[Abnormalities of catecholamine metabolism in Parkinson's disease (author's transl)].
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Biopterins↗
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Effect of hypoxia on monoamine synthesis in brains of developing rats.
Tyrosine and tryptophan hydroxylase activity was studied in the postnatal rat brain in vivo by measuring the accumulation of dihydroxyphenylalanine and 5-hydroxytryptophan, respectively after inhibition of L-aromatic amino acid decarboxylase with NSD 1015. With increasing age there was a significant increase in the amount of dopa and 5-HTP accumulated in the brain after administration of NSD 1015. After 30 min in a 12% oxygen environment there were significant reductions of tyrosine hydroxylase and tryptophan hydroxylase activity at 1,14 and 28 but not 4 days of postnatal age. Further, the decrease in 5-HTP accumulation was significantly more marked at 14 and 28 days than at 1 day of age. Thus, the oxygen-dependent synthesis of the neurotransmitter 5-hydroxytryptamine seems to be less vulnerable in the early postnatal rat brain.
5-Hydroxytryptophan↗
Lack of counteracting effect of liposomes on benserazide-induced hyperprolactinemia.
Benserazide induces an increase of serum prolactin in man, possibly as the result of an impairment of the dopamine effect on the pituitary and/or on the outer median eminence caused by the inhibition on L-dopa decarboxylase. On the other hand, liposomes obtained from bovine brain cortex phospholipids reduced serum prolactin possibly through an effect of phosphatidylserine on dopamine biosynthesis at the level of tyrosine hydroxylase. Benserazide, given orally (125 mg) to 5 normal subjects, induced an increase of serum prolactin that did not change when 300 mg of phospholipid liposomes were given intravenously 60 min later. An increase of L-dopa synthesis does not seen to be capable to overcome the effects of the decarboxylase inhibition.
Adult↗
Reduced tyrosine phosphorylation in polyamine-starved cells.
Onset of cell proliferation is associated with enhanced turnover of the polyamines putrescine, spermidine, and spermine, particularly evident in the massive increase in the activity of the rate-limiting enzyme in their production, ornithine decarboxylase (ODC). The physiological functions of these polyamines, however, have remained unclear. Here we report that treatment of LSTRA cells for 2-18 h with alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, decreased the amount of phosphotyrosine in several cellular substrates including the T cell protein tyrosine kinase p56lck. No reductions in the amount of p56lck, overall synthesis of protein and DNA, or cell viability were observed until much later. DFMO did not affect the catalytic activity of p56lck in vitro and the activity of p56lck immunoprecipitated from DFMO-treated cells was unaltered. Addition of putrescine, the reaction product of ODC, completely reversed the effect of DFMO on tyrosine phosphorylation. Finally, we provide evidence that polyamines reduce the activity of cellular protein tyrosine phosphatases toward endogenous substrates. Our results suggest that polyamines may influence the extent of tyrosine phosphorylation during cell proliferation and malignant transformation, perhaps by modulating the rate of dephosphorylation of specific target proteins.
Eflornithine↗
Specific localization of the guanosine triphosphate (GTP) cyclohydrolase I-immunoreactivity in the human brain.
Guanosine triphosphate (GTP) cyclohydrolase I (GCH) is the first and rate-limiting enzyme for biosynthesis of tetrahydrobiopterin, the cofactor of tyrosine hydroxylase (TH). Our previous study reported the presence of GCH in several neuronal groups in animal brains using a newly raised anti-GCH antibody. The present study aims at elucidating whether GCH and TH coexist in the same neurons of the human brain with the aid of immunohistochemical dual labeling. GCH-immunoreactivity was observed in the cell bodies and fibers of monoaminergic neurons of the human brain. Neurons which contain both enzymes are seen in the human substantia nigra, ventral tegmental area, locus coeruleus, dorsal raphe, and zona incerta. In these regions, almost all the cells also show immunoreactivity for aromatic L-amino acid decarboxylase (AADC), the second step enzyme for catecholamine synthesis, indicating that these neurons are catecholaminergic. However, some neurons in the dorsal and dorsomedial hypothalamic nuclei are stained only for GCH or TH. They appear to constitute an independent cell group in the human brain. The present observation suggests that L-dopa is not produced in the cells immunoreactive for TH but not for GCH, and that TH in these cells which lack GCH may have an unidentified role other than dopa synthesis.
