UNIPROT:P61278 - FACTA Search

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Query: UNIPROT:P61278 (somatostatin)
22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The results of an immunohistochemical investigation on neostriatum of 9 cases of Huntington's disease are reported. In all cases the typical neuropathological findings were present (striatum atrophy, neuronal degeneration, gliosis). We did investigate on paraffin slides Synaptophysin (SYN), Neurofilament-protein (NF68), GFAP as well as the neuropeptides Met-Enkephalin (MEnk), Substance P (SP), Somatostatin (SS) and Neuropeptide Y (NPY). These neuropeptides, in particular MEnk and SP, are reported to coexist with the inhibitory neurotransmitter GABA in the neurons of basal ganglia. In all cases, GFAP activity was increased. In 7 cases activity of SYN and NF68 was decreased. In 2 cases, however, SYN-immunoreactivity was increased; these findings might represent an expression of "regenerative" changes in surviving neurons. The reactions for neuropeptides did disclose, in accordance with the results of former investigators, a decreased activity of MEnk- and SP-neurons, whereas SS- and/or NPY-neurons appeared almost unchanged.
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PMID:[Immunohistochemical findings in Huntington's Chorea: report of 9 cases]. 920 76

Some authors have reported greater sparing of neurons containing somatostatin (SS)-neuropeptide Y (NPY)-NADPH-diaphorase (NADPHd) than projection neurons after intrastriatal injection of quinolinic acid (QA), an excitotoxin acting at NMDA receptors. Such findings have been used to support the NMDA receptor excitotoxin hypothesis of Huntington's disease (HD) and to claim that intrastriatal QA produces an animal model of HD. Other studies have, however, reported that SS/NPY/NADPHd interneurons are highly vulnerable to QA. We examined the influence of animal age (young versus mature), QA concentration (225 mM versus 50 mM), and injection speed (3 min versus 15 min) on the relative SS/NPY/NADPHd neuron survival in eight groups of rats that varied along these parameters to determine the basis of such prior discrepancies. Two weeks after QA injection, we analyzed the relative survival of neurons labeled by NADPHd histochemistry, SS/NPY immunohistochemistry, or cresyl violet staining (which stains all striatal neurons, the majority of which are projection neurons) in the so-called lesion transition zone (i.e., the zone of 40-60% neuronal survival). We found that age, and to a lesser extent injection speed, had a significant effect on relative SS/NPY/NADPHd interneuron survival. The NADPHd- and SS/NPY-labeled neurons typically survived better than projection neurons in young rats and more poorly in mature rats. This trend was greatly accentuated with fast QA injection. Age-related differences may be attributable to declines in projection neuron sensitivity to QA with age. Since rapid QA injections result in excitotoxin efflux, we interpret the effect of injection speed to suggest that brief exposure to a large dose of QA (with fast injection) may better accentuate the differential vulnerabilities of NADPHd/SS/NPY interneurons and projection neurons than does exposure to the same total amount of QA delivered more gradually (slow injection). These findings reconcile the discordant results found by previous authors and suggest that QA injected into rat striatum does reproduce the neurochemical traits of HD under some circumstances. These findings are consistent with a role of excitotoxicity in HD pathogenesis, and they also have implications for the basis of the more pernicious nature of striatal neuron loss in juvenile onset HD.
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PMID:Age-dependent differences in survival of striatal somatostatin-NPY-NADPH-diaphorase-containing interneurons versus striatal projection neurons after intrastriatal injection of quinolinic acid in rats. 927 55

