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PubMed1988

A nonisotopic method for determination of the in vivo activities of tyrosine hydroxylase in the rat adrenal gland.

A rapid and reliable method for determination of in vivo activities of tyrosine hydroxylase in the rat adrenal gland is presented. This method involves determining the rate of accumulation of 3,4-dihydroxyphenylalanine (Dopa) in the adrenal gland after decarboxylase inhibition by NSD 1015, using HPLC with electrochemical detection after purification of the acid-deproteinized tissue extract with Bio-Rex 70 columns followed by alumina batch method. Purification of the sample with alumina adsorption alone, a method usually used for purification of catecholamines and Dopa, was ineffective: epinephrine and norepinephrine, which are present in high concentrations, interfered with an accurate determination of Dopa, and dopamine, which is retained strongly on the reverse-phase column, interfered with a rapid analysis. Purification with Sephadex G-10 columns followed by alumina adsorption was also ineffective. After purification with columns of weak cation-exchange resins such as Bio-Rex 70 or Amberlite CG-50 followed by alumina adsorption, most of the epinephrine and norepinephrine was removed and dopamine was eliminated. Thus a rapid and accurate determination of Dopa could be made. Of the two cation exchangers, Bio-Rex 70 was more effective. Accumulation of Dopa in the adrenal gland was linear up to 30 min after administration of NSD 1015 and a plateau was reached with doses over 10 mg/kg. Using this method, we investigated the effects of immobilization stress, reserpine, and hypoxia on in vivo activities of tyrosine hydroxylase in the adrenal gland.

Adrenal Glands↗
PubMed1995

TOPA quinone, a kainate-like agonist and excitotoxin is generated by a catecholaminergic cell line.

The quinone derivative of 2,4,5-trihydroxyphenylalanine (TOPA) is a selective non-NMDA agonist and excitotoxin. While 3,4-dihydroxyphenylalanine (DOPA)-containing physiological solutions have been shown to generate TOPA and TOPA quinone (TOPA compounds), there have been no previous reports demonstrating the formation of this toxin in biological preparations. Here, using a pheochromocytoma catecholaminergic clonal cell line (PC12), we have identified TOPA compounds as by-products of catecholamine synthesis. PC12 cells incubated for 45 min with 30 microM tyrosine as a catecholamine precursor produced 1.0 +/- 0.2 pmol/10(6) cells of total TOPA compounds. The formation of these compounds could be enhanced nearly twofold when the cells were stimulated with 56 mM KCl. Moreover, the addition of a DOPA decarboxylase inhibitor (30 microM NSD-1015) increased the formation of TOPA compounds in both the unstimulated and stimulated conditions to a maximum of 5.5 +/- 0.7 pmol/10(6) cells after a 45 min incubation. A time-course analysis revealed that DOPA production above baseline levels coincided with the detectable generation of TOPA compounds. Finally, we observed an inhibition of TOPA compounds formation by 100 microM reduced glutathione, suggesting that these catecholamine products are formed from the extracellular autoxidation of DOPA. We propose that TOPA quinone may be an underestimated component of catecholamine toxicity that could be partly responsible for the demise of neurons in several neurodegenerative disorders, including Parkinson's and Huntington's disease. In addition, TOPA quinone may represent the first identified selective non-NMDA agonist that may be synthesized in the brain.

Adrenal Gland Neoplasms↗
PubMed1984

Enzyme changes in actively spiking areas of human epileptic cerebral cortex.

Five enzymes involved in glutamic acid, GABA, and catecholamine metabolism were measured in epileptic human brain. Electrocorticographically defined areas of focal spiking were compared with samples from surrounding nonspiking cortex. Comparative enzyme activities were as follows (mumol/h/g wet wt): glutamic acid dehydrogenase (GDH)--spiking 135.77 +/- 10.22 (mean +/- SEM), nonspiking 118.58 +/- 9.42 (p less than 0.001, N = 17); glutamic acid decarboxylase--spiking 10.63 +/- 0.95, nonspiking 9.96 +/- 1.10 (NS, N = 13); GABA-aminotransferase--spiking 36.49 +/- 1.05, nonspiking 36.46 +/- 1.48 (NS, N = 12); glutamine synthetase--spiking 96.94 +/- 3.81, nonspiking 96.52 +/- 4.10 (NS, N = 20); and tyrosine hydroxylase (TH; nmol/h/g)--spiking 16.23 +/- 2.39, nonspiking 10.67 +/- 1.95 (p less than 0.001, N = 14). Increased activity of GDH and TH may prove useful to characterize further areas of active spiking in human focal epilepsy.

