Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT₄ receptor activation (RS67333) on object recognition in mice

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• 作者：Thomas Freret^a ; ^{thomas.freret@unicaen.fr} ; Valentine Bouet^a ; Anne Quiedeville^a ; Gé ; rald Nee^a ; Patrick Dallemagne^b ; Christophe Rochais^b ; Michel Boulouard^a ; ^{michel.boulouard@unicaen.fr}
• 关键词：5HT ; 5-hydroxytryptamine ; 5-HT4R ; 5-hydroxytryptamine (serotonin) receptor 4 ; AD ; Alzheimer's disease ; APP ; amyloid precursor protein ; DNPZ ; donepezil ; AChE ; acetylcholinesterase ; AChEi ; acetylcholinesterase inhibitor ; MTDL ; Multi-Target-Directed Ligand
• 刊名：Behavioural Brain Research
• 出版年：2012
• 期刊代码：3_01664328
• 类别：neu
• 出版时间：21 April, 2012
• 卷：230
• 期：1
• 页码：304-308
• 文件大小：249 K

摘要

Facing inefficiency of current treatments to cure Alzheimer disease (AD), a pharmacological approach is now emerging on the assumption that a single compound may be able to hit multiple targets, namely Multi-Target-Directed Ligands (MTDLs). Displaying numerous advantages, several MTDL for AD have been recently described but none associating an inhibition of AChE and an activation of 5-HT₄R. The aim of this study was to validate the concept of a synergistic action of these two targets on episodic-like memory performances in mice. Among potent molecules, RS67333, a reference 5-HT₄R agonist and donepezil (DNPZ), a reference acetylcholinesterase inhibitor, have been particularly chosen because of their close chemical structure. Administered separately, RS67333 (0.3 and 1 mg/kg) and DNPZ (1 mg/kg) improved recognition performances compared to saline treated animals but not with lower doses. Co-administration of subactive doses of RS67333 (0.1 mg/kg) and DNPZ (0.3 mg/kg) improved memory, moreover, this improvement is prevented if a 5-HT₄R antagonist (GR125487, 10 mg/kg) is also administered. Activation of 5-HT₄R combined with inhibition of AChE with subactive doses of RS67333 and of DNPZ has synergistic effects on memory performances in mice. These molecules having close chemical structures, the synergistic effect of their combination affords new hope to chemist for the synthesis of MTDL.