Document Detail


Cytotoxicity of chloral-derived beta-carbolines is not specific towards neuronal nor dopaminergic cells.
MedLine Citation:
PMID:  16868795     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
beta-Carbolines structurally related to the selective dopaminergic neurotoxin 1-methyl-4- phenylpyridinium (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease. The chloral-derived mammalian alkaloid derivative 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) is formed endogenously by a Pictet-Spengler condensation from the biogenic amine tryptamine (Ta) and the hypnotic aldehyde chloral (Clo). Here we examine the dopaminergic toxicity of TaClo and related compounds by testing their differential cytotoxicities in dopaminergic SH-SY5Y and non-dopaminergic murine Neuro2A neuroblastoma cell lines as well as in heterologous expression systems of the dopamine transporter (DAT) using both HEK-293 and Neuro2A cells. All TaClo derivatives showed significant cytotoxicity in all cell lines after 72 hours with the following rank order of toxic potency: 1-Tribromomethyl-1,2,3,4-tetrahydro-beta-carboline (TaBro) > TaClo > MPP(+) > 1,2,3,4-tetrahydro-beta-carboline (THbetaC) > 2[N]-methyl-TaClo > 2[N]-methyl-THbetaC. In contrast to MPP(+), there was no selectivity towards dopaminergic cells or cells ectopically expressing the DAT in vitro. Our results suggest that TaClo and related analogs are strong cytotoxins without selectivity towards dopaminergic cells.
Authors:
A Storch; Y-I Hwang; G Bringmann; D Feineis; S Ott; R Brückner; J Schwarz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-08-01
Journal Detail:
Title:  Journal of neural transmission (Vienna, Austria : 1996)     Volume:  113     ISSN:  0300-9564     ISO Abbreviation:  J Neural Transm     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-11-19     Completed Date:  2007-10-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9702341     Medline TA:  J Neural Transm     Country:  Austria    
Other Details:
Languages:  eng     Pagination:  1895-901     Citation Subset:  IM    
Affiliation:
Department of Neurology, Technical University of Dresden, Dresden, Germany. alexander.storch@neuro.med.tu-dresden.de
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MeSH Terms
Descriptor/Qualifier:
1-Methyl-4-phenylpyridinium / toxicity
Animals
Brain Neoplasms / pathology
Carbolines / toxicity*
Cell Line, Tumor
Cell Survival / drug effects
Data Interpretation, Statistical
Dopamine / physiology*
Dopamine Agents / toxicity
Dopamine Plasma Membrane Transport Proteins / metabolism
Humans
MPTP Poisoning / pathology
Mice
Neuroblastoma / pathology
Neurons / drug effects*,  pathology
Piperazines / pharmacology
Chemical
Reg. No./Substance:
0/Carbolines; 0/Dopamine Agents; 0/Dopamine Plasma Membrane Transport Proteins; 0/Piperazines; 48134-75-4/1-Methyl-4-phenylpyridinium; 67469-78-7/vanoxerine

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