Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio) Attenuates Aβ Oligomer-Induced Cognitive Impairments in Mice.
作者： Liping Chen , Chunhui Huang , Jieyi Shentu , Minjun Wang , Sicheng Yan
关键词: Neuroprotection 、 Glycogen synthase 、 Microglia 、 Chemistry 、 Neuroinflammation 、 Indirubin 、 Glial fibrillary acidic protein 、 Kinase 、 Pharmacology 、 Tumor necrosis factor alpha
摘要: Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer neurodegenerative disorders. 7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) glycogen synthase kinase-3β (GSK3β), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2.3-23.3 μg/kg 7Bio effectively prevented β-amyloid (Aβ) oligomer-induced impairments spatial cognition recognition without affecting bodyweight motor functions in mice. Moreover, potently inhibited Aβ expression interleukin-6 (IL-6) tumor necrosis factor-α (TNF-α). Furthermore, significantly the decreased synapsin-1 PSD-95, biomarkers pre-synaptic post-synaptic proteins oligomer-treated The mean optical density (OD) with hyper-phosphorylated tau (pTau), glial fibrillary acidic protein (GFAP) CD45 positive staining hippocampus 7Bio-treated mice were compared those addition, Western blotting analysis showed attenuated oligomer-decreased pSer9-GSK3β. Those results suggested neuroinflammation, synaptic impairments, hyper-phosphorylation, activation astrocytes microglia, which may contribute neuroprotective 7Bio. Based on these findings, expected developed as a novel anti-AD lead compound.
frontiersin.org
core.ac.uk 
sci-hub.se 参考文章(42)
Jaida Begum, Vassiliki T Skamnaki, Colin Moffatt, Nicolas Bischler, Josephine Sarrou, Alexios-Leandros Skaltsounis, Demetres D Leonidas, Nikos G Oikonomakos, Joseph M Hayes, None, An evaluation of indirubin analogues as phosphorylase kinase inhibitors Journal of Molecular Graphics & Modelling. ,vol. 61, pp. 231- 242 ,(2015) , 10.1016/J.JMGM.2015.07.010
Shengquan Hu, Wei Cui, Zaijun Zhang, Shinghung Mak, Daping Xu, Gang Li, Yuanjia Hu, Yuqiang Wang, Mingyuen Lee, Karl Wahkeung Tsim, Yifan Han, None, Indirubin-3-Oxime Effectively Prevents 6OHDA-Induced Neurotoxicity in PC12 Cells via Activating MEF2D Through the Inhibition of GSK3β Journal of Molecular Neuroscience. ,vol. 57, pp. 561- 570 ,(2015) , 10.1007/S12031-015-0638-Y
Mudasir Maqbool, Mohammad Mobashir, Nasimul Hoda, Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease European Journal of Medicinal Chemistry. ,vol. 107, pp. 63- 81 ,(2016) , 10.1016/J.EJMECH.2015.10.018
Volkmar Tell, Max Holzer, Lydia Herrmann, Kazem Ahmed Mahmoud, Christoph Schächtele, Frank Totzke, Andreas Hilgeroth, Multitargeted drug development: Discovery and profiling of dihydroxy substituted 1-aza-9-oxafluorenes as lead compounds targeting Alzheimer disease relevant kinases Bioorganic & Medicinal Chemistry Letters. ,vol. 22, pp. 6914- 6918 ,(2012) , 10.1016/J.BMCL.2012.09.006
Ludovic Martin, Amandine Magnaudeix, Cornelia M. Wilson, Catherine Yardin, Faraj Terro, The new indirubin derivative inhibitors of glycogen synthase kinase-3, 6-BIDECO and 6-BIMYEO, prevent tau phosphorylation and apoptosis induced by the inhibition of protein phosphatase-2A by okadaic acid in cultured neurons Journal of Neuroscience Research. ,vol. 89, pp. 1802- 1811 ,(2011) , 10.1002/JNR.22723
Shugang Zhang, Yingdong Zhang, Ligang Xu, Xingjian Lin, Jie Lu, Qing Di, Jingping Shi, Jun Xu, Indirubin-3'-monoxime inhibits β-amyloid-induced neurotoxicity in neuroblastoma SH-SY5Y cells Neuroscience Letters. ,vol. 450, pp. 142- 146 ,(2009) , 10.1016/J.NEULET.2008.11.030
Yun Ding, Aimin Qiao, Guo-Huang Fan, Indirubin-3'-monoxime rescues spatial memory deficits and attenuates beta-amyloid-associated neuropathology in a mouse model of Alzheimer's disease. Neurobiology of Disease. ,vol. 39, pp. 156- 168 ,(2010) , 10.1016/J.NBD.2010.03.022
Ruzhu Chen, Yizheng Wang, Mingtao Li, Wenya Wang, Yi Yang, Chunyi Ying, Wenming Li, Haolan Ruan, Xiaonan Zhu, Yan You, Yifan Han, Inhibition of glycogen synthase kinase-3β protects dopaminergic neurons from MPTP toxicity Neuropharmacology. ,vol. 52, pp. 1678- 1684 ,(2007) , 10.1016/J.NEUROPHARM.2007.03.017
M-L Selenica, H S Jensen, A K Larsen, M L Pedersen, L Helboe, M Leist, J Lotharius, Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation British Journal of Pharmacology. ,vol. 152, pp. 959- 979 ,(2007) , 10.1038/SJ.BJP.0707471
Gerhard Eisenbrand, Frankie Hippe, Sandra Jakobs, Stephan Muehlbeyer, Molecular mechanisms of indirubin and its derivatives: novel anticancer molecules with their origin in traditional Chinese phytomedicine. Journal of Cancer Research and Clinical Oncology. ,vol. 130, pp. 627- 635 ,(2004) , 10.1007/S00432-004-0579-2