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PubMed1990

T cell antigen receptor-mediated activation of phospholipase C requires tyrosine phosphorylation.

Triggering of the antigen-specific T cell receptor-CD3 complex (TCR-CD3) stimulates a rapid phospholipase C-mediated hydrolysis of inositol phospholipids, resulting in the production of second messengers and in T cell activation and proliferation. The role of tyrosine phosphorylation in these events was investigated with a tyrosine protein kinase (TPK) inhibitor, genistein. At doses that inhibited TPK activity and tyrosine phosphorylation of the TCR zeta subunit, but not phospholipase C activity, genistein prevented TCR-CD3-mediated phospholipase C activation, interleukin-2 receptor expression, and T cell proliferation. These findings indicate that tyrosine phosphorylation is an early and critical event that most likely precedes, and is a prerequisite for, inositol phospholipid breakdown during receptor-mediated T cell activation.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

6-Methylmercaptopurine riboside is a potent and selective inhibitor of nerve growth factor-activated protein kinase N.

Protein kinase N (PKN) is a soluble, apparently novel serine protein kinase that is activated by nerve growth factor (NGF) and other agents in PC12 pheochromocytoma cells as well as in several nonneuronal cell lines. Purine analogs, such as 6-thioguanine and 2-aminopurine, have been found to inhibit PKN in vitro. When applied to intact cells, these compounds suppress certain biological responses to NGF, but not others, a findings suggesting the presence of multiple pathways in the NGF mechanism. We report here that 6-methylmercaptopurine riboside (6-MMPR) inhibits NGF-stimulated PKN activity in vitro with an apparent Ki of approximately 5 nM. This is approximately 1,000-fold lower than the Ki of the most potent purine inhibitor of PKN. Compounds similar to 6-MMPR, but lacking the methyl or riboside groups, were much less potent as PKN inhibitors. A survey of six additional purified protein kinases shows no inhibitory effect of 6-MMPR, thus indicating a good degree of specificity of this compound for PKN. In contrast to NGF-stimulated PKN, a PKN-like activity stimulated in PC12 cells in response to activation of cyclic AMP-dependent protein kinase was nearly insensitive to 6-MMPR. Application of 6-MMPR to intact PC12 cells resulted in blockade of several responses to NGF (neurite regeneration and ornithine decarboxylase induction) but not of several others (rapid enhancement of tyrosine hydroxylase phosphorylation and PKN activation). These findings suggest that 6-MMPR is a potent and selective agent for characterizing PKN in vitro and for assessing its potential role in the multiple pathways of the NGF mechanism of action.

Animals↗
PubMed2000

Gene therapy of Parkinson's disease using adeno-associated virus (AAV) vectors.

Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum. A promising approach to the gene therapy of PD is intrastriatal expression of dopamine-synthesizing enzymes [tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC)]. The most appropriate gene-delivery vehicles for neurons are adeno-associated virus (AAV) vectors, which are derived from non-pathogenic virus. Therefore, TH and AADC genes were introduced into the striatum in the lesioned side using separate AAV vectors in parkinsonian rats, and the coexpression of TH and AADC resulted in better behavioral recovery compared with TH alone. Another strategy for gene therapy of PD is the protection of dopaminergic neurons in the substantia nigra using an AAV vector containing a glial cell line-derived neurotrophic factor (GDNF) gene. Combination of dopamine-supplement gene therapy and GDNF gene therapy would be a logical approach to the treatment of PD.

Animals↗
PubMed1976

Dopaminergic neurons: an in vivo system for measuring drug interactions with presynaptic receptors.

An in vivo system has been used to investigate the ability of dopamine agonists and antagonists to alter dopamine synthesis by acting at what appear to be presynaptic dopamine receptors. In order to eliminate postsynaptically induced changes in dopamine synthesis caused by the effects of these drugs on the firing rate of dopamine neurons, gammabutyrolactone was administered to block impulse flow in the nigro-neostriatal pathway. The accumulation of Dopa in the rat striatum after administration of Dopa decarboxylase inhibitor was used as an index of striatal tyrosine hydroxylase activity. It was found that administration of the dopamine agonists, apomorphine or ET-495 [1-(2-pyrimidyl)-piperonyl-piperazine], modified the apparent activity of striatal tyrosine hydroxylase when impulse flow was blocked in dopamine neurons. This presynaptic effect of apomorphine could be prevented by low doses of loxapine haloperidol and spiroperidol. Chlorpromazine, fluphenazine, and thioridizine were much less effective than the butyrophenones in blocking the effects of apomorphine. Molindone and (+) butaclamol, but not (-) butaclamol, reversed the presynaptic agonist effects, pimozide was a weak blocker and clozapine had no effect at all. All these neuroleptics except (-) butaclamol caused a significant increase in Dopa accumulation when impulse flow was intact. Compared with haloperidol the phenothiazines and pimozide appeared less potent in reversing the presynaptic effects of apomorphine than in blocking the behavioral effects of this agonist. Possible functional significance of the presynaptic dopamine receptors are considered.