The present study determined the effects of intraventricularly administered glial cell line-derived neurotrophic factor on the behavioral and neurochemical sequelae of unilateral excitotoxic lesions of the striatum. Distinct asymmetrical rotational behavior in response to peripheral administration of amphetamine (5 mg/kg) was noted one and two weeks following injections of quinolinic acid (200 nmol) into two sites in the left striatum. In rats given a single intraventricular injection of glial cell line-derived neurotrophic factor (10-1000 micrograms) 30 min before the toxin, amphetamine-induced rotational behavior was significantly attenuated. Analysis of Nissl-stained coronal sections showed marked neuronal loss in the striatum ipsilateral to the quinolinic acid injections, which was at least partially prevented by glial cell line-derived neurotrophic factor D1 and D2 dopamine binding sites in the striatum, the majority of which are localized to subpopulations of GABAergic neurons, were decreased to a similar extent by quinolinic acid. Moreover, the reduction was attenuated by glial cell line-derived neurotrophic factor treatment to a similar degree, suggesting that the two subpopulations of GABAergic striatal output neurons are equally vulnerable to excitotoxic damage. Concomitant changes in neurotransmitter function as a result of the lesion were also observed: [3H]GABA uptake into striatal target tissues (globus pallidus and substantia nigra) was considerably reduced in the lesioned compared to the contralateral unlesioned tissues, as were [3H]choline and [3H]dopamine uptake into striatal synaptosomes. Similarly, striatal choline acetyltransferase activity was decreased by the lesion. Decrements in neuropeptide levels of similar magnitude were evident ipsilateral to the lesion; substance P, met-enkephalin and dynorphin A contents in the globus pallidus and substantia nigra were significantly reduced. Striatal somatostatin and neuropeptide Y levels were not altered. All of the neurochemical deficits induced by striatal quinolinic acid lesions were attenuated by intraventricular delivery of glial cell line-derived neurotrophic factor. Continuous intraventricular infusion of this trophic factor (10 micrograms/day) over a two-week period did not afford notable improvement compared to the single injection of 10 micrograms. In contrast, continuous infusion of brain-derived neurotrophic factor (10 micrograms/day) directly into the striatum did not affect any of the neurochemical parameters studied. However, neurotrophin-3 (10 micrograms/day) delivery into the striatum significantly increased [3H]GABA uptake, but only modestly affected [3H]choline uptake. The results indicate that glial cell line-derived neurotrophic factor counteracts neuronal damage induced by a striatal excitotoxic insult and support its potential use as a treatment for central nervous system disorders that may be a consequence of excitotoxic processes, such as Huntington's disease.
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PMID:Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioral and neurochemical deficits in a rodent model of Huntington's disease. 933 Mar 71

To evaluate the relative ability of those striatal neuron types containing calbindin or parvalbumin to withstand a Ca(2+)-mediated excitotoxic insult, we injected the NMDA receptor-specific excitotoxin quinolinic acid (QA) into the striatum in mature adult rats and 2 months later examined the relative survival of striatal interneurons rich in parvalbumin and striatal projection neurons rich in calbindin. To provide standardization to the survival of striatal neuron types thought to be poor in Ca2+ buffering proteins, the survival was compared to that of somatostatin-neuropeptide Y (SS/NPY)-containing interneurons and enkephalinergic projection neurons, which are devoid of or relatively poorer in such proteins. The various neuron types were identified by immunohistochemical labeling for these type-specific markers and their relative survival was compared at each of a series of increasing distances from the injection center. In brief, we found that parvalbuminergic, calbindinergic, and enkephalinergic neurons all showed a generally comparable gradient of neuronal loss, except just outside the lesion center, where calbindin-rich neurons showed significantly enhanced survival. In contrast, striatal SS/NPY interneurons were more vulnerable to QA than any of these three other types. These observed patterns of survival following intrastriatal QA injection suggest that calbindin and parvalbumin content does not by itself determine the vulnerability of striatal neurons to QA-mediated excitotoxicity in mature adult rats. For example, parvalbuminergic striatal interneurons were not impervious to QA, while cholinergic striatal interneurons are highly resistant and SS/NPY+ striatal interneurons are highly vulnerable. Both cholinergic and SS/NPY+ interneurons are devoid of any known calcium buffering protein. Similarly, calbindin does not prevent striatal projection neuron vulnerability to QA excitotoxicity. Nonetheless, our data do suggest that calbindin may offer striatal neurons some protection against moderate excitotoxic insults, and this may explain the reportedly slightly greater vulnerability of striatal neurons that are poor in calbindin to ischemia and Huntington's disease.
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PMID:Relative resistance of striatal neurons containing calbindin or parvalbumin to quinolinic acid-mediated excitotoxicity compared to other striatal neuron types. 950 Sep 58

