title: Novel multipotent AChEI-CCB attenuates hyperhomocysteinemia-induced memory deficits and Neuropathologies in rats.
abstract: Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3β. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Jiangsu Simovay Pharmaceutical Co., Ltd., Nanjing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kuan
authors.initials: K
authors.lastname: Zeng
authors.affiliation: Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jichang
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiao-Chuan
authors.initials: XC
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D000077265:Donepezil; D004359:Drug Therapy, Combination; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006710:Homocysteine / Q000633:toxicity; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000150:complications*; D007189:Indans / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009543:Nifedipine / Q000031:analogs & derivatives / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D016622:Silver Staining; D013619:Tacrine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D002800:Cholinesterase Inhibitors; D007189:Indans; D009419:Nerve Tissue Proteins; D010880:Piperidines; C000600497:SCR1693; C035100:nilvadipine; D006710:Homocysteine; D013619:Tacrine; D000077265:Donepezil; D009543:Nifedipine
keywords: Alzheimer's disease; GSK-3β; PP2A; SCR1693; hyperhomocysteinemia; tau