4-Butyrolactone↗
PubMed1989

Iron-induced lipid peroxidation and inhibition of dopamine synthesis in striatum synaptosomes.

Crude striatum synaptosomes (P2 fraction) from Fischer 344 female rats were incubated in the presence of ADP-chelated Fe3 (0.5-50 microM) and ascorbate (250 microM). Intrasynaptosomal conversion of tyrosine to dopamine (DA) was measured by 14CO2 evolution from L-[1-14C]tyrosine in the absence of added cofactors and DOPA decarboxylase. Malondialdehyde (MDA) was measured as an index of lipid peroxidation. A concentration-dependent inhibition of DA synthesis by ADP-Fe3./ascorbate was found with 50% inhibition occurring at 2.5 microM Fe3 concentration. This was accompanied by marked accumulation of MDA. Ascorbate or ADP alone did not affect DA synthesis and ADP-Fe3 in the absence of exogenous ascorbate was effective only above 25 microM. Exogenously added MDA did not inhibit DA synthesis. Purified synaptosomes were isolated from peroxidized and control P2 actions using sucrose gradients. Membrane microviscosity of the purified synaptosomes was assessed by nitroxyl spin labels of stearic acid using electron paramagnetic resonance techniques. There was a significant increase in membrane microviscosity as a result of ADP-Fe3./ascorbate induced peroxidation. Maleimide nitroxide spin-label binding to protein sulfhydryls was significantly modified by peroxidation of striatum synaptosomes. The weakly immobilized component of the sulfhydryl spin-label (w) was drastically decreased whereas the strongly immobilized component (s) was modified less, thus leading to a marked reduction of w/s ratio. The exposure of striatum synaptosomes to the peroxidizing system resulted in a significant increase in total iron and in a 25% decrease in protein sulfhydryl content. It is concluded that iron-induced damage to the DA synthetic system is mediated by alterations of the structural properties of nerve ending membranes.

Adenosine Diphosphate↗
PubMed1980

Morphine differentially alters synthesis and turnover of dopamine in central neuronal systems.

On the basis of biochemical indices of dopamine (DA) nerve activity (decline of DA after inhibition of tyrosine hydroxylase, accumulation of DOPA after inhibition of DOPA decarboxylase) it was revealed that morphine increases the activity of nigrostriatal and mesolimbic DA nerves which terminate in the striatum, nucleus accumbens and olfactory tubercle, but reduce the activity of tuberoinfundibular DA nerves which terminate in the median eminence. Morphine had no effect on tuberohypophyseal DA nerves which project to the posterior pituitary. Naloxone was without effect per se, but blocked the effects of morphine on DOPA accumulation. Thus, morphine differentially alters the diverse DA neuronal systems in the rat brain.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Activation and desensitization by cyclic antidepressant drugs of alpha2-autoreceptors, alpha2-heteroreceptors and 5-HT1A-autoreceptors regulating monamine synthesis in the rat brain in vivo.

The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the alpha2C-autoreceptor modulating dopa/noradrenaline synthesis, and the alpha2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipramine (1-10 mg/kg), protriptyline (0.3-10 mg/kg) and nisoxetine (3-10 mg/kg), selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%-40%) and hippocampus (20%-53%). Fluoxetine (1-10 mg/kg) and zimelidine (1-10 mg/kg), selective 5-HT reuptake blockers, did not alter dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%-43%) and hippocampus (27%-54%). Desipramine and protryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1-21 days) or fluoxetine (3 mg/kg for 3-21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1-21 days) did not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%-37%, days 1-14) followed by recovery to control values (day 21). Fluoxetine (3-21 days) did not alter brain dopa synthesis. To further assess the desensitization of alpha2C-autoreceptors, alpha2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at alpha2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxetine-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%). These findings indicate that acute treatment with cyclic antidepressant drugs results in activation of inhibitory alpha2C-autoreceptors, alpha2A-heteroreceptors and/or 5-HT1A-autoreceptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, whereas chronic treatment with these drugs is followed by desensitization of these presynaptic receptors.