Adolescent↗
PubMed1997

Autoantibodies to sympathetic ganglia, GAD, or tyrosine phosphatase in long-term IDDM with and without ECG-based cardiac autonomic neuropathy.

OBJECTIVE: To evaluate the association of autoantibodies to complement-fixing sympathetic ganglia (CF-SG), and tyrosine phosphatase (IA-2) with electrocardiogram (ECG)-based cardiac autonomic neuropathy (CAN) in long-term IDDM. RESEARCH DESIGN AND METHODS: We examined the prevalence of autoantibodies to CF-SG (by complement-fixing indirect immunoflourescence), GAD, and IA-2 (by radioligand assay) and islet cells (by indirect immunofluorescence) in 96 long-term IDDM patients (41 with ECG-based CAN, > or = 2 of 5 cardiac reflex tests abnormal; 55 without ECG-based CAN). As a control group, 89 healthy nondiabetic subjects were investigated. RESULTS: CF-SG autoantibodies were observed more frequently in long-term IDDM patients than in the control group (25 vs. 4%, P = 0.0001). Of the IDDM patients, 14 (34%) with CAN and 10 (18%) without CAN presented with CF-SG autoantibodies (P = 0.06). GAD or IA-2 autoantibodies were detected in 14 (34%) and 17 (41%) IDDM patients with CAN, compared with 24 (44%) and 29 (53%) IDDM patients without CAN (P = 0.2, P = 0.2). Islet cell antibodies were observed in 6 (15%) IDDM patients with and in 9 (16%) IDDM patients without CAN (P = 0.5). CONCLUSIONS: In long-term IDDM, the role of CF-SG autoantibodies, which tend to be more frequent in patients with ECG-based CAN, requires further investigations. The persistence of GAD and IA-2 autoantibodies is not related to ECG-based CAN.

Adult↗
PubMed1999

Role of tyrosine kinase, ODC, and p34cdc2 kinase and cyclin B-associated cdc2 in jejunal enterocyte proliferation, maturation, and exfoliation in diabetic and DFMO-treated rats.

BACKGROUND: Several signal transduction pathways involved in rapidly proliferating cells of the intestine are currently not well understood. In the jejunum, crypt enterocytes are constantly replicating, lower villi are maturing, and upper villi are constantly shed. Type I diabetes is associated with jejunal mucosal hyperplasia, and administration of diflouromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), causes hypoplasia. Phosphorylation of proteins controls cellular proliferation and/or exfoliation. Cell division cycle kinase (p34cdc2) and cyclin B-associated p34cdc2 kinase regulate the cell cycle during the transition from G2-M phase. Our aims were to: 1) investigate the activities of tyrosine kinase, ODC, total p34cdc2 kinase, and cyclin B-associated p34cdc2 kinase and 2) phosphorylate proteins at tyrosine residues in jejunal upper villi, lower villi, and crypt enterocytes of DFMO-treated control and diabetic rats. METHODS: Diabetes was induced by streptozotocin. DFMO was administered in drinking water in both control and diabetic groups for 10 days after the induction of diabetes. Jejunal enterocytes were isolated and kept frozen at -70 degrees C until ready to process. RESULTS: Diabetic rats showed jejunal mucosal hyperplasia as indicated by increases in the jejunal mucosal weight/cm and DNA content compared to control rats. Diabetic crypt enterocytes showed significant increases in activities of tyrosine kinase, ODC, total p34cdc2 kinase, and cyclin B-associated cdc2 as well as increased phosphorylation of proteins at tyrosine residues compared to control rats. DFMO prevented diabetes-induced jejunal hyperplasia, and decreased the activities of these enzymes and phosphorylation of proteins at tyrosine residues in both diabetic and control rats. Phosphorylation of a 14 kd protein became prominent in crypt, upper villi, and lower villi enterocytes of DFMO-treated diabetic and control groups. CONCLUSION: Diabetic jejunal mucosal hyperplasia appears to involve activation of complex signal transduction pathways such as tyrosine kinase, ODC, p34cdc2 kinase, and cyclin B. These enzymes are involved in proliferation and/or exfoliation of jejunal enterocytes. Our results also suggest that tyrosine phosphorylation of a 14 kd protein may be involved in cell exfoliation and that jejunal mucosal hypoplasia may be a synergistic effect caused by down regulation of the above enzymes.

