Biomedical subjects

B Kittner

Publications and source records attributed to B Kittner.

7 recordsLinked to original sources

PubMed1992

Rating scales and computed tomography in multi-infarct dementia.

Forty patients who fulfilled the DSM-III-R criteria for multi-infarct dementia and had a score of 7 points or more on Hachinski ischemia score (HIS) were analyzed with the purpose to correlate the rating scales and CT scans. Among the examined patients there were 32 women with the average age of 68.5 +/- 9.8 years and 8 men with the average age of 68.8 +/- 10.4 years. No significant difference between sex in relation to Folstein Mini-mental state examination (MMSE), Gottfries-Brane-Steen scale (GBS) and Sandoz clinical assessment-geriatric scale (SCAG) was found. There is no correlation of GBS and SCAG on MMSE. With regression analysis a good correlation was found between GBS and SCAG, and we suggest that in such studies only one of these two scales is sufficient. CT abnormalities were found in about 77% of examined patients without difference according to sex. But, GBS score demonstrated greater disability among MID patients with abnormal CT scans than in MID patients with normal CT scans. In medical history of male MID patients completed stroke was significantly more common than among women, while the female MID patients had in their history significantly more frequent transient ischemic attack (TIA). This finding should be checked in a greater patient population. It is stressed that in everyday clinical practice it is necessary to use the diagnosis of multi-infarct dementia, e.g. to differentiate cerebral diseases according to etiology and pathogenesis.

Aged↗

PubMed1987

PC12 cells: a model system for studying drug effects on dopamine synthesis and release.

PC12 cells were used as a model system to examine drug effects on dopamine synthesis and release. It could be demonstrated that KCl treatment induced release of endogenous dopamine, simultaneously DOPA synthesis was increased. Despite of the increase in DOPA synthesis the intracellular concentration of tetrahydrobiopterin (the co-factor of tyrosine hydroxylase) remained stable, indicating that the catalytic recycling of the used tetrahydrobiopterin is much more rapid than the tetrahydrobiopterin consumption by tyrosine hydroxylation. Reserpine induced a decrease of intracellular dopamine but no dopamine reached the extracellular space, instead all dopamine was depleted into the cytoplasma and metabolized to DOPAC. Nitrendipine had no effect on intracellular dopamine storage, Bay K 8644 induced a small decrease of intracellular dopamine and a small increase in DOPA production. N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W7) induced a reserpine-like depletion at concentrations above 1 X 10(-6) M. The KCl-induced dopamine release and the stimulation of DOPA production were blocked by 1 X 10(-7) M nitrendipine and enhanced by 1 X 10(-7) M Bay K 8466, whereas 1 X 10(-6) M W7 had no effect on both parameters. These findings were compared to data obtained in other tissues reported in the literature indicating that PC12 cells are a useful model for studying drug effects on catecholamine synthesis and release.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1986

Apomorphine does not decrease tissue levels of tetrahydrobiopterin in vivo.

It was reported that R(-)apomorphine and other catechols are potent inhibitors of dihydropteridine reductase in vitro. It was suggested that decreased levels of tetrahydrobiopterin may represent a mechanism by which R(-)apomorphine inhibits catecholamine synthesis in vivo. This paper demonstrates that tetrahydrobiopterin levels are not affected either in vitro (PC12 cells) or in vivo (rat liver and corpus striatum) by treatment with R(-)apomorphine, whereas DOPA (3,4-dihydroxyphenylalanine) production (PC12 cells, corpus striatum) is reduced. This indicates that R(-)apomorphine does not inhibit DOPA production by reducing 6(R)-L-erythro-tetrahydrobiopterin) levels.

Animals↗

PubMed1986

Direct inhibition of tyrosine hydroxylase from PC-12 cells by catechol derivatives.

Several drugs with a catechol moiety were studied for their potency to inhibit tyrosine hydroxylase (TH) from PC-12 cells in vitro. When the natural compounds tested were compared, dopamine, norepinephrine and 2(3,4-dihydroxyphenyl)-ethanol (DOPET) were most effective (IC50 between 1.4 and 3.6 microM with 0.5 microM 6(R,S)-L-erythro-5,6,7,8-tetrahydrobiopterin as cofactor). 3,4-Dihydroxyphenylalanine (DOPA; IC50: 35 microM) and 3,4-dihydroxyphenylacetic acid (DOPAC; IC50: 180 microM were less potent inhibitors. Among the synthetic drugs possessing catechol moiety, isoproterenol, (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN) and (+/-)-2-dimethylamino-6,7-dihydroxy-tetrahydronaphthalene (TL-99) had the same inhibitory effects as the natural catecholamines (IC50 between 1.6 and 3.9 microM), whereas the apomorphine derivatives and 2,3,4,5-tetrahydro-1-phenyl-1 H-3-benzazepine-7,8-diol (SKF 38393) were even more potent (IC50: 0.5-0.8 microM). These results demonstrate that natural catechols and certain drugs (e.g. 6,7-ADTN, TL-99, SKF 38393) are more effective direct blockers of tyrosine hydroxylase than generally assumed provided appropriate assay conditions are used. In the case of dopamine and norepinephrine, these findings suggest a reevaluation of their role for feedback control of tyrosine hydroxylase in vivo.