5-Hydroxytryptophan↗
PubMed1996

Mechanisms involved in the spasmolytic effect of extracts from Sabal serrulata fruit on smooth muscle.

1. The effects of two extracts from Sabal serrulata fruits [total lipidic (L) and saponifiable (S)] on smooth muscle contractions have been assayed. 2. Both extracts (0.1-1 mg/ml) relaxed the tonic contraction induced by norepinefrine (30 nM) on rat aorta [EC50, 0.53 +/- 0.05 mg/ml (L) and 0.5 +/- 0.04 mg/ml (S)] and by KCl (60 mM) on rat uterus. The Sabal extracts (0.3-1 mg/ml) also antagonized the dose-response curve of contractions induced by acetylcholine (0.1-100 microM) on urinary bladder. 3. dL-Propranolol (1 microM) but not the inactive (R)-(+)-propranolol(1 microM) potentiated the Sabal extracts relaxant effect by lowering the EC50 (0.35 +/- 0.2 vs 0.20 +/- 0.01 mg/ml for L and 0.43 +/- 0.02 vs 0.19 +/- 0.02 mg/ml, P < 0.01, for S extract). 4. Cycloheximide (10 micrograms/ml) antagonized the effect of extracts from Sabal. However, actinomycin D (5 micrograms/ml) significantly (P < or = 0.01) antagonized the effect of the total lipidic extract without modifying that of the saponifiable extract. 5. The relaxant effect of both extracts was not modified by the tyrosine kinase inhibitor genistein (10 microM) or the ornithine decarboxylase inhibitor alpha-difluoromethyl-ornithine (10 mM).

Adrenergic beta-Antagonists↗
PubMed1991

Application of high-performance liquid chromatography to the study of biogenic amine-related enzymes.

The application of high-performance liquid chromatography to the study of biogenic amine-related enzymes is reviewed. Biogenic amines include catecholamines (dopamine, norepinephrine and epinephrine), indoleamines (serotonin and melatonin), imidazoleamines (histamine), polyamines (putrescine, spermidine and spermine) and acetylcholine. Three particular aspects are covered. The first aspect is the assay of enzyme activities of biogenic amine-related enzymes, such as tyrosine hydroxylase, tryptophan hydroxylase, aromatic L-amino acid decarboxylase, dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase. The introduction of highly sensitive assays of biogenic amines with electrochemical detection or fluorescence detection have made possible the non-isotopic assay of these activities, replacing the previously used radioisotopic methods. The second aspect is the purification of these enzymes. Since biogenic amine-synthesizing enzymes are generally unstable, rapid and efficient purification of these enzymes is very useful. The third aspect is the assay of biogenic amines (for example, acetylcholine and polyamines) using post-column derivatization with biogenic amine oxidases and electrochemical detection.

Animals↗
PubMed1997

In vitro study of H+-sensitive neurons in the ventral medullary surface of neonate rats.

We hypothesized that the direct stimulus of the central chemoreceptor neurons is the CO2/H+-induced change in intracellular pH (pHi). If it is true, pHi responses during hypercapnic stimulation should be exhibited in the central chemoreceptor neurons in the ventral medullary surface (VMS) and some neurons in the CO2/H+ sensitive regions such as the nucleus tractus solitarii of the medial dorsal medulla (MDM). To test this hypothesis, the cultured VMS and MDM neurons (control) derived from one day-old neonate rats were labeled with H+-sensitive fluorescent indicator 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF), and were exposed to perfusate of various pHs. The H+-sensitive neurons were determined by a rapid decrease in the intracellular BCECF fluorescence intensity. In almost all the MDM neurons (99.6%) and 94% of the VMS neurons, the intracellular BCECF fluorescence intensity remained unchanged when the extracellular pH (pHo) was decreased. In contrast, in 0.4% of the MDM neurons (8/1800) and in 6% of the VMS neurons (111/1800), the intracellular BCECF fluorescence intensity decreased when the pHo was decreased from 7.4 to 7.2. This subpopulation of MDM and VMS neurons were considered to be H+-sensitive neurons. The H+-sensitive neurons in the VMS showed positive immunoreactivity to glutamate (57%, 17/30) and glutamic acid decarboxylase (23%, 7/30), but no immunoreactivity to choline acetyltransferase, tyrosine hydroxylase, phenylethanolamine N-methyltransferase, somatostatin, serotonin and substance P. These results indicate that the H+-sensitive neurons are present specifically in the VMS, and are mainly glutamatergic and GABAergic.