The pattern and time-course of cellular, neurochemical and receptor changes in the striatum and substantia nigra were investigated following unilateral quinolinic acid lesions of the striatum in rats. The results showed that in the central region of the striatal lesion there was a major loss of Nissl staining of the small to medium sized cells within 2 h and a substantial loss of neuronal staining within 24 h after lesioning. Immunohistochemical studies showed a total loss of calbindin immunoreactivity, a known marker of GABAergic striatal projection neurons, throughout the full extent of the quinolinic acid lesion within 24 h. Similarly, within 24 h, there was a total loss of somatostatin/neuropeptide Y cells in the centre of the lesion but in the periphery of the lesion these cells remained unaltered at all survival times. Striatal GABA(A) receptors remained unchanged in the lesion for 7 days, and then declined in density over the remainder of the time course. Glial fibrillary acidic protein immunoreactive astrocytes were present in the periphery of the lesion at 7 days, occupied the full extent of the lesion by 4 weeks, and remained elevated for up to 2 months. In the substantia nigra, following placement of a striatal quinolinic acid lesion, there was: a loss of substance P immunoreactivity within 24 h; a marked astrocytosis evident from 1-4 weeks postlesion; and, a major increase in GABA(A) receptors in the substantia nigra which occurred within 2 h postlesion and was sustained for the remainder of the time course (15 months). This study shows that following quinolinic acid lesions of the striatum there is a major loss of calbindin and somatostatin/neuropeptide Y immunoreactive cells in the striatum within 24 h, and a marked increase in GABA(A) receptors in the substantia nigra within 2 h. These findings are similar to the changes in the basal ganglia in Huntington's disease and provide further evidence supporting the use of the quinolinic acid lesioned rat as an animal model of Huntington's disease.
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PMID:Chemical and anatomical changes in the striatum and substantia nigra following quinolinic acid lesions in the striatum of the rat: a detailed time course of the cellular and GABA(A) receptor changes. 1058 60

Huntington's disease is a devastating progressive neurodegenerative illness characterized by massive neuronal loss in the striatum. It is caused by the presence of an expanded CAG repeat in the gene encoding huntingtin, a protein of unknown function. We have examined the expression of neurotransmitters and other antigens present in striatal neurons with immunohistochemistry, and the level of expression of mRNAs encoding enkephalin, substance P, and glutamic acid decarboxylases with quantitative in situ hybridization histochemistry, in the striatum of two mouse models of Huntington's disease: transgenic animals expressing exon 1 of the human huntingtin gene with 144 CAG repeats and "knock-in" mice containing a chimeric mouse/human exon 1 with 71 or 94 CAG repeats inserted by homologous targeting. Although the transgenic (but not the knock-in) mice were previously shown to display prominent huntingtin- and ubiquitin-containing nuclear inclusions in striatal neurons, in situ nick translation followed by emulsion autoradiography did not reveal any DNA damage in striatum or cortex in these mice. Immunolabeling for calbindin D 28K, enkephalin, substance P, glutamic acid decarboxylases (M(r) 65,000 or 67,000, GAD65 and GAD67), somatostatin, choline acetyltransferase, parvalbumin, and glial fibrillary acidic protein were remarkably similar in transgenic, knock-in, and wild-type mice. Both transgenic and knock-in mice, however, showed a marked decrease in the level of expression of enkephalin mRNA in striatal neurons without significant decreases in mRNAs encoding substance P, GAD65, or GAD67. The data indicate that decreased expression of enkephalin mRNA may be an early sign of neuronal dysfunction due to the Huntington's disease mutation.
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PMID:Decrease in striatal enkephalin mRNA in mouse models of Huntington's disease. 1073 39

