Premium
Modification of tyrosine hydroxylase activity by chloral derived β‐carbolines in vitro
Author(s) -
Riederer Franz,
Luborzewski Alexander,
God Ralf,
Bringmann Gerhard,
Scholz Joachim,
Feineis Doris,
Moser Andreas
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.00875.x
Subject(s) - tyrosine hydroxylase , mptp , neurotoxin , chemistry , in vitro , enzyme , tyrosine 3 monooxygenase , biochemistry , enzyme assay , pharmacology , endocrinology , biology , dopamine , dopaminergic
β‐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 β‐carboline derivative 1‐trichloromethyl‐1,2,3,4‐tetrahydro‐β‐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‐β‐carboline (1‐CCl 2 ‐THβC) 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 ‐THβC inhibited TH in concentrations of 0.1 m m , while 1‐CCl 2 ‐THβC in low concentrations enhanced TH activity. When TH was activated by PACAP‐27, TaClo, 2‐Me‐TaClo, or 1‐CCl 2 ‐THβC also inhibited activated enzyme activity in high concentrations. However, in the case of 2‐Me‐TaClo and 1‐CCl 2 ‐THβC 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 ‐THβC did not modify enzyme activity. After activation of hTH1 by PKA all the tetrahydro‐β‐carbolines investigated in this study decreased l ‐DOPA formation. We suggest that these β‐carbolines modulate dopamine synthesis by interacting with a protein kinase TH‐activating system.