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At least 1,711 records · Page 95Linked to original sources
PubMed1996

Antibodies to the 37,000-Mr tryptic fragment of islet antigen were detected in Japanese insulin-dependent diabetes mellitus patients.

Sera from 30 Japanese insulin-dependent diabetes mellitus (IDDM) patients of short duration were examined to determine whether they had antibodies to proteolytic fragments of islet antigen, the molecular weights of which were 37,000 and/or 40,000 Mr (37KAb). The median age and disease duration of the patients were 13 (range 6-22) years old and 12 (range; 0-24) months, respectively. Twelve out of the 30 IDDM patients (40%) had 37KAb, while none of the 16 control subjects was positive for 37KAb. The frequency of the 37KAb was not correlated with disease duration tested. We further investigated the antibodies to ICA512, by radioligand binding assay, which has been proposed to be a target antigen for the 37 KAb. Twenty-two (73.3%) patients had antibodies to ICA512 (ICA512AA), but none of the control subjects did. The levels of ICA512AA, which were described as indexes using standard sera, were significantly higher in the patients than in the control subjects (1.436 +/- 2.674 and 0.001 +/- 0.002, respectively, P < 0.05). The frequency of antibodies to glutamic acid decarboxylase 65 (GAD65Ab) was also higher in the patients than in the control subjects (70% and 0%, respectively), but 7 out of 9 GAD65Ab-negative patients had ICA512AA and/or 37KAb. Since 93% of the IDDM patients had at least one of these antibodies, combined analysis with 37KAb, ICA512AA, and GAD65Ab facilitates diagnosis of Japanese IDDM.

Adolescent↗
PubMed2002

Quantitative [18F]fluorodopa/PET and histology of fetal mesencephalic dopaminergic grafts to the striatum of MPTP-poisoned minipigs.

The functional restoration of the dopamine innervation of striatum in MPTP-poisoned Göttingen minipigs was assessed for 6 months following grafting of fetal pig mesencephalic neurons. Pigs were assigned to a normal control group and a MPTP-poisoned group, members of which received no further treatment, or which received bilateral grafts to the striatum of tissue blocks harvested from E28 fetal pig mesencephalon with and without immunosuppressive treatment after grafting, or with additional co-grafting with immortalized rat neural cells transfected to produce GDNF. In the baseline condition, and again at 3 and 6 months postsurgery, all animals were subjected to quantitative [18F]fluorodopa PET scans and testing for motor impairment. At the end of 6 months, tyrosine hydroxylase (TH)-containing neurons were counted in the grafts by stereological methods. The MPTP poisoning persistently reduced the magnitude of k3(D), the relative activity of DOPA decarboxylase in striatum, by 60%. Grafting restored the rate of [18F]fluorodopa decarboxylation to the normal range, and normalized the scores in motor function. The biochemical and functional recovery was associated with survival of approximately 100,000 TH-positive graft neurons in each hemisphere. Immunosuppression did not impart a greater recovery of [18F]fluorodopa uptake, nor were the number of TH-positive graft neurons or the volumes of the grafts increased in the immunosuppressed group. Contrary to expectation, co-grafting of transfected GDNF-expressing HiB5 cells, a rat-derived neural cell line, tended to impair the survival of the grafts with the lowest values for graft volumes, TH-positive cell numbers, behavioral scores, and relative DOPA decarboxylase activity. From the results we conclude that pig ventral mesencephalic allografts can restore functional dopamine innervation in adult MPTP-lesioned minipigs.

Animals↗
PubMed1988

Localization of L-glutamate decarboxylase immunoreactivity in the major pelvic ganglion and in the coeliac-superior mesenteric ganglion complex of the rat.

