Promising tacrine/huperzine A-based dimeric acetylcholinesterase inhibitors for neurodegenerative disorders: From relieving symptoms to modifying diseases through multitarget

• Type of Material: Article
• Authors: Shinghung Mak, HKUST Shenzhen Research Institute; Wenming Li, Emory University; Hongjun Fu, Ohio State University; Jialie Luo, Washington Univ; Wei Cui, Ningbo University; Shengquan Hu, Shenzhen University; Yuanping Pang, Mayo Clinic, Rochester; Paul R Carlier, Virginia Tech; Karl Wahkeung Tsim, HKUST Shenzhen Research Institute; Rongbiao Pi, Sun Yat-sen University; Yifan Han, Hong Kong Polytechnic University
• Language: English
• Date: 2021-07-05
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 International Society for Neurochemistry
• Final Published Version (URL): http://dx.doi.org/10.1111/jnc.15379
• Title of Journal or Parent Work: JOURNAL OF NEUROCHEMISTRY
• Volume: 158
• Issue: 6
• Start Page: 1381
• End Page: 1393
• Grant/Funding Information: This work was supported by grants from the Research Grants Council of Hong Kong (644106M, 660807M, 560909M, 561011M, and 15101014 to Yifan Han) and grants from the National Institutes of Health (AG058866 to Wenming Li).
• Keywords: IN-VIVO; Neurosciences; TARGET-DIRECTED LIGANDS; MEF2D; HUPERZINE-A; Neurosciences & Neurology; COGNITIVE DYSFUNCTION; NMDA RECEPTOR; MULTIFUNCTIONAL DIMER; Science & Technology; dimeric acetylcholinesterase inhibitors; neurodegenerative disorders; Life Sciences & Biomedicine; neuroprotection; D-ASPARTATE RECEPTORS; NEURONAL APOPTOSIS; multifunctional compounds; ALZHEIMERS-DISEASE; Biochemistry & Molecular Biology; AMYLOID-BETA OLIGOMERS; disease-modifying

Abstract

Neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, are devastating diseases in the elderly world, which are closely associated with progressive neuronal loss induced by a variety of genetic and/or environmental factors. Unfortunately, currently available treatments for neurodegenerative disorders can only relieve the symptoms but not modify the pathological processes. Over the past decades, our group by collaborating with Profs. Yuan-Ping Pang and Paul R. Carlier has developed three series of homo/hetero dimeric acetylcholinesterase inhibitors derived from tacrine and/or huperzine A. The representative dimers bis(3)-Cognitin (B3C), bis(12)-hupyridone, and tacrine(10)-hupyridone might possess disease-modifying effects through the modulation of N-methyl-d-aspartic acid receptors, the activation of myocyte enhancer factor 2D gene transcription, and the promotion of neurotrophic factor secretion. In this review, we summarize that the representative dimers, such as B3C, provide neuroprotection against a variety of neurotoxins via multiple targets, including the inhibitions of N-methyl-d-aspartic acid receptor with pathological-activated potential, neuronal nitric oxide synthase, and β-amyloid cascades synergistically. More importantly, B3C might offer disease-modifying potentials by activating myocyte enhancer factor 2D transcription, inducing neuritogenesis, and promoting the expressions of neurotrophic factors in vitro and in vivo. Taken together, the novel dimers might offer synergistic disease-modifying effects, proving that dimerization might serve as one of the strategies to develop new generation of therapeutics for neurodegenerative disorders. (Figure presented.).