Animals↗
PubMed1998

Distribution and phenotype of neurons containing the ATP-sensitive K+ channel in rat brain.

Select groups of neurons within the brain alter their firing rate when ambient glucose levels change. These glucose-responsive neurons are integrated into systems which control energy balance in the body. They contain an ATP-sensitive K+ channel (KATP) which mediates this response. KATP channels are composed of an inwardly rectifying pore-forming unit (Kir6.1 or Kir6.2) and a sulfonylurea binding site. Here, we examined the anatomical distribution and phenotype of cells containing Kir6.2 mRNA within the rat brain by combinations of in situ hybridization and immunocytochemistry. Cells containing Kir6. 2 mRNA were widely distributed throughout the brain without apparent concentration in areas known to contain specific glucose-responsive neurons. Kir6.2 mRNA was present in neurons expressing neuron-specific enolase, tyrosine hydroxylase, neuropeptide Y (NPY) and the glutamic acid decarboxylase isoform, GAD65. No astrocytes expressing glial fibrillary acidic protein or oligodendrocytes expressing carbonic anhydrase II were found to co-express Kir6.2 mRNA. Virtually all of the NPY neurons in the hypothalamic arcuate n. and catecholamine neurons in the substantia nigra, pars compacta and locus coeruleus contained Kir6.2 mRNA. Epinephrine neurons in the C2 area also expressed high levels of Kir6.2, while noradrenergic neurons in A5 and A2 areas expressed lower levels. The widespread distribution of Kir6.2 mRNA suggests that the KATP channel may serve a neuroprotective role in neurons which are not directly involved in integrating signals related to the body's energy homeostasis.

Adenosine Triphosphate↗
PubMed1996

The alpha 2-adrenoceptor antagonist idazoxan is an agonist at 5-HT1A autoreceptors modulating serotonin synthesis in the rat brain in vivo.

The in vivo effects of the alpha 2-adrenoceptor idazoxan, rauwolscine and phentolamine on alpha 2-auto/heteroreceptors and 5-HT1A autoreceptors modulating the synthesis of dopa/noradrenaline and 5-HTP/serotonin were assessed in rats, using the accumulation of dopa and 5-HTP after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation. The acute administration of idazoxan (0.1-40 mg/kg) induced a pronounced dose-dependent increase in the synthesis of dopa in the cerebral cortex (22-86%) and hippocampus (8-80%), as a consequence of the powerful blockade of alpha 2-autoreceptors. However, idazoxan did not increase the synthesis of 5-HTP in these brain regions, as it would have been expected by the concurrent blockade of alpha 2-heteroreceptors on serotonergic terminals. Instead, idazoxan decreased the synthesis of 5-HTP in the cerebral cortex (13-33%) and hippocampus (25-48%), suggesting that these inhibitory effects were mediated through activation of 5-HT1A autoreceptors. Similar results were obtained for rauwolscine. Pre-treatment of rats with the selective 5-HT1A receptor antagonist WAY100135 (10 mg/kg) fully antagonized the inhibitory effects of idazoxan (10 mg/kg) on 5-HTP synthesis, but it did not prevent the stimulatory effects of idazoxan on dopa synthesis. The results indicate that idazoxan is a potent and specific agonist at 5-HT1A autoreceptors modulating brain serotonin synthesis in vivo.

Animals↗
PubMed1993

Inhibition of aromatic L-amino acid decarboxylase under physiological conditions: optimization of 3-hydroxybenzylhydrazine concentration to prevent concurrent inhibition of monoamine oxidase.

The activity of the enzyme tyrosine hydroxylase (TH; EC 1.14.16.2) is commonly studied indirectly by quantifying the formation of the product, 3,4-dihydroxyphenylalanine (DOPA), after inhibition of aromatic L-amino acid decarboxylase (AAAD; EC 4.1.1.28), the enzyme which metabolizes DOPA. This study was done to determine if the concentration of the hydrazine derivative 3-hydroxybenzylhydrazine (NSD-1015), a drug frequently used in vitro to inhibit AAAD, could be adjusted such that it would inhibit that enzyme, but would not simultaneously inhibit a second, potentially important enzyme, monoamine oxidase (MAO; EC 1.4.3.4). MAO catalyzes the formation of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylglycol (DOPEG) from dopamine (DA) and norepinephrine (NE), respectively. Five concentrations of NSD-1015 in superfusate (0.01 to 20 microM) were tested in strips of canine portal vein superfused and stimulated in vitro. DOPA, DA, NE, and DOPEG in superfusate and in the veins after superfusion were quantified by HPLC with electrochemical detection. The efficacy of NSD-1015 in inhibiting AAAD and MAO was determined by examining the levels of DOPA and DOPEG, respectively. NSD-1015, only when applied at 0.1 microM, resulted in the marked augmentation of total DOPA levels, but did not affect levels of DOPEG, which suggests that this concentration of the drug inhibits AAAD, but does not inhibit MAO. Therefore, it is concluded that, of the concentrations of NSD-1015 tested, 0.1 microM is the optimum concentration to use in this preparation for studies designed to examine TH activity by measuring DOPA after the inhibition of AAAD.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Do all of human midbrain tyrosine hydroxylase neurons synthesize dopamine?

