UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Systemic administration of the mitochondrial toxin 3-nitropropionic acid (3-NP) to rats results in selective striatal lesions and serves as an experimental model of Huntington's disease (HD). However, the effects of the 3-NP treatment are unpredictable and result in lesions of variable severity. The present study was aimed at further characterizing the variability of the striatal lesions induced by systemic administration of 3-NP using osmotic pumps. Hematoxylin-eosin (HE) and Nissl stains as well as immunohistochemical labelling of astrocytes and striatal neurones were performed to analyse the neurotoxic effects of 3-NP. In general, chronic systemic administration of 3-NP resulted in obvious bilateral striatal lesions, which ranged from mild to severe, together with a subtle, but detectable behavioural lesion. Severe type lesions showed marked neuronal loss and an increased expression of glial fibrillary acidic protein (GFAP) in astrocytes surrounding the lesion area, whereas in the core of the lesion GFAP-immunoreactivity was absent. The mild type lesion was characterized by a substantial loss of striatal neurones and an increased expression of GFAP-positive astrocytes throughout the lesion. In a number of 3-NP-treated animals, neither type of lesion was observed, although these animals demonstrated behavioural changes in the paw test compared to controls. In the striatum of these tested 3-NP-treated animals, compromised rk' neurones were detected, suggestive of subtle and early 3-NP-induced neuronal injury. Similar dark neurones were also detected in mild and severe lesions and were immunocytochemically characterized as gamma-aminobutyric acid (GABA) and substance P containing spiny neurones, which belong to the neuronal population that is affected in early HD. These results indicate that systemic administration of 3-NP to rats may result in a spectrum of striatal pathology of which the morphology of the mild type lesion resembles the characteristic HD neuropathology most closely.
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PMID:3-Nitropropionic acid induces a spectrum of Huntington's disease-like neuropathology in rat striatum. 1063 1

Detailed analysis of a novel transgenic model of basal ganglia disease has been undertaken. In this model the expression of an attenuated form of the diphtheria toxin gene was tightly controlled by D1 dopamine receptor regulatory domains. The behavioral and both direct toxin-mediated and transneuronal effects observed in pups in the first postnatal week have been described. Although younger pups are bradykinetic, older pups have a hyperkinetic syndrome with gait abnormality, postural instability and myoclonic jerks typical of human basal ganglia diseases such as Huntington's disease. As expected, striatal D1 dopamine receptor, dynorphin and substance P transcripts were not detected by in situ hybridization but there was a 27% increase in striatal D2 dopamine receptor messenger RNA and a 65% increase in enkephalin messenger RNA expression. Receptor autoradiographic studies confirmed the lack of D1-class binding in the mutant striatum and in contrast to young pups, a substantial increase in striatal D2-class binding. Autoradiographic quantitation also showed a 30% increase in striatal dopamine transporter binding. In addition to the changes described in the striatopallidal and nigrostriatal pathways, up-regulated dynorphin and substance P messenger RNA expression was also seen in the cortex. The capacity of the developing brain for neurochemical adaptation following injury is dramatic. The results show that primary loss of D1 dopamine receptor-positive striatonigral pathway neurons is sufficient to generate a hyperkinetic phenotype.
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PMID:Late direct and transneuronal effects in mice with targeted expression of a toxin gene to D1 dopamine receptor neurons. 1068 10

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

In order to investigate the sequence and pattern of neurodegeneration in Huntington's disease, the distribution and density of cannabinoid CB(1), dopamine D(1) and D(2), adenosine A(2a) and GABA(A) receptor changes were studied in the basal ganglia in early (grade 0), intermediate (grades 1, 2) and advanced (grade 3) neuropathological grades of Huntington's disease. The results showed a sequential pattern of receptor changes in the basal ganglia with increasing neuropathological grades of Huntington's disease. First, the very early stages of the disease (grade 0) were characterized by a major loss of cannabinoid CB(1), dopamine D(2) and adenosine A(2a) receptor binding in the caudate nucleus, putamen and globus pallidus externus and an increase in GABA(A) receptor binding in the globus pallidus externus. Second, intermediate neuropathological grades (grades 1, 2) showed a further marked decrease of CB(1) receptor binding in the caudate nucleus and putamen; this was associated with a loss of D(1) receptors in the caudate nucleus and putamen and a loss of both CB(1) and D(1) receptors in the substantia nigra. Finally, advanced grades of Huntington's disease showed an almost total loss of CB(1) receptors and the further depletion of D(1) receptors in the caudate nucleus, putamen and globus pallidus internus, and an increase in GABA(A) receptor binding in the globus pallidus internus. These findings suggest that there is a sequential but overlapping pattern of neurodegeneration of GABAergic striatal efferent projection neurons in increasing neuropathological grades of Huntington's disease. First, GABA/enkephalin striatopallidal neurons projecting to the globus pallidus externus are affected in the very early grades of the disease. Second, GABA/substance P striatonigral neurons projecting to the substantia nigra are involved at intermediate neuropathological grades. Finally, GABA/substance P striatopallidal neurons projecting to the globus pallidus internus are affected in the late grades of the disease. In addition, the finding that cannabinoid receptors are dramatically reduced in all regions of the basal ganglia in advance of other receptor changes in Huntington's disease suggests a possible role for cannabinoids in the progression of neurodegeneration in Huntington's disease.
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PMID:The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease. 1082 33

