title: Meserine, a novel carbamate AChE inhibitor, ameliorates scopolamine-induced dementia and alleviates amyloidogenesis of APP/PS1 transgenic mice.
abstract: OBJECTIVE
  To investigate whether Meserine, a novel phenylcarbamate derivative of (-)-meptazinol, possesses beneficial activities against cholinergic deficiency and amyloidogenesis, the two major pathological characteristics of Alzheimer's disease (AD).
  
  
  METHODS
  Ellman's assay and Morris water maze were used to detect acetylcholinesterase (AChE) activity and evaluate spatial learning and memory ability, respectively. Both high content screening and Western blotting were carried out to detect β-amyloid precursor protein (APP), while RT-PCR and ELISA were conducted to detect APP-mRNA and β-amyloid peptide (Aβ).
  
  
  RESULTS
  In scopolamine-induced dementia mice, Meserine (1 mg/kg, i.p.) significantly ameliorated spatial learning and memory deficits, which was consistent with its in vitro inhibitory ability against AChE (recombinant human AChE, IC50 = 274 ± 49 nM). Furthermore, Meserine (7.5 mg/kg) injected intraperitoneally once daily for 3 weeks lowered APP level by 28% and Aβ42 level by 42% in APP/PS1 transgenic mouse cerebrum. This APP modulation action might be posttranscriptional, as Meserine reduced APP by about 30% in SH-SY5Y-APP695 cells but did not alter APP-mRNA level. And both APP and Aβ42 lowering action of Meserine maintained longer than that of rivastigmine.
  
  
  CONCLUSIONS
  Meserine executes dual actions against cholinergic deficiency and amyloidogenesis and provides a promising lead compound for symptomatic and modifying therapy of AD.
authors.affiliation: Department of Pharmacology & Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Bi-Yun
authors.initials: BY
authors.lastname: Shao
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
authors.forename: Xin-Xing
authors.initials: XX
authors.lastname: Ge
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.forename: Pan
authors.initials: P
authors.lastname: Jiang
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Le
authors.forename: Zhui-Bai
authors.initials: ZB
authors.lastname: Qiu
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000188:drug therapy* / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D003704:Dementia / Q000139:chemically induced* / Q000188:drug therapy*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D008621:Meptazinol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000473:pathology; D048448:Phenylcarbamates / Q000494:pharmacology / Q000627:therapeutic use*; D053764:Presenilin-1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012601:Scopolamine
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D053764:Presenilin-1; D012333:RNA, Messenger; C000591387:meserine; D008621:Meptazinol; D012601:Scopolamine; D000110:Acetylcholinesterase
keywords: AChE inhibitor; Alzheimer's disease; Meserine; β-amyloid peptide; β-amyloid precursor protein