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Neurochem Int. 2017 Sep;108:157-168. doi: 10.1016/j.neuint.2017.03.007. Epub 2017 Mar 10.

Oxoisoaporphine alkaloid derivative 8-1 reduces Aβ1-42 secretion and toxicity in human cell and Caenorhabditis elegans models of Alzheimer's disease.

Author information

1
Affiliated Hospital of Guilin Medicine University, Guilin, Guangxi, China.
2
Jiangxi Research Institute of Ophthalmology and Visual Sciences, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China.
3
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.
4
Affiliated Hospital of Guilin Medicine University, Guilin, Guangxi, China. Electronic address: daicw1104@163.com.
5
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.

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 Aβ1-42 secretion 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.

KEYWORDS:

Alzheimer's disease; Aβ(1-42); Caenorhabditis elegans; Oxoisoaporphine alkaloid derivative; SH-SY5Y cell

PMID:
28286208
DOI:
10.1016/j.neuint.2017.03.007
[Indexed for MEDLINE]

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