The different types of striatal neuron show a range of vulnerabilities to a variety of insults. This can be clearly seen in Huntington's disease where a well mapped pattern of pathological events occurs. Medium spiny projection (MSP) neurons are the first striatal cells to be affected as the disease progresses whilst interneurons, in particular the NADPH diaphorase positive ones, are spared even in the late stages of the disease. The MSP neurons themselves are also differentially affected. The death of MSP neurons in the patch compartment of the striatum precedes that in the matrix compartment and the MSP neurons of the dorsomedial caudate nucleus degenerate before those in the ventral lateral putamen. The enkephalin positive striatopallidal MSP neurons are also more vulnerable than the substance P/dynorphin MSP neurons. We review the potential causes of this selective vulnerability of striatopallidal neurons and discuss the roles of endogenous glutamate, nitric oxide and calcium binding proteins. It is concluded that MSP neurons in general are especially susceptible to disruptions of cellular respiration due to the enormous amount of energy they expend on maintaining unusually high transmembrane potentials. We go on to consider a subpopulation of enkephalinergic striatopallidal neurons in the rat which are particularly vulnerable. This subpopulation of neurons readily undergo apoptosis in response to experimental manipulations which affect dopamine and/or corticosteroid levels. We speculate that the cellular mechanisms underlying this cell death may also operate in degenerative disorders such as Huntington's disease thereby imposing an additional level of selectivity on the pattern of degeneration. The possible contribution of the selective death of striatopallidal neurons to a number of clinically important psychiatric conditions including obsessive compulsive disorders and Tourette's syndrome is also discussed.
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PMID:The selective vulnerability of striatopallidal neurons. 1084 58

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

This paper reviews the major anatomical and chemical features of the various types of interneurons in the human striatum, as detected by immunostaining procedures applied to postmortem tissue from normal individuals and patients with Huntington's disease (HD). The human striatum harbors a highly pleomorphic population of aspiny interneurons that stain for either a calcium-binding protein (calretinin, parvalbumin or calbindin D-28k), choline acetyltransferase (ChAT) or NADPH-diaphorase, or various combinations thereof. Neurons that express calretinin (CR), including multitudinous medium and a smaller number of large neurons, are by far the most abundant interneurons in the human striatum. The medium CR+ neurons do not colocalize with any of the known chemical markers of striatal neurons, except perhaps GABA, and are selectively spared in HD. Most large CR+ interneurons display ChAT immunoreactivity and also express substance P receptors. The medium and large CR+ neurons are enriched with glutamate receptor subunit GluR2 and GluR4, respectively. This difference in AMPA GluR subunit expression may account for the relative resistance of medium CR+ neurons to glutamate-mediated excitotoxicity that may be involved in HD. The various striatal chemical markers display a highly heterogeneous distribution pattern in human. In addition to the classic striosomes/matrix compartmentalization, the striosomal compartment itself is composed of a core and a peripheral region, each subdivided by distinct subsets of striatal interneurons. A proper knowledge of all these features that appear unique to humans should greatly help our understanding of the organization of the human striatum in both health and disease states.
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PMID:Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington's disease. 1108 88

Neural and stem cell transplantation is emerging as a potential treatment for neurodegenerative diseases. Transplantation of specific committed neuroblasts (fetal neurons) to the adult brain provides such scientific exploration of these new potential therapies. Huntington's disease (HD) is a fatal, incurable autosomal dominant (CAG repeat expansion of huntingtin protein) neurodegenerative disorder with primary neuronal pathology within the caudate-putamen (striatum). In a clinical trial of human fetal striatal tissue transplantation, one patient died 18 months after transplantation from cardiovascular disease, and postmortem histological analysis demonstrated surviving transplanted cells with typical morphology of the developing striatum. Selective markers of both striatal projection and interneurons such as dopamine and c-AMP-related phosphoprotein, calretinin, acetylcholinesterase, choline acetyltransferase, tyrosine hydroxylase, calbindin, enkephalin, and substance P showed positive transplant regions clearly innervated by host tyrosine hydroxylase fibers. There was no histological evidence of immune rejection including microglia and macrophages. Notably, neuronal protein aggregates of mutated huntingtin, which is typical HD neuropathology, were not found within the transplanted fetal tissue. Thus, although there is a genetically predetermined process causing neuronal death within the HD striatum, implanted fetal neural cells lacking the mutant HD gene may be able to replace damaged host neurons and reconstitute damaged neuronal connections. This study demonstrates that grafts derived from human fetal striatal tissue can survive, develop, and are unaffected by the disease process, at least for 18 months, after transplantation into a patient with HD.
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PMID:Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology. 1113 40

Intrastriatal injection of quinolinate has been proven to be a very useful animal model to study the pathogenesis and treatment of Huntington's disease. To determine whether growth factors of the neurotrophin family are able to prevent the degeneration of striatal projection neurons, cell lines expressing brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4/5 (NT-4/5) were grafted in the adult rat striatum before quinolinate injection. Three days after lesioning, ongoing cell death was assessed by in situ detection of DNA fragmentation. In animals grafted with the control cell line, quinolinate injection induced a gradual cell loss that was differentially prevented by intrastriatal grafting of BDNF-, NT-3-, or NT-415-secreting cells. Seven days after lesioning, we characterized striatal projection neurons that were protected by neurotrophins. Quinolinate injection, alone or in combination with the control cell line, induced a selective loss of striatal projection neurons. Grafting of a BDNF-secreting cell line pre-vented the loss of all types of striatal projection neurons analyzed. Glutamic acid decarboxylase 67-, preproenkephalin-, and preprotachykinin A- but not prodynorphin-expressing neurons were protected by grafting of NT-3- or NT-4/5-secreting cells but with less efficiency than the BDNF-secreting cells. Our findings show that neurotrophins are able to promote the survival of striatal projection neurons in vivo and suggest that BDNF might be beneficial for the treatment of striatonigral degenerative disorders, including Huntington's disease.
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PMID:Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 prevent the death of striatal projection neurons in a rodent model of Huntington's disease. 1118 72

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