Aromatic-L-Amino-Acid Decarboxylases↗
Ornithine decarboxylase transformation of NIH/3T3 cells is mediated by altered epidermal growth factor receptor activity.
Ornithine decarboxylase (ODC) has been shown to be oncogenic in transfected NIH/3T3 cells overexpressing the enzyme from a heterologous promoter. These cells, designated as NODC-2 cells, acquire proliferative properties associated with tumorigenic transformation such as loss of contact inhibition, decreased population doubling time, anchorage-independent growth, and tumor production in nude mice. At least one of these parameters, loss of contact inhibition, remains dependent on elevated ODC levels. We have used these cells to investigate the molecular mechanisms by which ODC overexpression drives cell transformation and to examine the involvement of other proto-oncogene products in this process. An interaction between ODC overexpression and the epidermal growth factor receptor (EGF-R) was suggested initially by the elevation of both basal (300%) and ligand-induced (457%) EGF-R tyrosine kinase activities in NODC-2 cells compared to similarly treated control NLK cells. Disruption of EGF-R mediated signal transduction in NODC-2 cells both by treatment with tyrphostin-25 or by transfection with a vector expressing a dominant negative EGF-R mutant resulted in reacquisition of contact-inhibited growth and suppression of anchorage-independent, clonogenic growth in soft agar. We conclude that ODC-induced transformation of NIH/3T3 cells is mediated, at least partly, by alterations in EGF-R signal transduction activity.
3T3 Cells↗
Turnover of dopamine and dopamine metabolites in rat brain: comparison between striatum and substantia nigra.
Measurements of the turnover of dopamine (DA) and DA metabolites have been performed in the striatum and substantia nigra (SN) of the rat. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid have been assessed from the disappearance rates after blocking their formation by inhibition of monoamine oxidase by pargyline and of catechol-O-methyltransferase by tropolone. DA turnover has been measured as 3-methoxytyramine (3-MT) plus DA accumulation rate after MAO inhibition by pargyline and as accumulation rate of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of aromatic amino acid decarboxylase by NSD 1015 or NSD 1034. These measures of DA turnover have been compared with alpha-methyl-p-tyrosine (alpha-MT)-induced DA disappearance rate. In SN all the different measures of DA turnover are in the same range (55-62 nmol/g protein/h) whereas in striatum DOPA accumulation rate after NSD 1015 and alpha-MT-induced DA disappearance rate (16-23 nmol/g/h) are much lower than DOPAC disappearance rate after pargyline, 3-MT plus DA accumulation rate after pargyline, and DOPA accumulation rate after NSD 1034 (39-46 nmol/g/h). The data confirm our previous findings indicating that the fractional turnover rate of DA is more rapid in SN than in striatum and that O-methylation of DA is relatively more important in SN. In striatum at least two pools of DA with different turnover rates appear to exist, whereas in SN, DA behaves as if located in a single compartment.
3,4-Dihydroxyphenylacetic Acid↗
Postnatal elevation of brain tyrosine hydroxylase activity, without concurrent increases in steady-state catecholamine levels, resulting from dl-alpha-methylparatyrosine administration during embryonic development.
Increased specific activity of tyrosine hydroxylase (TH) in the brains of embryonic and 29-day-old chickens results from exposure to reserpine during the early stages of embryogenesis. We have also reported significant increases in the steady-state concentrations of catecholamines (CAs) in the brains of these 29-day-old chickens, suggesting permanent alterations in the control mechanisms during a critical period of development. The specificity of embryonic CA depletion in the above findings was examined usind dl-alpha-methyl-para-tyrosine (AMPT) as a depleting agent. AMPT, injected in varying doses into the yolk sac of fertilized chicken eggs prior to incubation, caused embryonic CA depletion by day 10 of embryogenesis but repletion had occurred by 20 days of embryogenesis. TH activity in whole brain and brain parts was elevated in a dose-related fashion at 29 days postnatally by AMPT. However, no changes in steady-state CA levels in whole brain were observed at this time after AMPT. Differences in the responses to reserpine and AMPT are discussed with respect to their pharmacological actions. The data support the contention that early embryonic CA depletion can result in long-term increases in TH activity postnatally, but steady-state levels of product need not necessarily be altered.
Age Factors↗
Enzymes of catecholamine metabolism in the brains of rat strains differing in their preference for or tolerance of ethanol.
