title: DL0410 Ameliorates Memory and Cognitive Impairments Induced by Scopolamine via Increasing Cholinergic Neurotransmission in Mice.
abstract: Deficiency of the cholinergic system is thought to play a vital role in cognitive impairment of dementia. DL0410 was discovered as a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinestease (BuChE), with potent efficiency in in-vitro experiments, but its in vivo effect on the cholinergic model has not been evaluated, and its action mechanism has also not been illustrated. In the present study, the capability of DL0410 in ameliorating the amnesia induced by scopolamine was investigated, and its effect on the cholinergic system in the hippocampus and its binding mode in the active site of AChE was also explored. Mice were administrated DL0410 (3 mg/kg, 10 mg/kg, and 30 mg/kg), and mice treated with donepezil were used as a positive control. The Morris water maze, escape learning task, and passive avoidance task were used as behavioral tests. The test results indicated that DL0410 could significantly improve the learning and memory impairments induced by scopolamine, with 10 mg/kg performing best. Further, DL0410 inhibited the AChE activity and increased acetylcholine (ACh) levels in a dose-dependent manner, and interacted with the active site of AChE in a similar manner as donepezil. However, no difference in the activity of BuChE was found in this study. All of the evidence indicated that its AChE inhibition is an important mechanism in the anti-amnesia effect. In conclusion, DL0410 could be an effective therapeutic drug for the treatment of dementia, especially Alzheimer's disease.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. lianwenwen1989@imm.ac.cn.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Lian
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. fangjiansong0815@163.com.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Fang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. xulvjie@imm.ac.cn.
authors.forename: Lvjie
authors.initials: L
authors.lastname: Xu
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. zhouwei@imm.ac.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. kangde@imm.ac.cn.
authors.forename: De
authors.lastname: Kang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. xiongwandi@imm.ac.cn.
authors.forename: Wandi
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. jhaoer@imm.ac.cn.
authors.forename: Hao
authors.initials: H
authors.lastname: Jia
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. liuailin@imm.ac.cn.|Beijing Key Laboratory of Drug Target Research and Drug Screening, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. liuailin@imm.ac.cn.|State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. liuailin@imm.ac.cn.
authors.forename: Ai-Lin
authors.initials: AL
authors.lastname: Liu
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. dugh@imm.ac.cn.|Beijing Key Laboratory of Drug Target Research and Drug Screening, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. dugh@imm.ac.cn.|State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. dugh@imm.ac.cn.
authors.forename: Guan-Hua
authors.initials: GH
authors.lastname: Du
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D018679:Cholinergic Agonists / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D012601:Scopolamine / Q000009:adverse effects; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D018679:Cholinergic Agonists; D002800:Cholinesterase Inhibitors; D012601:Scopolamine; D000110:Acetylcholinesterase
keywords: ACh; AChE inhibitor; BuChE inhibitor; DL0410; alzheimer’s disease