于检测空间记忆功能和神经元损伤。免疫印迹和免疫组化被用来研究004在Tau病理中的机制。结果表明,004可以降低大鼠PC12细胞的细胞死亡并提高其存活率,并减少海马神经元损伤。004改善了经OKA治疗的大鼠的学习和记忆功能。机理研究表明004通过下调蛋白激酶CDK5和GSK3β的活性并增加PP2A的活性来抑制Tau蛋白的磷酸化。总体而言,004改善了OKA引起的空间记忆障碍和神经元细胞损伤。另一方面,004通过调节CDK5,GSK3β和PP2A抑制Tau过度磷酸化。