Animals↗
PubMed1992

Rapid fibroblast growth factor-induced increases in protein phosphorylation and ornithine decarboxylase activity: regulation by heparin and comparison to nerve growth factor-induced increases.

Fibroblast growth factors (FGFs), like nerve growth factor (NGF), induce morphological differentiation of PC12 cells. This activity of FGF is regulated by glycosaminoglycans. To further understand the mechanisms of FGF and glycosaminoglycan actions in PC12 cells, we studied the regulation of protein phosphorylation and ornithine decarboxylase (ODC) activity by FGF in the presence and absence of heparin. As with NGF, aFGF and bFGF increased the incorporation of radioactive phosphate into the protein tyrosine hydroxylase (TH). The increase in TH phosphorylation was localized to the tryptic peptide, T3. Both T3 and T1 phosphorylations occur in response to NGF, but there was no evidence that aFGF or bFGF stimulated the phosphorylation of the T1 peptide. This result suggests differential regulation of second messenger systems by NGF and FGF in PC12 cells. Heparin, at a concentration that potentiated aFGF-induced neurite outgrowth 100-fold (100 micrograms/ml), did not alter the ability of aFGF to increase S6 phosphorylation or ODC activity. One milligram per milliliter of heparin, a concentration that inhibited bFGF-induced neurite outgrowth, also inhibited bFGF-induced increases in S6 phosphorylation and ODC activity. These observations suggest (i) that acidic and basic FGF activate a protein kinase, possibly protein kinase C, resulting in the phosphorylation of peptide T3 of TH; (ii) that the FGFs and NGF share some but not all second messenger systems; (iii) that heparin potentiates aFGF actions and inhibits bFGF actions in PC12 cells via distinct mechanisms; (iv) that heparin does not potentiate the neurite outgrowth promoting activity of aFGF by enhancing binding to its PC12 cell surface receptor; and (v) that heparin may coordinately regulate several activities of bFGF (induction of protein phosphorylation, ODC and neurite outgrowth) via a common mechanism, most likely by inhibiting the productive binding of bFGF to its PC12 cell surface receptor.

Animals↗
PubMed1984

24-Hour changes in catecholamine synthesis in rat and hamster pineal glands.

The purpose of this study was to examine the 24-hour variation in endogenous tyrosine hydroxylase (TH) activity and thus catecholamine (CA) synthesis in the hamster and rat pineal gland. To determine CA synthesis a time course of the accumulation of dihydroxyphenylalanine (DOPA) after DOPA decarboxylase inhibition with m-hydroxybenzylhydrazine (NSD-1015) was measured at 0, 15 and 30 min by liquid chromatography with electrochemical detection. Animals were under long photoperiods (LD 14:10; lights on at 06.00 h). In the hamster pineal gland, CA synthesis was greater in the dark (24.00 h) (0.017 ng/pineal/min) than in the light (12.00 h) (0.008 ng/pineal/min). Similarly, CA synthesis in the rat pineal was 0.037 ng/pineal/min (dark) and 0.005 ng/pineal/min (light). In a 24-hour study, animals were injected with NSD-1015,30 min prior to killing to determine if 24-hour changes were present in CA synthesis. In the hamster, DOPA in the dark (p less than 0.001) was significantly greater than in the light (1.33 +/- 0.42 ng/pineal at 06.00 h; 0.33 +/- 0.07 at 13.00 h) in this study. No significant difference was measured in norepinephrine (NE) concentration during this 24-hour period. In the rat, DOPA accumulation was significantly different (p less than 0.001) in the dark as compared to the light (0.86 +/- 0.09 ng/pineal at 03.00 h; 0.21 +/- 0.08 at 12.30 h). Within this 24-hour period, NE concentration fluctuated significantly between 2.28 +/- 0.33 ng/pineal (15.30 h) to 4.65 +/- 0.59 (05.30 h). These results indicate for the first time a definite 24-hour rhythm in endogenous TH activity and NE synthesis in the hamster pineal gland even though NE content does not change. In addition, a 24-hour change in CA synthesis and content is present in the rat pineal gland.