The localization of L-glutamate decarboxylase (GAD), the GABA-synthesizing enzyme, was studied in the rat major pelvic ganglion and in the coeliac-superior mesenteric ganglion complex by indirect immunofluorescence technique with a specific antiserum raised in rabbits. GAD immunoreactivity was demonstrated in small cells of these ganglia. The GAD-immunoreactive small cells were 10-20 microns in diameter and formed clusters or occurred as solitary cells. The principal neurons were non-reactive but they were surrounded by immunoreactive processes. Studies on colocalization of GAD with tyrosine hydroxylase (TH), the rate-limiting enzyme of the catecholamine synthesis, in the major pelvic ganglion and in the coeliac-superior mesenteric ganglion complex indicated that all GAD-immunoreactive small cells were also labelled with TH. In the major pelvic ganglion all TH-immunoreactive SIF cells were also immunoreactive for GAD. However, in the coeliac-superior mesenteric ganglion complex there occurred TH-immunoreactive small cells which showed no immunoreactivity to GAD. It is suggested that the small GAD-immunoreactive cells represent small intensely fluorescent (SIF) cells.

Animals↗
PubMed1982

Beta-bungarotoxin-induced cell-death of neurons in chick retina.

The cytotoxicity of beta-bungarotoxin (beta-BTX), a snake venom neurotoxin with phospholipase A2 activity, for chick neurons was investigated using organ and monolayer cultures of retina. Beta-BTX led to a marked reduction in the total activities of choline acetyltransferase and glutamate decarboxylase of retina cultures at concentrations as low as 100 pM. The total activity of lactate dehydrogenase was, however, much less affected by beta-BTX. Also, the total activity of tyrosine hydroxylase of organ-cultured retina decreased only at 30-50 fold higher concentrations of the toxin. The total activity of the glial marker glutamine synthetase was not changed by beta-BTX. In contrast to this selectivity for neurons displayed by beta-BTX, non-neurotoxic phospholipases A2 from bee venom and porcine pancreas led to a simultaneous loss of both neuronal and glial marker enzymes. Light and electron microscopy of organ-cultured retina showed that only cells in the ganglion cell layer and the inner third of the amacrine cell layer degenerated after incubation with beta-BTX. In the toxin-sensitive cells, the Golgi apparatus and the endoplasmatic reticulum appeared the first subcellular structures to be affected. It is concluded that beta-BTX preferentially recognizes and/or destroys cholinergic and GABAergic cells in the amacrine and ganglion cell layers of the developing chick retina. This toxin may thus be a useful probe to investigate cell surface properties of cholinergic and GABAergic neurons in the chick central nervous system.

Animals↗
PubMed2005

Induction of ornithine decarboxylase in T/C-28a2 chondrocytes by lysophosphatidic acid: signaling pathway and inhibition of cell proliferation.

Among several extracellular messengers tested, lysophosphatidic acid (LPA) was able to cause the most marked induction of ornithine decarboxylase (ODC) in serum-starved human T/C-28a2 chondrocytes. LPA also induced the activation/phosphorylation of Src, Akt and p44/42 MAPK, and the translocation of PKC-delta from cytosol to membrane coupled to its tyrosine phosphorylation. Experiments with selective signaling inhibitors indicate that LPA leads to Src activation through Gi protein-coupled receptors. In turn Src can activate PI3K and PKC-delta, and all these signaling proteins are required for ODC induction. In conclusion these results show that chondrocytes may be a novel target for LPA action. However, although LPA is considered a mitogen for several cell types and ODC induction is generally correlated to cell growth, LPA was not able to stimulate chondrocyte growth, but rather exerted an anti-proliferative effect.

Cell Division↗
PubMed1988

Purification and characterization of aromatic L-amino acid decarboxylase from rat kidney and monoclonal antibody to the enzyme.