Huntington's disease (HD) is a hereditary autosomal dominant neurodegenerative disease characterized by motor, cognitive and psychiatric symptoms. It affects about 1 in 10,000 individuals. The onset of symptoms typically occurs in the third or fourth decade of life, though it may appear at any age. The molecular basis of the disease is the expansion of the trinucleotide CAG in the first exon of a gene on chromosome four (4p 16.3). This gene encodes the protein huntingtin of 3136 amino acids. The mutation of huntingtin produces an expanded stretch of glutamine (Gln) residues. This CAG/polyGln expansion has 6 to 39 units in normal individuals and 36 to 180 units in HD patients. The normal function of huntingtin and the pathogenic mechanisms caused by the expanded polyGln of mutant huntingtin remain incompletely characterized. Huntingtin appears to be associated with synaptic vesicles and/or microtubules and seems to have an important role in vesicular transport and/or the binding to the cytoskeleton. It is thought that this protein is important in embryogenesis and that its mutant form alters the function of the mitochondrial respiratory chain. The toxic gain of function caused by huntingtin could either be an overactivity of the normal function or the introduction of a novel function. Its interactions with other proteins could lead to an impairment of the cellular function or to its own polymerization to form insoluble aggregates. The intraneuronal aggregates could affect gene transcription, protein interactions, protein transport inside the nucleus and cytoplasm, and the vesicular transport. However, since a dissociation between the aggregation of huntingtin and the selective pattern of striatal neuronal loss has been demonstrated, it is believed that other properties of the mutant huntingtin, like proteolysis and the interactions with other proteins that affect vesicular trafficking and nuclear transport, could be responsible for the neurodegeneration. On gross examination, 80% of HD brains show atrophy of the frontal lobes. A bilateral, symmetric atrophy of the striatum is observed in 95% of the HD brains. The mean brain weight in HD patients is approximately 30% lower than in normal individuals. Striatal degeneration has an ordered and topographic distribution. The tail of the caudate nucleus shows more degeneration than the head. The caudate atrophy is associated to a gradual atrophy and neuronal loss in other brain regions as the disease progresses. The striatal and cerebral cortex projection neurons are much more susceptible to the disease than interneurons. In the neostriatum, the levels of GABA, dynorphin and substance P are decreased, but the concentrations of somatostatin and neuropeptide Y increase. An impairment of energy metabolism in HD and a sensitivity to oxidative stress and to the cytotoxic effects of glutamate seem to contribute to the neuronal death in HD. It is proposed that melatonin should be assayed in cell cultures and in transgenic animals due to its potent antioxidant and free radical scavenger properties.
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PMID:[Huntington disease. A review]. 1096 Oct 47

In a transgenic mouse model of the neurodegenerative disorder Huntington's disease (HD), age-dependent neurologic defects are accompanied by progressive alterations in glucose tolerance that culminate in the development of diabetes mellitus and insulin deficiency. Pancreatic islets from HD transgenic mice express reduced levels of the pancreatic islet hormones insulin, somatostatin, and glucagon and exhibit intrinsic defects in insulin production. Intranuclear inclusions accumulate with aging in transgenic pancreatic islets, concomitant with the decline in glucose tolerance. HD transgenic mice develop an age-dependent reduction of insulin mRNA expression and diminished expression of key regulators of insulin gene transcription, including the pancreatic homeoprotein PDX-1, E2A proteins, and the coactivators CBP and p300. Disrupted expression of a subset of transcription factors in pancreatic beta cells by a polyglutamine expansion tract in the huntingtin protein selectively impairs insulin gene expression to result in insulin deficiency and diabetes. Selective dysregulation of gene expression in triplet repeat disorders provides a mechanism for pleiotropic cellular dysfunction that restricts the toxicity of ubiquitously expressed proteins to highly specialized subpopulations of cells.
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PMID:Huntington's disease of the endocrine pancreas: insulin deficiency and diabetes mellitus due to impaired insulin gene expression. 1258 50

