Open AccessMeserine, a Novel Carbamate AC hE Inhibitor, Ameliorates Scopolamine‐Induced Dementia and Alleviates Amyloidogenesis of APP / PS 1 Transgenic Mice
Author(s) -
Shao BiYun,
Xia Zheng,
Xie Qiong,
Ge XinXing,
Zhang WeiWei,
Sun Jian,
Jiang Pan,
Wang Hao,
Le WeiDong,
Qiu ZhuiBai,
Lu Yang,
Chen HongZhuan
Publication year - 2014
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12183
Subject(s) - morris water navigation task , acetylcholinesterase , rivastigmine , chemistry , donepezil , amyloid precursor protein , cholinergic , pharmacology , aché , genetically modified mouse , cholinesterase , biochemistry , endocrinology , alzheimer's disease , medicine , transgene , dementia , enzyme , hippocampus , disease , gene
Summary Aims 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, IC 50 = 274 ± 49 nM ). Furthermore, Meserine (7.5 mg/kg) injected intraperitoneally once daily for 3 weeks lowered APP level by 28% and Aβ 42 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‐APP 695 cells but did not alter APP‐ mRNA level. And both APP and Aβ 42 lowering action of Meserine maintained longer than that of rivastigmine. Conclusion Meserine executes dual actions against cholinergic deficiency and amyloidogenesis and provides a promising lead compound for symptomatic and modifying therapy of AD .