Aromatic L-amino acid decarboxylase was purified from rat kidney to homogeneity, as judged by polyacrylamide gel electrophoresis, in the presence and absence of sodium dodecyl sulfate (SDS). The final preparation showed an activity of 3,4-dihydroxyphenylalanine (dopa) decarboxylation of approximately 11,000 nmol/min/mg of protein at 37 degrees C. The purified enzyme also catalyzed the decarboxylation of 5-hydroxytryptophan, tyrosine, tryptophan, and phenylalanine. The enzyme appeared to be composed of two identical subunits, each possessing a molecular weight of 48,000. The isoelectric point of the enzyme was estimated to be 6.7 in the presence of 8 M urea and 5.60-5.85 in its absence. To examine the identity of aromatic L-amino acid decarboxylase from various tissues, a monoclonal antibody directed against the enzyme from rat kidney was prepared. Immunotitration and analysis by antibody-affinity chromatography followed by SDS-polyacrylamide gel electrophoresis revealed that the enzymes from the striatum, adrenal medulla, pineal gland, liver, and kidney were indistinguishable with respect to immunological cross-reactivity and molecular size.

Amino Acids↗
PubMed2005

Expression of GAD65 and GAD67 immunoreactivity in MPTP-treated monkeys with or without L-DOPA administration.

This study investigated the consequences of levodopa treatment on the expression of the 65- and 67-kDa isoforms of glutamate decarboxylase (GAD65 and GAD67) immunoreactivity in the basal ganglia and cortex of monkeys rendered Parkinsonian by systemic MPTP administration. All MPTP-treated monkeys showed Parkinsonian impairment and selective loss of tyrosine hydroxylase (TH) with sparing of GAD immunoreactive (-ir) fibers and terminals in basal ganglia. The distribution of GAD65- and GAD67-ir in the cortex, caudate, and putamen was not significantly different in MPTP vs. naïve monkeys nor as a function of L-DOPA treatment. In comparison, the expression of GAD67- but not GAD65-ir was augmented in the globus pallidus in MPTP-treated monkeys. Quantification revealed significant increases in number of GAD67-ir neurons in the external and internal segments of the globus pallidus while no significant difference in the number of GAD65-ir neurons was observed. L-DOPA treatment did not significantly change the number of GAD65- or GAD67-ir pallidal neurons following MPTP. These results support and extend the findings that transcriptional elevation of GAD67 occurs in the globus pallidus and demonstrate that GAD65 and GAD67 are differentially altered following lesion. The finding of elevated GAD67 expression in the pallidum is consistent with alterations in inhibitory neurocircuitry playing a key role in the pathophysiology of motor disturbances in Parkinson's disease.

Animals↗
PubMed2001

Neuronal ectopic expression of tyrosine hydroxylase in the mouse striatum by combined administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 3-nitropropionic acid.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a dopaminergic neurotoxin which inhibits mitochondrial complex I. 3-Nitropropionic acid (3-NPA) inhibits mitochondrial complex II and produces specific striatal lesions. In order to produce a combined striatal neuronal and dopaminergic afferent lesion, we administered both toxins simultaneously to the mouse. The combination brought about a lesion in the striatum that was not simply additive of the two combined toxins. Intriguingly, a group of striatal neurons became immunoreactive to tyrosine hydroxylase after day 1. Some of them were clearly visible up to the dendritic details. Immuno-electron microscopy indicated that the tyrosine hydroxylase-positive striatal neurons contained densely immunoreactive polyribosomes. Reverse transcriptase-polymerase chain reaction analysis indicated the up-regulation of tyrosine hydroxylase mRNA in the treated striatum. These neurons were also immunoreactive to aromatic L-amino acid decarboxylase.We conclude that the combined administration of MPTP and 3-NPA caused a more profound damage to the nigro-striatal dopaminergic system, and thus some striatal neurons capable of up-regulating tyrosine hydroxylase were induced to produce dopamine, probably to compensate for the dopamine depletion.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1977

Decarboxylation-dependent transamination catalyzed by mammalian 3,4-dihydroxyphenylalanine decarboxylase.

