Modification of tyrosine hydroxylase activity by chloral derived beta-carbolines in vitro.
Beta-carbolines have been suggested to be involved in the pathogenesis of Parkinson's disease as a result of their structural similarity to the neurotoxin N -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The chloral-derived beta-carboline derivative 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) causes cell loss in neuronal and glial cell cultures and induces a slowly developing neurodegenerative process in rats. In our experiments, effects of TaClo and its derivatives 2-methyl-TaClo (2-Me-TaClo), and 1-dichloromethylene-1,2,3,4-tetrahydro-beta-carboline (1-CCl(2) -THbetaC) on tyrosine hydroxylase (TH) activity were investigated in TH assays using homogenate preparations of the rat nucleus accumbens and recombinant human TH (hTH1). TH activity was determined in vitro by measuring l-DOPA production with HPLC-ECD. Using homogenate preparations, TaClo, 2-Me-TaClo, and 1-CCl(2) -THbetaC inhibited TH in concentrations of 0.1 mm, while 1-CCl(2) -THbetaC in low concentrations enhanced TH activity. When TH was activated by PACAP-27, TaClo, 2-Me-TaClo, or 1-CCl(2) -THbetaC also inhibited activated enzyme activity in high concentrations. However, in the case of 2-Me-TaClo and 1-CCl(2) -THbetaC a biphasic effect was observed with a marked increase of TH activity in the nanomolar range. In our experiments using recombinant hTH1, TaClo, 2-Me-TaClo, or 1-CCl(2) -THbetaC did not modify enzyme activity. After activation of hTH1 by PKA all the tetrahydro-beta-carbolines investigated in this study decreased l-DOPA formation. We suggest that these beta-carbolines modulate dopamine synthesis by interacting with a protein kinase TH-activating system.
Riederer
Franz
F
Neurochemical Research Group, Department of Neurology, Medical University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
Luborzewski
Alexander
A
God
Ralf
R
Bringmann
Gerhard
G
Scholz
Joachim
J
Feineis
Doris
D
Moser
Andreas
A
D000818:Animals; D002243:Carbolines / Q000737:chemistry* / Q000494:pharmacology; D002697:Chloral Hydrate / Q000031:analogs & derivatives* / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007980:Levodopa / Q000032:analysis / Q000096:biosynthesis; D009714:Nucleus Accumbens / Q000201:enzymology; D010300:Parkinson Disease / Q000209:etiology; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000737:chemistry* / Q000187:drug effects*
C459449:1-dichloromethylene-1,2,3,4-tetrahydro-beta-carboline; C459448:1-trichloromethyl-1,2,3,4-teetrahydro-2-methyl-beta-carboline; D002243:Carbolines; C067372:1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline; D002697:Chloral Hydrate; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; C021100:trichloroacetaldehyde