Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer's Disease.

ACS Chemical Neuroscience
Zhenquan XuanWei Cui

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, a multitarget-directed ligands (MTDLs) strategy has been developed to treat AD. We have previously designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognitive-enhancing ability in AD animal models. In this study, A10E could prevent cognitive impairments in APP/PS1 transgenic mice and β-amyloid (Aβ) oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aβ production and deposition, alleviate neuroinflammation, enhance BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit Aβ oligomers-induced neurotoxicity via the activation of tyrosine kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore, Aβ oligomerization and fibrillization could be directly disrupted by A10E. Importantly, A10E at high concentrations did no...Continue Reading

References

Jun 1, 1995·Clinical Pharmacokinetics·S MaddenB K Park
Sep 7, 1999·Bioorganic & Medicinal Chemistry Letters·P R CarlierY P Pang
Feb 17, 2000·Neurochemistry International·E J CoulsonC L Masters
Aug 24, 2000·Journal of Neuroscience Research·X Q XiaoX C Tang
Feb 16, 2005·Sub-cellular Biochemistry·Nibaldo C InestrosaMarcela Colombres
Aug 4, 2005·Journal of the American Chemical Society·Haim HavivJoel L Sussman
Oct 14, 2005·Journal of Medicinal Chemistry·Richard Morphy, Zoran Rankovic
Dec 15, 2006·Toxicology Letters·Qin MengAugustinus Bader
Nov 28, 2007·Biochemical and Biophysical Research Communications·Hongjun FuYifan Han
Apr 5, 2011·Annual Review of Neuroscience·Richard J O'Brien, Philip C Wong
Mar 20, 2012·Cell·Yadong Huang, Lennart Mucke
Feb 26, 2013·Archives of Pharmacal Research·Preet Anand, Baldev Singh
Apr 23, 2013·Neuropharmacology·Graciano LealCarlos B Duarte
May 20, 2014·Molecular Neurobiology·Markus P KummerMichael T Heneka
Nov 27, 2014·Frontiers in Behavioral Neuroscience·Anshula SamarajeewaMichael A Beazely
May 1, 2015·Expert Opinion on Drug Discovery·Daniela PuzzoOttavio Arancio
Jul 8, 2015·Neuropeptides·Sagar H Barage, Kailas D Sonawane
Oct 21, 2015·Evidence-based Complementary and Alternative Medicine : ECAM·Marcin OzarowskiTeresa Bobkiewicz-Kozłowska
Oct 29, 2015·Journal of Neurochemistry·Myles R MinterPeter J Crack
Jul 26, 2016·Frontiers in Neuroscience·José Marco-ContellesLhassane Ismaili
Jan 31, 2017·Journal of Enzyme Inhibition and Medicinal Chemistry·Wen-Yu WuJin-Ao Duan
Apr 7, 2017·Journal of Neurochemistry·Saket M NigamMark P Mattson
May 10, 2017·Journal of Agricultural and Food Chemistry·Siying XiangJinrong Zhang
Sep 6, 2017·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·C A LaneJ M Schott
Jun 1, 2018·Brain : a Journal of Neurology·Harald HampelZaven S Khachaturian
Jun 12, 2018·Journal of Visualized Experiments : JoVE·Huang ChunhuiCui Wei
Sep 10, 2018·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Shuang LiuQihai Gong
Sep 11, 2018·Journal of Alzheimer's Disease : JAD·Sid E O'BryantRobert A Rissman
Dec 12, 2018·Methods in Molecular Biology·Ann-Katrin KraeuterZoltán Sarnyai
Feb 2, 2019·Current Topics in Medicinal Chemistry·Mridula Saxena, Ragini Dubey

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