The degeneration of selective and specific types of neurons is a characteristic feature in several neurodegenerative disorders. N-methyl-D-aspartate receptor (NMDAR) agonist quinolinic acid (QUIN)-induced excitotoxicity has been implicated in neurodegeneration and mimics Huntington's disease (HD) by the loss of medium-sized spiny projection neurons while sparing medium-sized aspiny interneurons in the striatum. Previous work suggests that somatostatin/neuropeptide Y (SST/NPY)-containing neurons are selectively preserved in HD due to the presence of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) and the lack of NMDAR. In the present study, the distribution of somatostatin (SST), neuropeptide Y (NPY), nitric oxide synthase (nNOS), NMDA receptor type-1 (NR1), and the enzyme NADPH-d was determined in cultured striatal neurons with the effect of QUIN and N-methyl-D-aspartate (NMDA). SST/NPY-positive neurons, which constitute approximately 8-10% of striatal neurons, are selectively spared in QUIN/NMDA-treated cultures. nNOS and NADPH-d-positive neurons, comprising 3.8% of the neuronal population, also exhibit selective resistance to excitotoxicity. Most NR1-positive neurons, which constitute >80% of the total neuronal population, are lost in majority upon treatment with QUIN and NMDA. SST and NADPH-d-positive neurons also colocalize with Cu/Zn superoxide dismutase (Cu/Zn SOD). In conclusion, our results thus demonstrate that SST/NPY/nNOS-positive neurons are selectively spared in NMDA agonist-induced excitotoxicity, which could be attributed to the presence of Cu/Zn SOD and NADPH-d in addition to the low abundance of NMDAR on these neurons.
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PMID:Characterization of striatal cultures with the effect of QUIN and NMDA. 1509 1

Recent evidence has shown that the activity of cAMP responsive element-binding protein (CREB) and of CREB-binding protein (CBP) is decreased in Huntington's disease (HD) [Steffan et al. (2000)Proc. Natl Acad. Sci. USA, 97, 6763-6768; Gines et al. (2003)Hum. Mol. Genet., 12, 497-508; Rouaux et al. (2004) Biochem. Pharmacol., 68, 1157-1164; Sugars et al. (2004)J. Biol. Chem., 279, 4988-4999]. Such decrease is thought to reflect the impaired energy metabolism observed in a HD mouse model, where a decline in striatum cAMP levels has been observed [Gines et al. (2003)Hum. Mol. Genet., 12, 497-508]. Increased levels of CREB have also been demonstrated to exert neuroprotective functions [Lonze & Ginty (2002)Neuron, 35, 605-623; Lonze et al. (2002)Neuron, 34, 371-385]. Our study aimed to investigate the distribution of CREB in the neuronal subpopulations of the striatum in normal rats compared to the HD model of quinolinic acid lesion. Twenty-five Wistar rats were administered quinolinic acid 100 mm into the right striatum, and killed after 24 h, 48 h, 1 week, 2 weeks, and six weeks, respectively. The contralateral striata were used as controls. Dual-label immunofluorescence was employed using antibodies against phosphorylated CREB and each of the different neuronal subpopulations markers. Our results show that activated CREB levels decrease progressively in projection neurons and parvalbumin (PARV) and calretinin (CALR) interneurons, whereas such levels remain stable in cholinergic and somatostatin interneurons. Thus, we speculate that the ability of cholinergic interneurons to maintain their levels of CREB after excitotoxic lesions is one of the factors determining their protection in Huntington's disease.
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PMID:Striatal modulation of cAMP-response-element-binding protein (CREB) after excitotoxic lesions: implications with neuronal vulnerability in Huntington's disease. 1642 Apr 11

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