We examined whether all of human midbrain tyrosine hydroxylase (TH) neurons substantially synthesize dopamine (DA) using dual labeling immunohistochemical technique of TH and aromatic L-amino acid decarboxylase (AADC). In the substantia nigra, besides many neurons doubly stained for TH and AADC, neurons stained only for TH and only for AADC (D-neurons [C.B. Jaeger, D.A. Ruggiero, V.R. Albert, T.H. Joh, D.J. Reis, Immunocytochemical localization of aromatic l-amino acid decarboxylase, in: A. Björklund, T. Hökfelt (Eds.), Handbook of Chemical Neuroanatomy, Classical Transmitters in the CNS, Vol. 2, Part 1, Elsevier, Amsterdam, 1984, pp. 387-408.]) were identified. In the ventral tegmental area, dually labeled neurons and TH-only-positive neurons were found. It is indicated that the number of midbrain TH neurons does not reflect the exact number of DA neurons.

Adult↗
PubMed1995

Methylfolate modulates potassium evoked neuro-secretion: evidence for a role at the pteridine cofactor level of tyrosine 3-hydroxylase.

We have previously shown that 5-methyltetrahydrofolate influences neuro-secretion. The present study more precisely characterises the processes involved and considers one probable site of action. Focusing on the tyrosine-noradrenalin axis in cerebellum we showed 5-methyltetrahydrofolate causes a significant reduction in the apparent K+ evoked secretion of noradrenalin to only 12.9% of control release. Evidence supports the idea that this could actually be due to increased synthesis leading to; depletion of reserves, possibly through leakage, exocytotic inhibition via activation of presynaptic receptors or end product inhibition by noradrenalin at the pteridine cofactor level of tyrosine hydroxylase: a) concomitant decreased measurement of perfusate and intracellular tyrosine with released noradrenalin following 5-methyltetrahydrofolate treatment supports the idea of increased transmitter turn over; b) kinetic studies indicate that at saturating concentrations of tyrosine and in the presence of an inhibitor of L-DOPA decarboxylase, 5-methyltetrahydrofolate partially duplicates the rate limiting behaviour of a synthetic pteridine cofactor--DL,2-amino-4-hydroxy-6,7,dimethyltetrahydropteridine. We debate whether, in vivo, CSF 5-methyltetrahydrofolate might interact at the tetrahydrobiopterin cofactor level of tyrosine hydroxylase and other aromatic amino-acid hydroxylases.

Animals↗
PubMed1998

Dopamine synthesizing enzymes in paraventricular hypothalamic neurons of the human and monkey (Macaca fuscata).

Using immunohistochemistry, we demonstrated that paraventricular hypothalamic neurons immunoreactive for tyrosine hydroxylase (TH) were not immunopositive for the second step catecholamine synthesizing enzyme L-amino acid decarboxylase (AADC) in the human and monkey Macaca fuscata. In the latter species, they were not immunoreactive for dopamine. It is most likely that primate paraventricular TH-containing neurons do not synthesize dopamine.

Adult↗
PubMed1986

Age-related increase in presynaptic noradrenergic markers of the rat cerebral cortex.

Age-related alterations in the noradrenergic innervation of the cerebral cortex were investigated in young (3-4 months) and aged (28-29 months) Fischer-344 rats. The concentration of noradrenaline and the activity of tyrosine hydroxylase, the probable rate-limiting step in catecholamine biosynthesis, were significantly higher in the aged cerebral cortex, but no differences in L-3,4-dihydroxyphenylalanine decarboxylase activity were observed. The specific high-affinity uptake of noradrenaline by homogenates of the aged cerebral cortex exhibited higher maximal uptake, but lower affinity, than those of young rats. These results suggest increased presynaptic noradrenergic activity in the cerebral cortex of aged Fischer-344 rats.

Aging↗