In addition to the usual decarboxylation, pig kidney 3,4-dihydroxyphenylalanine (dopa) decarboxylase catalyzes a decarboxylation-dependent transamination which converts dopa into 3,4-dihydroxyphenylacetaldehyde and sinultaneously converts enzyme-bound pyridoxal-P into pyridoxamine-P. Similar reactions occur when this enzyme acts on m-tyrosine, alpha-methyldopa, and alpha-methyl-m-tyrosine. The transamination occurs in about 0.02% of decarboxylations of dopa and m-tyrosine and in about 2% of decarboxylations of alpha-methyldopa and alpha-methyl-m-tyrosine. The fraction of decarboxylations proceeding by the transamination pathway is independent of pH. This reaction appears to result from a divergence in the normal mechanism of decarboxylation; the quinoid intermediate which is formed by decarboxylation of the substrate-pyridoxal-P-Schiff base ordinarily protonates on the alpha carbon of the amino acid, but protonation occasionally occurs at the benzylic carbon of the coenzyme, and this latter route leads to transamination.

Animals↗
PubMed1979

Histological and neurochemical effects of fetal treatment with methylazoxymethanol on rat neocortex in adulthood.

Forebrain microencephaly results when developing rats are exposed to methylazoxymethanol acetate (MAM) at 15 days of gestation (DG). This potent alkylating agent is selectively cytotoxic for dividing cells. Since distinct neuronal populations in neocortex vary greatly with respect to timing of mitotic activity during gestation, it was predicted that some groups would be differentially reduced by treatment. Histological examination of neocortex from treated rats grown to adulthood revealed major losses of laminae II--IV with relative preservation of deeper layers. The atrophic adult neocortex was further characterized by assay of several defined pre- and postsynaptic neurochemical markers. Total markers for GABAergic neurons were greatly reduced (glutamate decarboxylase -71%, [3H]GABA synaptosomal uptake -63% and endogenous GABA -59%). Total [3H]GABA binding to cortical membranes was reduced 67%. Total [3H]glutamate synaptosomal uptake and endogenous glutamate were reduced 71% and 65% respectively. In contrast, total presynaptic markers for noradrenergic innervation were minimally altered but concentration of tyrosine hydroxylase, [3H]norepinephrine synaptosomal uptake and endogenous norepinephrine were increased by 275%, 130% and 133%, respectively. Concentration of cholinergic presynaptic markers was also increased (choline acetyltransferase +97%, endogenous acetylcholine +64%) in atrophic cortex, but to a lesser degree than for noradrenergic innervation. Specific binding of muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate and the beta-adrenergic receptor antagonist [3H]dihydroalprenolol was reduced 25% and 29% respectively in treated cortex. Thus, MAM treatment at 15 DG severely reduces intrinsic neuronal populations including GABAergic and glutamatergic neurons, and produces a shrunken cortex relatively hyperinnervated by noradrenergic and cholinergic neurons. MAM-induced microencephaly is a useful model system for producing relatively selective lesions of telencephalic neurons and for study of altered neurochemical relationships following developmentally incurred brain damage.

Acetylcholine↗
PubMed1992

Transforming growth factor alpha protection against drug-induced injury to the rat gastric mucosa in vivo.

This study was designed to determine whether transforming growth factor alpha (TGF alpha) protects rat gastric mucosa against ethanol- and aspirin-induced injury. Systemic administration of TGF alpha dose-dependently decreased 100% ethanol-induced gastric mucosal injury; a dose of 50 micrograms/kg delivered intraperitoneally 15 min before ethanol decreased macroscopic mucosal injury by > 90%. At the microscopic level, TGF alpha prevented deep gastric necrotic lesions and reduced disruption of surface epithelium. Pretreatment with orogastric TGF alpha (200 micrograms/kg) only partially (40%) decreased macroscopic ethanol damage. Intraperitoneal administration of TGF alpha at a dose of 10 micrograms/kg, which does not significantly inhibit gastric acid secretion, decreased aspirin-induced macroscopic damage by > 80%. TGF alpha protection does not seem to be mediated by prostaglandin, glutathione, or ornithine decarboxylase-related events, as evidenced by lack of influence of the inhibition of their production. Pretreatment with the sulfhydryl blocking agent N-ethylmaleimide partially abolished (40%) the protective effect of TGF alpha. In addition, systemic administration of TGF alpha resulted in a two-fold increase in tyrosine phosphorylation of phospholipase C-gamma 1 and in a time- and dose-dependent increase in levels of immunoreactive insoluble gastric mucin; these events occurred in a time frame consistent with their participation in the protective effect of TGF alpha.

