Inhibitory potency of 4- substituted sampangine derivatives toward Cu2+ mediated aggregation of amyloid β-peptide, oxidative stress, and inflammation in Alzheimer's disease

Chunling Su; Yusi Chen; Kelin Chen; Wei Li; Huang Tang

doi:10.1016/j.neuint.2020.104794

Inhibitory potency of 4- substituted sampangine derivatives toward Cu²⁺ mediated aggregation of amyloid β-peptide, oxidative stress, and inflammation in Alzheimer's disease

Neurochem Int. 2020 Oct:139:104794. doi: 10.1016/j.neuint.2020.104794. Epub 2020 Jul 7.

Authors

Chunling Su¹, Yusi Chen¹, Kelin Chen¹, Wei Li¹, Huang Tang²

Affiliations

¹ State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin City, Guangxi, China.
² State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin City, Guangxi, China. Electronic address: hyhth@163.com.

PMID: 32650027
DOI: 10.1016/j.neuint.2020.104794

Abstract

Cu²⁺ plays a key role in the pathogenesis of Alzheimer's disease (AD). The dysregulation of Cu²⁺ can cause neuronal damage and aggravate development of AD. Moreover, a series of 4-substituted sampangine derivatives have been investigated as inhibitors of acetylcholinesterase and β-amyloid (Aβ) aggregation for the treatment of AD in our previous studies. In the present study, we reported that one of these derivatives SD-1 was able to modulate Cu²⁺-mediated multiple pathological elements in AD. The high selectivity of SD-1 for Cu²⁺ over other biologically relevant metal ions was demonstrated by ITC. Western blotting analysis, light-scattering study, DCF-DA assay and paralysis experiment indicated that SD-1 suppressed the formation of Cu²⁺-Aβ species, alleviated the Cu²⁺-Aβ species induced neurotoxicity and inhibited the production of ROS catalyzed by Cu²⁺-Aβ species in SH-SY5Y cells over-expressing the Swedish mutant form of human APP (APPsw SH-SY5Y) and Aβ42 transgenic C elegans (CL2020). Furthermore, SD-1 inhibited the expressions of NO, iNOS, TNF-α, IL-1β and IL-6 induced by Cu²⁺ in BV2 microglial cells. Collectively, these findings provided valuable insights into the design and development of potent metal-chelating agents for AD treatment.

Keywords: Alzheimer's disease; Inflammation; Oxidative stress; Sampangine alkaloid derivatives; β-amyloid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkaloids / chemistry
Alkaloids / pharmacology
Alkaloids / therapeutic use*
Alzheimer Disease / drug therapy
Alzheimer Disease / genetics
Alzheimer Disease / metabolism*
Amyloid beta-Peptides / toxicity*
Animals
Animals, Genetically Modified
Caenorhabditis elegans
Cell Line, Tumor
Copper / toxicity*
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology
Heterocyclic Compounds, 4 or More Rings / therapeutic use*
Humans
Mice
Microglia / drug effects
Microglia / metabolism
Naphthyridines / chemistry
Naphthyridines / pharmacology
Naphthyridines / therapeutic use*
Oxidative Stress / drug effects*
Oxidative Stress / physiology
Peptide Fragments / toxicity*
Protein Aggregation, Pathological / drug therapy
Protein Aggregation, Pathological / genetics
Protein Aggregation, Pathological / metabolism*

Substances

Alkaloids
Amyloid beta-Peptides
Heterocyclic Compounds, 4 or More Rings
Naphthyridines
Peptide Fragments
amyloid beta-protein (1-42)
Copper
sampangine