title: A novel drug candidate for Alzheimer's disease treatment: gx-50 derived from Zanthoxylum bungeanum.
abstract: This study focused on a promising drug candidate, N-[2-(3,4-dimethoxyphenyl)ethyl]-3-phenyl-acrylamide (gx-50), a compound extracted from Sichuan pepper (Zanthoxylum Bungeanum), to determine whether it would be an effective therapeutic for Alzheimer's disease (AD) via biological experiments. In vivo, we determined the pharmacokinetic profile of gx-50 and evaluated the effect of gx-50 on the cognitive abilities of amyloid-β protein precursor transgenic (AβPP-Tg) mice by Morris water maze testing. In addition, we examined the effects of gx-50 on amyloid-β (Aβ) oligomers in the brains of AβPP-Tg mice by immunohistochemistry. In vitro, we observed a direct effect of gx-50 on Aβ oligomers by atomic force microscopy, detected the neuroprotective effects of gx-50 by western blotting and cell apoptosis assays, and measured its effects on intracellular calcium currents by laser confocal microscopy. Experiments in vivo showed that gx-50 could penetrate the blood brain barrier and improve the cognitive abilities of mice. Moreover, gx-50 treatment decreased the accumulation of Aβ oligomers in the cerebral cortex. The results in vitro demonstrated that gx-50 could disassemble Aβ oligomers, inhibit Aβ-induced neuronal apoptosis and apoptotic gene expression, and reduce neuronal calcium toxicity. These results strongly suggest that gx-50 is a potential candidate drug for treating AD.
authors.affiliation: School of Life Science and Biotechnology, Shanghai JiaoTong University, Shanghai, China.
authors.forename: Maoping
authors.initials: M
authors.lastname: Tang
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Wangjie
authors.initials: W
authors.lastname: Xu
authors.forename: Shengtian
authors.initials: S
authors.lastname: Li
authors.forename: Lianyun
authors.initials: L
authors.lastname: Wang
authors.forename: Dongqing
authors.initials: D
authors.lastname: Wei
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Qiao
mesh_terms: D000178:Acrylamides / Q000494:pharmacology / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity; D008517:Phytotherapy / Q000379:methods*; D028321:Plant Preparations / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058225:Plaque, Amyloid / Q000188:drug therapy; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D032106:Zanthoxylum / Q000737:chemistry*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000178:Acrylamides; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D028321:Plant Preparations; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D051028:bcl-2-Associated X Protein; C583359:lemairamin; D002118:Calcium