The activities of the catecholamine-synthesizing and inactivating enzymes were determined in whole brains of two pairs of rat strains differing in their genetically-determined behavioural responses to ethanol. The alcohol-tolerant (AT) rats did not show any significant differences in enzyme activities when compared with the non-tolerant (ANT) strain. The activity of tyrosine hydroxylase was found to be significantly higher in brains of the alcohol-preferring (AA) rats, than in those of the alcohol-non-preferring (ANA) strain.
Animals↗
Endogenously released L-dopa itself tonically functions to potentiate postsynaptic D2 receptor-mediated locomotor activities of conscious rats.
A non-effective dose of exogenously applied L-dopa itself stereoselectively potentiates postsynaptic D2 receptor-mediated locomotor activities of rats. We further attempted to clarify whether or not endogenously released L-dopa tonically functions to potentiate activities of these receptors, simultaneously monitoring locomotor activities and basal release of L-dopa and dopamine during striatal microdialysis in conscious rats. Quinpirole (1 mg/kg, s.c.) alone, a selective D2 agonist, increased locomotor activities and decreased basal L-dopa and dopamine release 20-140 min after injection. Pretreatment with alpha-methyl-p-tyrosine (3 mg/kg, i.p.), a tyrosine hydroxylase inhibitor, decreased locomotor activities and further decreased L-dopa release without modification of dopamine release, compared to quinpirole alone, whereas 3-hydroxybenzylhydrazine (100 mg/kg, i.p.), a central dopa decarboxylase inhibitor, further increased locomotor activities and markedly increased L-dopa release without modification of dopamine release. Endogenously released L-dopa itself functions tonically to potentiate activities of postsynaptic D2 receptors relevant to locomotor movement of rats.
Animals↗
Is the mesocortical dopaminergic system involved in Parkinson disease?
Tyrosine hydroxylase was used to identify catecholaminergic neurons in the substantia nigra and ventral tegmental area of the human mesencephalon. High enzyme activity in the normal ventral tegmental area indicated the presence of numerous cathecholaminergic neurons, most likely dopamine cells. Tyrosine-hydroxylase activity was decreased in the ventral tegmental area of parkinsonian patients, implying a lesion of the mesocortical dopamine system in Parkinson disease.
Aged↗
Regional distribution and control of tyrosine hydroxylase activity in the quail brain.
Tyrosine hydroxylase (TH) activity, the rate-limiting step in the synthesis of catecholamines, was quantified in the preoptic area-hypothalamus of adult male Japanese quail by a new assay measuring the tritiated water production from 3,5-[3H]-L-tyrosine. Maximal levels of activity were observed at a 20-25 microM concentration of substrate, with more than 50% inhibition of the activity being recorded at a 100 microM concentration. TH activity was linear as a function of the incubation time during the first 20 min and maximal at a pH of 6.0. TH was heterogeneously distributed in the quail brain with highest levels of activity being found (in decreasing order) in the mesencephalon, diencephalon, and telencephalon. Given the large size of the telencephalon, this is the brain area that contains, as a whole, the highest level of enzyme activity. TH inhibitors that have been well-characterized in mammals, such as 3-iodo-L-tyrosine and L-alpha-methyl-p-tyrosine (AMPT) completely inhibited the enzyme activity at a 100 microM concentration. In mammals, the accumulation of catecholamines exerts a negative feedback control on TH activity. Similar controls were observed in the quail brain. Two inhibitors of the DOPA decarboxylase that should lead to accumulation of DOPA depressed TH activity by 60% or more, and the inhibitor of the dopamine beta-hydroxylase, fusaric acid that should cause an accumulation of dopamine, suppressed 90% of the TH activity. The addition of exogenous DOPA, dopamine, or norepinephrine to the brain homogenates also strongly inhibited TH activity, independently confirming the feedback effects of the enzyme products on the enzyme activity. These data demonstrate that TH activity in the quail brain is heterogeneously distributed and acutely regulated, as it is in mammals, by the accumulation of its products and of the derived catecholamines.
Animals↗
Distribution of glutamic acid decarboxylase mRNA-containing neurons in rat medulla projecting to thoracic spinal cord in relation to monoaminergic brainstem neurons.