Adrenal Gland Neoplasms↗

PubMed1985

Effect of apomorphine, alpha-methylparatyrosine, haloperidol and reserpine on DOPA production in clonal cell lines (PC-12 and N1E-115).

The effect of various drugs on DOPA production in the pheochromocytoma clone PC-12 and the neuroblastoma clone N1E-115 was studied. The N1E-115 cells contain only very low amounts of dopamine due to a lack of the aromatic L-amino acid decarboxylase, whereas the PC-12 cells are rich in dopamine. alpha-Methyl-p-tyrosine and apomorphine blocked DOPA production in both cell clones. Reserpine and haloperidol reduced the intracellular dopamine in the PC-12 cells and simultaneously induced a blockade of cellular DOPA production. The released dopamine was primarily recovered as 3,4-dihydroxyphenylacetic acid indicating a release of dopamine into the cytoplasm. This transient increase of cytoplasmic dopamine by reserpine or haloperidol brings about the inhibition of DOPA production in the PC-12 cells. Our results show that the PC-12 clone especially reacts to various drugs like other in vitro systems and may serve as an additional model for studying drug effects on catecholamine biosynthesis and metabolism.

Adrenal Gland Neoplasms↗

PubMed1985

Evaluation of neurotropic drug actions on tyrosine hydroxylase activity and dopamine metabolism in clonal cell lines.

Two clonal cell lines (the pheochromocytoma clone PC-12 and the neuroblastoma clone N1E-115) were used to compare direct and indirect drug effects on tyrosine hydroxylase and dopamine turnover. Both clones contain the cofactor of tyrosine hydroxylase, tetrahydrobiopterin, in sufficient concentrations. 2,4-Diamino-6-hydroxy-pyrimidine (DAO-Pyr), an inhibitor of GTP cyclohydrolase, which is the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, lowers DOPA production indicating that cofactor supply is a limiting factor for catecholamine synthesis. DOPA synthesis in the PC-12 cells can be stimulated by incubation with the natural cofactor tetrahydrobiopterin, but also by its possible precursors sepiapterin and dihydrobiopterin or the analogs methyl-tetrahydropterin and dihydropterin. The regulating enzyme for DOPA synthesis, tyrosine hydroxylase, can be inhibited by certain drugs either directly or indirectly by increasing dopamine concentrations in the cytoplasm after release from its vesicular stores. Using the neuroblastoma clone N1E-115 which lacks DOPA decarboxylase and thus contains only low levels of dopamine the site of action of certain drugs could be determined. Drugs affecting the tyrosine hydroxylase directly (alpha-methyl-para-tyrosine, apomorphine) decreased DOPA production in both clones, while drugs acting via interference with the vesicular stores (reserpine, amphetamine, nigericin) were effective only in the PC-12 cells. After total depletion of dopamine by nigericin at high concentrations or long-term incubation with 3-hydroxybenzyl-hydrazine (NSD 1015), DOPA production increased in the PC-12 cells indicating a usually occurring regulation of tyrosine hydroxylase by cytoplasmic dopamine. Dopamine concentration in the cytoplasm was calculated to be in the range of 1 X 10(-6) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Effects of apomorphine enantiomers and of lisuride on 3,4-dihydroxyphenylalanine production in striatal synaptosomes.

The effects of lisuride and of the R(-)- and S(+)-enantiomers of apomorphine were examined on 3,4-dihydroxyphenylalanine (DOPA) production by striatal synaptosomes and by crude, soluble striatal tyrosine hydroxylase. Due to their catechol structure, the enantiomers were almost equally effective in blocking soluble tyrosine hydroxylase (EC 1.14.16.2) (IC50 = 470 and 890 nM for R(-)- and S(+)-apomorphine, respectively), provided incubations were performed at pH 7.2 with 1 mM tetrahydrobiopterin as cofactor. The enantiomers were similarly effective in blocking synaptosomal DOPA production (IC50 = 410 and 970 nM for R(-)- and S(+)-apomorphine, respectively). As S(+)-apomorphine but not R(-)-apomorphine is considered to be a dopamine antagonist, these results support the assumption that the block of synaptosomal DOPA production by both apomorphine enantiomers is due to a direct inhibition of tyrosine hydroxylase. Lisuride at high concentrations (10-100 microM) blocked DOPA production in striatal synaptosomes; simultaneously, intrasynaptosomal dopamine was depleted. These data support the assumption that lisuride inhibits DOPA production indirectly, similar to reserpine. In accordance with this assumption, lisuride was without effect on DOPA production in dopamine-depleted synaptosomes. These results demonstrate that inhibition of synaptosomal DOPA production by at least some dopamine agonists may be explained by direct inhibitory effects on tyrosine hydroxylase.

3,4-Dihydroxyphenylacetic Acid↗