Animals↗
PubMed1991

Effects of nitroglycerin on release, synthesis and metabolism of norepinephrine and activation of tyrosine hydroxylase in guinea-pigs.

Nitroglycerin produced concentration-dependent increases in outflow of norepinephrine (NE) in perfused guinea-pig hearts. These effects of nitroglycerin were inhibited by guanethidine, but were not blocked by desmethylimipramine or rauwolscine. Nitroglycerin-induced increases in NE outflow correlated with its positive chronotropic responses. Higher concentrations of nitroglycerin also increased outflow of 3,4-dihydroxyphenylglycol (DOPEG) which were inhibited by desmethylimipramine. Nitroglycerin-induced maximal outflow of NE occurred during the first 2 min, but maximal outflow of DOPEG was 2-4 min. In addition, the 3,4-dihydroxyphenylalanine formation in atrial and striatal slices were enhanced by nitroglycerin in the presence of m-hydroxybenzylhydrazine dihydrochloride (an inhibitor of aromatic L-amino acid decarboxylase). The results suggest that nitroglycerin increases release of NE which correlates with cardiac stimulation by the drug. The drug also stimulates tyrosine hydroxylase activity resulting in increased synthesis of NE.

Animals↗
PubMed1991

Aromatic L-amino-acid decarboxylase (DOPA decarboxylase) gene expression in dopaminergic and serotoninergic cells of the rat brainstem.

In situ hybridization was performed in the rat brain to detect aromatic L-amino acid decarboxylase (AADC) mRNA using 35S-labeled oligonucleotide probes derived from rat kidney AADC cDNA. Results demonstrated AADC mRNA in areas containing dopaminergic and serotoninergic cell bodies. Combined immunohistochemistry for tyrosine- or tryptophan hydroxylase and in situ hybridization for AADC mRNA demonstrated the dopaminergic or serotoninergic nature of cells containing AADC mRNA. Tyrosine hydroxylase-positive mesencephalic neurons containing a very low or no AADC mRNA signal were also observed.

5-Hydroxytryptophan↗
PubMed1991

Insulin-like growth factor-I enhances tyrosine hydroxylase activation in bovine chromaffin cells.

Previous studies have shown that insulin-like growth factor-I (IGF-I) enhances secretagogue-stimulated Ca2+ uptake and catecholamine release in bovine chromaffin cells. This report describes the effect of IGF-I on the activity of tyrosine hydroxylase (tyrosine 3-monooxygenase, EC 1.14.16.2), the major regulatory enzyme in the pathway of catecholamine biosynthesis. Tyrosine hydroxylase activity was assayed by measuring 3,4-dihydroxyphenylalanine (Dopa) accumulation in the presence of brocresine, an inhibitor of Dopa decarboxylase. Chromaffin cells cultured in serum-free medium produced approximately 40% less Dopa when stimulated by 55 mM K+ than did cells that had been cultured in the presence of serum. Incubation of cells for 3 days in serum-free medium containing 10 nM IGF-I restored high K(+)-stimulated Dopa accumulation to a level comparable to that seen in cells cultured continuously in serum-containing medium. In eight experiments, IGF-I increased high K(+)-stimulated Dopa accumulation (expressed as picomoles per minute per milligram of protein) by 96 +/- 13%. IGF-I increased the protein content of chromaffin cells by approximately 30%; consequently, its effect on tyrosine hydroxylase activity was even greater when Dopa synthesis was expressed as picomoles per minute per 10(7) cells. IGF-I also enhanced the rate of Dopa accumulation in cells stimulated by dimethylphenylpiperazinium, 8-bromo-cyclic AMP, phorbol 12,13-dibutyrate, or Ba2+. The effect of IGF-I on high K(+)-stimulated tyrosine hydroxylase activity was measurable when enzyme activity was assayed in vitro, suggesting that this effect was due to a stable modification of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Noninvasive assessment of aromatic L-amino acid decarboxylase activity in aging rhesus monkey brain in vivo.