Recent neurophysiological work has suggested the existence of monosynaptic gamma-aminobutyric acidergic (GABAergic) projections from the medulla oblongata to sympathetic preganglionic neurons. The purpose of the present study was to identify the possible anatomical location of these neurons. The location of GABAergic neurons with projection to the thoracic spinal cord was studied by using in situ hybridization for both 65-kD and 67-kD isoforms of glutamic acid decarboxylase (GAD) mRNA (GAD-65 and GAD-67, respectively) combined with midthoracic spinal cord injections of the tracer Fast Blue. Tyrosine hydroxylase (TH) or tryptophan hydroxylase immunohistochemistry was combined with GAD mRNA detection and Fast Blue to determine whether any bulbospinal catecholaminergic or serotonergic cell groups in the medulla also are GABAergic. GAD-67 and GAD-65 mRNA-containing neurons had similar distribution patterns in the medulla oblongata, with some areas exhibiting lighter labeling for GAD-65 mRNA. GABAergic bulbospinal neurons were located in the caudal part of the solitary nucleus, the parasolitary nucleus, the vestibular nuclei, the ventral medial medulla, the raphe nuclei, and parapyramidal areas. TH-immunoreactive neurons in the A1, A2, C1, and C2 areas or the area postrema did not contain either GAD-67 or GAD-65 mRNA. GAD mRNA-positive bulbospinal cells were present medial to theA1 and C1 catecholaminergic cell groups, with little or no overlap. Serotonergic neurons positive for GAD mRNAwere found in the parapyramidal area and just dorsal to the pyramidal tract in the raphe magnus. This population included bulbospinal neurons. In conclusion, GABAergic neurons with projections to the thoracic spinal cord exist in a restricted number of medullary nuclei from which inhibitory sympathetic control may originate.
Animals↗
Selective induction of tyrosine hydroxylase and dopamine beta-hydroxylase in sympathetic ganglia in organ culture: role of glucocorticoids as modulators.
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Adrenalectomy↗
Value of antibodies to islet protein tyrosine phosphatase-like molecule in predicting type 1 diabetes.
Islet antigens associated with type 1 diabetes include a recently identified protein tyrosine phosphatase-like molecule IA-2, which contains the intracellular fragment IA-2ic. To determine whether combinations of antibodies including those to IA-2 characterize and predict type 1 diabetes, we studied antibodies to IA-2, IA-2ic, glutamic acid decarboxylase (GAD65), and islet cell antibodies (ICAs) in 1) 60 newly diagnosed type 1 diabetic patients followed for 1 year, 2) 31 monozygotic twin pairs discordant for type 1 diabetes followed up to 12 years (11 twins developed diabetes), 3) 18 dizygotic twin pairs discordant for type 1 diabetes, and 4) normal healthy control subjects. Newly diagnosed type 1 diabetic patients frequently had antibodies to IA-2 (62%), IA-2ic (67%), GAD65 (77%), and ICAs (85%). The intracellular fragment of IA-2 probably contains the immunodominant epitope as 137 of 143 samples with IA-2 antibodies from type 1 diabetic patients also had IA-2ic antibodies. Monozygotic twins were usually discordant for antibody specificities. Concordance was higher in monozygotic than matched dizygotic twins for both antibody combinations (33 vs. 6%, P < 0.05) and the development of diabetes (33 vs. 0%, P < 0.01). In monozygotic twins, all the antibodies were highly predictive of type 1 diabetes (positive predictive values all >87%), although antibodies were also detected in twins at low risk of disease. In summary, IA-2 emerges as a major antigen associated with type 1 diabetes and distinct from GAD65. Type 1 diabetes-associated autoimmunity, which is probably induced by environmental factors, does not necessarily herald progression to the disease. However, genetic factors may influence the development of combinations of disease-associated antibodies and the progression to type 1 diabetes.
Adolescent↗
Differences in development and cellular composition between neuronal cultures of rat accessory and main olfactory bulbs.
