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Journal of Neural Transmission

, Volume 113, Issue 12, pp 1895–1901 | Cite as

Cytotoxicity of chloral-derived β-carbolines is not specific towards neuronal nor dopaminergic cells

  • A. Storch
  • Y.-I. Hwang
  • G. Bringmann
  • D. Feineis
  • S. Ott
  • R. Brückner
  • J. Schwarz
Article

Summary.

β-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-β-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-β-carboline (TaBro) > TaClo > MPP+ > 1,2,3,4-tetrahydro-β-carboline (THβC) > 2[N]-methyl-TaClo > 2[N]-methyl-THβC. 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.

Keywords: Dopamine transporter, 1,2,3,4-tetrahydro-β-carboline (THβC), 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo), 1-methyl-4-phenylpyridinium (MPP+), Parkinson’s disease 

Abbreviations:

βC

β-carboline

DAT

dopamine transporter

DHβC

3,4-dihydro-β-carboline

HEK-293

human embryonic kidney 293 cells

HEK-hDAT

dopamine transporter transfected HEK-293 cells

IQ

isoquinoline

MPP+

1-methyl-4-phenylpyridinium ion

MPTP

1-methyl-4-phenyl-2,3,6-tetrahydropyridine

TaClo

1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline

THβC

1,2,3,4-tetrahydro-β-carboline

wt

wild type

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • A. Storch
    • 1
  • Y.-I. Hwang
    • 2
  • G. Bringmann
    • 3
  • D. Feineis
    • 3
  • S. Ott
    • 2
  • R. Brückner
    • 3
  • J. Schwarz
    • 4
  1. 1.Department of NeurologyTechnical University of DresdenDresdenGermany
  2. 2.Department of NeurologyUniversity of UlmUlmGermany
  3. 3.Institute of Organic ChemistryUniversity of WürzburgWürzburgGermany
  4. 4.Department of NeurologyUniversity of LeipzigLeipzigGermany

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