The effect of aging on aromatic L-amino acid decarboxylase (AAAD) activity in rhesus monkey striatum was assessed in vivo using PET imaging. Two analogs of L-DOPA, 6-fluoro-m-tyrosine (FMT) and 6-fluoro-L-DOPA (FDOPA), were used to image rhesus monkeys of various ages. Results show that when the animals were grouped between young (3-11 years) and aged (25-37 years), FDOPA uptake in the older animals showed a 21% decline (P < 0.0005), while FMT uptake in young and older animals were not different. On the other hand, when individual uptake values were plotted vs. age, linear regression analysis showed FDOPA uptake similarly declined with age (r = -0.84, P < 0.001) while FMT uptake increased with age (r = 0.66, P < 0.05). Since FMT pharmacokinetics has been shown to be unaffected by metabolic steps occurring after the AAAD step, while FDOPA traces all the steps involved in L-DOPA metabolism, FMT is a suitable tracer to assess AAAD activity while FDOPA traces dopamine turnover. Based on these tracer characteristics, this study found that AAAD activity is maintained or increased in the aging rhesus monkey striatum while the FDOPA uptake decreases with age consistent with age-related declines in neuronal mechanisms whose overall effect is increased striatal dopamine turnover and clearance. Furthermore, comparison of results of this study with previous studies support the notion that the effect of aging in the dopamine system is different from that of MPTP-induced parkinsonism.

Aging↗
PubMed2005

Mothers' experiences of serious life events increase the risk of diabetes-related autoimmunity in their children.

OBJECTIVE: Stressful life events have been shown to constitute a risk factor for type 1 diabetes during childhood. Our aim was to investigate in the general child population (i.e., irrespective of genetic risk for type 1 diabetes) whether mothers' experiences of serious life events, such as divorce and violence, were associated with diabetes-related autoimmunity in their children at age 2.5 years. RESEARCH DESIGN AND METHODS: The study cohort was comprised of the first 5,986 consecutive children and their families from the prospective population-based All Babies in Southeast Sweden project for whom 2.5-year study data were available. Data were drawn from parental questionnaires that included questions about experiences of serious life events and the blood samples taken from the children when the children were age 2.5 years. The blood samples were analyzed for diabetes-related autoantibodies against tyrosine phosphatase and GAD. RESULTS: Mothers' experiences of divorce (odds ratio 3.6, 95% CI 1.4-9.6, P < 0.05) and violence (2.9, 1.0-7.8, P < 0.05) were associated with diabetes-related autoimmunity in the children, independent of a family history of type 1 diabetes. CONCLUSIONS: The results support the beta-cell stress hypothesis and suggest that maternal experiences of serious life events such as divorce and violence seem to be involved in the induction or progression of diabetes-related autoimmunity in children at age 2.5 years, independent of family history of type 1 diabetes.

Adult↗
PubMed1998

Cooperativity between the polyamine pathway and HER-2neu in transformation of human mammary epithelial cells in culture: role of the MAPK pathway.

Our experiments were designed to test the cooperativity between the polyamine pathway and HER-2neu in inducing transformation of human mammary epithelial cells in culture. Using the MCF-10A breast epithelial cell line, we observed that induction of overexpression of ornithine decarboxylase (ODC) (the first rate-limiting enzyme in polyamine biosynthesis) markedly potentiated the anchorage-independent growth stimulating effect of the beta2 isoform of neu differentiating factor (NDF) known to activate HER-2neu in MCF-10A cells. ODC overexpression, on the other hand, did not enhance growth in liquid culture, thus pointing to a specific effect on transformation rather than proliferation. ODC-overexpressing MCF-10A cells exhibited increased MAPK phosphorylation in response to administration of NDF and/or epidermal growth factor (EGF). In contrast, the phosphorylation of the members of the stress-activated protein kinase cascade p38 and SEK were not affected by ODC overexpression. Of note, in the absence of EGF and NDF, ODC overexpression failed to induce both clonogenicity and MAPK activation. These results suggest that increased polyamine biosynthetic activity critically interacts with HER-2neu in promoting human mammary cell transformation in culture and that the MAPK cascade is an important mediator of this interaction. If confirmed in future in vivo studies, our results may identify important new targets for the chemoprevention of human breast cancer.

Breast↗