We previously established a primary culture system of the accessory olfactory bulb (AOB) to investigate the functional roles of individual types of neuron in pheromonal signal processing. However, the detailed characteristics of cultured AOB neurons were not yet apparent. In the present study, we address the cytological aspects of cultured AOB neurons using immunocytochemical staining methods. Cultured AOB neurons were compared with cultured main olfactory bulb (MOB) neurons in neuronal composition, maturational time course, and cell size. The number of total neurons, measured by microtubule-associated protein 2 (MAP2) immunostaining, progressively decreased, and glutamic acid decarboxylase positive (GAD+) interneurons were scarcely changed in their number in both AOB and MOB cultures over the culture periods. In contrast, the number of tyrosine hydroxylase positive (TH+) neurons in AOB cultures showed a slight, but significant, increase over time in culture, while those in MOB cultures remarkably decreased. The numbers of total neurons and GAD+ neurons were significantly greater in AOB cultures than in MOB cultures at all investigated time points. However, the numbers of TH+ neurons were lower at 7 days in vitro (DIV) and greater at 21 DIV in AOB cultures than in MOB cultures. The somatic sizes of all types of neurons at 14 DIV were significantly larger in AOB cultures than in MOB cultures. Furthermore, the frequency distributions of somatic sizes of total, GAD+, and TH+ neurons were significantly different between AOB and MOB cultures. These subtle differences in vitro may reflect in vivo differences between the AOB and MOB.
Animals↗
An immunohistochemical study of regenerating newt retinas.
Light-microscopical examination was carried out to investigate the emergence and development of several classes of immunoreactive cells in regenerating retinas of the adult newt (Triturus pyrrhogaster) after total retinal ablation. Immunoreactive proliferating cell nuclear antigen (ir-PCNA, a marker for replicating cells) was present in nuclei of all neuroblasts in the early mono-layered to several-layered stages (15-20 days after retinal ablation; days 15-20), but was lost progressively in an intermediate-to-central/peripheral order as cells and layers increased (days 20-25). Cells, which had lost ir-PCNA, began to separate to form the outer nuclear, inner nuclear and ganglion cell layers around days 25-30 (the cell separation stage). Finally, the location of ir-PCNA was restricted to a band of neuroblast cells at the retinal margin (days 30-35) as seen in intact adult retinas. Visinin-immunoreactive (ir) cells, mainly destined to be cones, appeared first singly or as clusters at the most distal layer in the intermediate region of retinas multi-layered with PCNA-ir neuroblasts, which was followed by appearance of opsin-ir rod outer segments and tyrosine hydroxylase-ir amacrine cells around the cell separation stage. Shortly later, cells respectively immunoreactive to glutamic acid decarboxylase, neuropeptide Y, serotonin, glucagon, glutamine synthetase, glial fibrillary acidic protein, substance P and protein kinase C were found to emerge also in an intermediate-to-central/peripheral sequence. Some of the glucagon-ir cells appeared to be of an interplexiform type.
Animals↗
The effect of oral 5-HTP administration on 5-HTP and 5-HT immunoreactivity in monoaminergic brain regions of rats.
5-Hydroxytryptophan (5-HTP), which is the rate-limiting precursor in serotonin (5-hydroxytryptamine (5-HT)) biosynthesis, is used as an oral supplement to enhance serotonin levels in humans. To evaluate its effects on serotonin levels and localization, 5-hydroxytryptophan was administered to Sprague-Dawley rats either orally or via intraperitoneal injection. 5-Hydroxytryptophan-immunoreactivity was co-localized with serotonin-immunoreactivity in the serotonergic dorsal raphe nucleus of control animals and this was not changed in animals given 5-hydroxytryptophan. Oral 5-HTP administration increased the intensity of both 5-HTP and serotonin immunoreactivity in raphe neurons. However, 5-HTP treatment also caused ectopic 5-hydroxytryptophan-immunoreactivity and serotonin-immunoreactivity in normally dopaminergic neurons of the substantia nigra par compacta. Serotonin-immunoreactivity was confined to neurons that also displayed amino acid decarboxylase immunoreactivity, but in a small percentage of substantia nigra neurons, serotonin immunoreactivity was not co-localized with tyrosine hydroxylase-immunoreactivity. The intensity of the immunoreactivity to serotonin and 5-hydroxytryptophan in the substantia nigra was maximal within 2h of 5-hydroxytryptophan administration and returned to control levels by 24h. This time course mirrored changes in HPLC measurements of 5-hydroxytryptophan, serotonin, and the metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the urine. 5-Hydroxytryptophan administration did not cause ectopic appearance of either serotonin or 5-hydroxytryptophan in the noradrenergic locus coeruleus. These results suggest that a single oral dose of 5-HTP increases the 5-HTP and serotonin content of serotonergic neurons and causes the transient ectopic appearance of serotonin in some normally non-serotonergic neurons.
5-Hydroxytryptophan↗