Document Detail


A safe, blood-brain barrier permeable triphenylmethane dye inhibits amyloid-β neurotoxicity by generating nontoxic aggregates.
MedLine Citation:
PMID:  22860159     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Growing evidence suggests that on-pathway amyloid-β (Aβ) oligomers are primary neurotoxic species and have a direct correlation with the onset of Alzheimer's disease (AD). One promising therapeutic strategy to block AD progression is to reduce the levels of these neurotoxic Aβ species using small molecules. While several compounds have been shown to modulate Aβ aggregation, compounds with such activity combined with safety and high blood-brain barrier (BBB) permeability have yet to be reported. Brilliant Blue G (BBG) is a close structural analogue of a U.S. Food and Drug Administration (FDA)-approved food dye and has recently garnered prominent attention as a potential drug to treat spinal cord injury due to its neuroprotective effects along with BBB permeability and high degree of safety. In this work, we demonstrate that BBG is an effective Aβ aggregation modulator, which reduces Aβ-associated cytotoxicity in a dose-dependent manner by promoting the formation of off-pathway, nontoxic aggregates. Comparative studies of BBG and three structural analogues, Brilliant Blue R (BBR), Brilliant Blue FCF (BBF), and Fast Green FCF (FGF), revealed that BBG is most effective, BBR is moderately effective, and BBF and FGF are least effective in modulating Aβ aggregation and cytotoxicity. Therefore, the two additional methyl groups of BBG and other structural differences between the congeners are important in the interaction of BBG with Aβ leading to formation of nontoxic Aβ aggregates. Our findings support the hypothesis that generating nontoxic aggregates using small molecule modulators is an effective strategy for reducing Aβ cytotoxicity. Furthermore, key structural features of BBG identified through structure-function studies can open new avenues into therapeutic design for combating AD.
Authors:
H Edward Wong; Wei Qi; Hyung-Min Choi; Erik J Fernandez; Inchan Kwon
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-09-06
Journal Detail:
Title:  ACS chemical neuroscience     Volume:  2     ISSN:  1948-7193     ISO Abbreviation:  ACS Chem Neurosci     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2012-08-03     Completed Date:  2013-04-04     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101525337     Medline TA:  ACS Chem Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  645-57     Citation Subset:  IM    
Affiliation:
Department of Chemical Engineering, University of Virginia, Charlottesville, Virginia 22911, USA.
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MeSH Terms
Descriptor/Qualifier:
Amyloid beta-Peptides / antagonists & inhibitors*,  drug effects,  toxicity*
Blood-Brain Barrier / physiology*
Cell Survival / drug effects
Dose-Response Relationship, Drug
Fluorescent Dyes
Humans
Microscopy, Electron, Transmission
Nerve Fibers / drug effects,  ultrastructure
Neuroprotective Agents / pharmacology*
Oxazines / chemistry
Protein Binding
Rosaniline Dyes / pharmacology*
Thiazoles
Trityl Compounds / pharmacology*
Xanthenes / chemistry
Chemical
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Fluorescent Dyes; 0/Neuroprotective Agents; 0/Oxazines; 0/Rosaniline Dyes; 0/Thiazoles; 0/Trityl Compounds; 0/Xanthenes; 2390-54-7/thioflavin T; 550-82-3/resazurin; 6104-58-1/coomassie Brilliant Blue; 8O4UTW9E17/triphenylmethane
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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