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LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy

文献类型：期刊论文

作者Guo, Xiao-dan1,3; Sun, Guang-long1,3; Zhou, Ting-ting1,3; Wang, Yi-yang1,3; Xu, Xin1,3; Shi, Xiao-fan1,3; Zhu, Zhi-yuan1,3; Rukachaisirikul, Vatcharin2; Hu, Li-hong1,3; Shen, Xu1,3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2017-08
卷号38期号:8页码:1104-1119
关键词Alzheimer's disease LX2343 cognitive deficits oxidative stress tauopathy mitochondria GSK-3 beta inhibitor neuroprotection ICV-STZ rats
ISSN号1671-4083
DOI10.1038/aps.2016.128
文献子类Article
英文摘要Alzheimer's disease (AD) is a progressive neurodegenerative disease leading to the irreversible loss of brain neurons and cognitive abilities, and the vicious interplay between oxidative stress (OS) and tauopathy is believed to be one of the major players in AD development. Here, we demonstrated the capability of the small molecule N-(1,3-benzodioxol-5-yl)-2-[ 5-chloro-2-methoxy( phenylsulfonyl)anilino]acetamide (LX2343) to ameliorate the cognitive dysfunction of AD model rats by inhibiting OS-induced neuronal apoptosis and tauopathy. Streptozotocin (STZ) was used to induce OS in neuronal cells in vitro and in AD model rats that were made by intracerebroventricular injection of STZ (3 mg/kg, bilaterally), and Morris water maze test was used to evaluate the cognitive dysfunction in ICV-STZ rats. Treatment with LX2343 (5-20 mu mol/L) significantly attenuated STZ-induced apoptosis in SH-SY5Y cells and mouse primary cortical neurons by alleviating OS and inhibiting the JNK/p38 and pro-apoptotic pathways. LX2343 was able to restore the integrity of mitochondrial function and morphology, increase ATP biosynthesis, and reduce ROS accumulation in the neuronal cells. In addition, LX2343 was found to be a non-ATP competitive GSK-3 beta inhibitor with IC50 of 1.84 +/- 0.07 mu mol/L, and it potently inhibited tau hyperphosphorylation in the neuronal cells. In ICV-STZ rats, administration of LX2343 (7, 21 mg.kg(-1).d(-1), ip, for 5 weeks) efficiently improved their cognitive deficits. LX2343 ameliorates the cognitive dysfunction in the AD model rats by suppressing OS-induced neuronal apoptosis and tauopathy, thus highlighting the potential of LX2343 for the treatment of AD.
WOS关键词PROGRESSIVE SUPRANUCLEAR PALSY ; SPORADIC ALZHEIMERS-DISEASE ; GLYCOGEN-SYNTHASE KINASE-3 ; P301S TRANSGENIC MICE ; MITOCHONDRIAL DYSFUNCTION ; THERAPEUTIC STRATEGIES ; MEMORY IMPAIRMENT ; ANIMAL-MODEL ; TAU ; STREPTOZOTOCIN
资助项目National Natural Science Foundation of China[81220108025] ; National Natural Science Foundation of China[81473141] ; NSFC-TRF collaboration projects[81561148011] ; NSFC-TRF collaboration projects[DBG5980001] ; Drug Innovation Project of SIMM[CASIMM0120154035] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040303]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:6040859
WOS记录号WOS:000406872200002
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/272546]  
专题药理学第三研究室
上海中药现代化研究中心
通讯作者Hu, Li-hong; Shen, Xu
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
2.Prince Songkla Univ, Dept Chem, Fac Sci, Hat Yai 90112, Songkhla, Thailand
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Guo, Xiao-dan,Sun, Guang-long,Zhou, Ting-ting,et al. LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy[J]. ACTA PHARMACOLOGICA SINICA,2017,38(8):1104-1119.
APA Guo, Xiao-dan.,Sun, Guang-long.,Zhou, Ting-ting.,Wang, Yi-yang.,Xu, Xin.,...&Shen, Xu.(2017).LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy.ACTA PHARMACOLOGICA SINICA,38(8),1104-1119.
MLA Guo, Xiao-dan,et al."LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy".ACTA PHARMACOLOGICA SINICA 38.8(2017):1104-1119.

入库方式： OAI收割

来源：上海药物研究所

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