title: Oxoisoaporphine alkaloid derivative 8-1 reduces Aβ1-42secretion and toxicity in human cell and Caenorhabditis elegans models of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a multifactorial neurodegenerative disease and a growing health problem worldwide. Because the drugs currently used to treat AD have certain drawbacks such as single targeting, there is a need to develop novel multi-target compounds, among which oxoisoaporphine alkaloid derivatives are promising candidates. In this study, the possible anti-AD activities of 14 novel oxoisoaporphine alkaloid derivatives that we synthesized were screened and evaluated. We found that, in the 14 novel derivatives, compound 8-1 significantly reduced Aβ1-42secretion in SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw). Next, we found that compound 8-1 could down-regulate the expression level of β-amyloid precursor protein (APP) in APPsw cells. Moreover, compound 8-1 significantly delayed paralysis in the Aβ1-42-transgenic Caenorhabditis elegans strain GMC101, which could be explained by the fact that compound 8-1 down-regulated acetylcholinesterase activity, protected against H2O2-induced acute oxidative stress and paraquat-induced chronic oxidative stress, and enhanced autophagy activity. Taken together, our data suggest that compound 8-1 could attenuate the onset and development of AD.
authors.affiliation: Affiliated Hospital of Guilin Medicine University, Guilin, Guangxi, China.
authors.forename: Liyingzi
authors.initials: L
authors.lastname: Huang
authors.affiliation: Jiangxi Research Institute of Ophthalmology and Visual Sciences, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Affiliated Hospital of Guilin Medicine University, Guilin, Guangxi, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Pu
authors.affiliation: Affiliated Hospital of Guilin Medicine University, Guilin, Guangxi, China.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Kong
authors.affiliation: Affiliated Hospital of Guilin Medicine University, Guilin, Guangxi, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Fu
authors.affiliation: Affiliated Hospital of Guilin Medicine University, Guilin, Guangxi, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Xing
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, Guangxi, China.
authors.forename: Shenqi
authors.initials: S
authors.lastname: Wei
authors.affiliation: Affiliated Hospital of Guilin Medicine University, Guilin, Guangxi, China. Electronic address: daicw1104@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, Guangxi, China. Electronic address: hyhth@163.com.
authors.forename: Huang
authors.initials: H
authors.lastname: Tang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D017173:Caenorhabditis elegans; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D010793:Phthalazines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C520741:8-1 compound; D016229:Amyloid beta-Peptides; D052117:Benzodioxoles; D010446:Peptide Fragments; D010793:Phthalazines; C075222:amyloid beta-protein (1-42); C008175:isoapomorphine; D001058:Apomorphine
keywords: Alzheimer's disease; Aβ(1-42); Caenorhabditis elegans; Oxoisoaporphine alkaloid derivative; SH-SY5Y cell