Animals↗
PubMed1999

[18F]Fluoro-beta-fluoromethylene-m-tyrosine derivatives show stereo, geometrical, and regio specificities as in vivo central dopaminergic probes in monkeys.

Stereo (D and L), geometrical (E and Z), and regiospecific (2-, 4-, and 6-[18F]fluoro) analogs of beta-fluoromethylene-m-tyrosine (FMMT) have been investigated in adult vervet monkeys (Cercopithecus aethiops sabaeus, n = 12) in vivo with positron emission tomography (PET). Brain transport through the blood-brain barrier and central aromatic amino acid decarboxylase (AAAD)-mediated decarboxylation rates were established. Results show strict structural dependency of the kinetic behavior of radiofluorinated FMMT analogs, with the E-isomer exhibiting a higher specificity over the (Z) geometrical counterpart for central dopaminergic structures. The 6-[18F]fluoro substituted L-(E)-FMMT was also favored over the 2- and 4-[18F]fluorosubstituted isomers in terms of their ability to localize in the same brain areas. The role of PET in drug development is also exemplified in this work.

Animals↗
PubMed1991

The stimulation of quiescent rat fibroblasts by v-src and v-fps oncogenic protein-tyrosine kinases leads to the induction of a subset of immediate early genes.

The stimulation of quiescent murine fibroblasts by growth factors and by phorbol esters results in a rapid and transient transcriptional activation of a large group of so-called immediate early genes. Several such genes were found to be induced in chicken embryo fibroblasts following activation of a temperature sensitive (ts) Rous sarcoma virus v-src mutant following temperature shift (Simmons et al., 1989). In contrast, the classical immediate early genes c-myc, c-fos and c-jun were essentially uninducible upon activation of a ts v-src mutant in rat-1 fibroblasts (Welham et al., 1990). We have cloned 9 cDNAs of genes that are rapidly and transiently inducible in rat fibroblasts by ts v-src mutants, and by a ts Fujinami sarcoma virus v-fps mutant. Six of these cDNAs are derived from the known immediate early genes NGFI-A, KC, c-fos, tissue factor, PC4 and ornithine decarboxylase; the other three cDNAs have not been described before. These 9 genes showed individual profiles of inducibility by fetal calf serum, epidermal growth factor (EGF) and by phorbol esters. Their response to the retroviral oncogenic protein-tyrosine kinases correlated best with the one to EGF, suggesting a common pathway of signal transduction. c-fos did not respond strongly to this pathway but was well induced by fetal calf serum. NGFI-A, however, was induced to a similar extent by all activators tested. Furthermore, we demonstrated that the induction of several of these genes by the retroviral oncogenic protein-tyrosine kinases is rapid, direct and occurs at the transcriptional level.

Animals↗
PubMed1994

Adrenal response to long-term hypoxia is still increased after carotid body denervation in rat.

This study investigated the effects of long-term normobaric hypoxia (10% O2 in N2 for 2, 7, 14, and 28 days) on the metabolism of catecholamines in rat adrenals and the role of the carotid body chemoreceptors in the adrenal response. The content and utilization of dopamine were significantly increased from the 7th day of hypoxia and remained enhanced thereafter. The content of norepinephrine and epinephrine decreased after 2 days of hypoxia and increased thereafter; after 28 days of hypoxia the norepinephrine amounts remained enhanced but the epinephrine levels were no longer significantly increased. In vivo tyrosine hydroxylation increased after 7 days of hypoxia. Bilateral transection of the carotid sinus nerve 1 wk before hypoxia failed to abolish the increase in the content and utilization of dopamine after 7, 14, or 21 days of hypoxic exposure. These results indicate that long-term normobaric hypoxia elicits a long-lasting increase in the metabolism of catecholamines in adrenals, especially as assessed by dopamine measurement, and that this response does not involve a carotid body chemoreflex pathway.

Adrenal Glands↗