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)

We have recently examined the status of the endocannabinoid transmission in the basal ganglia in Huntington's disease (HD) using a rat model generated by bilateral intrastriatal injections of 3-nitropropionic acid (3-NP). In these previous studies, we focused on the early phase of hyperactivity that occurs 1-2 weeks after the lesion, comparable to early grades of the human disease, while in the present study, we wanted to explore the late akinetic phase observed 3-4 weeks after the lesion (similar to advanced grades). First, we confirmed that 3-NP-lesioned rats exhibited a marked akinesia tested at 4 weeks post-lesion. We observed a marked reduction in ambulatory and exploratory activities and a trend towards a decrease in stereotypies, paralleled by a strong increase in the time spent in inactivity. There was also a profound reduction in GABA contents and glutamic acid decarboxylase activity, particularly in the caudate-putamen and the globus pallidus. Dopamine and DOPAC contents, as well as the activity of tyrosine hydroxylase, were also reduced, particularly in the caudate-putamen. mRNA levels for neuronal-specific enolase, proenkephalin and substance P were also dramatically reduced in the caudate-putamen, thus indicating a death of both the direct (striatonigral) and the indirect (striatopallidal) GABAergic projection pathways, which corresponded with a marked loss of CB(1) receptor-mRNA levels observed in both parts, lateral and medial, of the caudate-putamen. However, losses of CB(1) receptor binding were confined to the globus pallidus and the caudate-putamen, whereas there were no changes in the substantia nigra and the entopeduncular nucleus. Finally, we failed to reduce the marked akinesia found in these animals by administering SR141716A, a selective antagonist of CB(1) receptors, which had exhibited hyperlocomotor effects in previous studies with naive animals. In summary, behavioral and biochemical changes observed in rats intrastriatally lesioned with 3- NP were compatible with a profound degeneration of striatal efferent GABAergic neurons, similar to those occurring in advances stages of the human disease. As expected, a loss of CB(1) receptors was evident in the basal ganglia of these rats during the late akinetic stage of the disease. Further studies should demonstrate whether these receptors might be a target for a new therapy in HD, a disease with a poor pharmacological outcome.
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PMID:Loss of cannabinoid CB(1) receptors in the basal ganglia in the late akinetic phase of rats with experimental Huntington's disease. 1270 98

While the excitotoxic vulnerability of striatal neurons is known to be greater in juvenile than adult animals, it is uncertain if striatal neuron types decline differentially in their vulnerability with age. To examine this issue, we unilaterally injected quinolinic acid (QA), an N-methyl-d-aspartate (NMDA) receptor agonist, into the striatum of juvenile and adult rats, and used in situ hybridization histochemistry with oligonucleotide probes for preproenkephalin and preprotachykinin mRNA to label surviving enkephalinergic (ENK) and substance P-containing (SP) neurons in adjacent sections through the injection center. The results confirmed that the region of severe damage is greater in young than adult animals, but revealed that at the very center of the QA injection, labeled neuron abundance was lower in adult than juvenile striatum. In juvenile rats, the vulnerability of the ENK neurons at all distances from the injection center was the same as that of the SP neurons. By contrast, in adult rats, the ENK neuron survival was greater than the SP neuron survival at all distances beyond the lesion center. The SP neuron survival outside the injection center in the adult rats was similar to that in juvenile rats, while the ENK neuron survival beyond the injection center was better in adult than juvenile rats. These data indicate that there is an age-dependent decrease in the vulnerability of ENK but not SP striatal projection neurons to QA-mediated injury in rats. The results also raise the possibility that, if an excitotoxic process is involved in HD pathogenesis, a differential age-related decline in the sensitivity of striatal projection neuron types to this process may contribute to the more uniform striatal neuron loss in juvenile-onset Huntington's disease (HD) and the more differential loss in adult-onset HD.
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PMID:Enkephalinergic striatal projection neurons become less affected by quinolinic acid than substance P-containing striatal projection neurons as rats age. 1476 98

Prior studies suggest differences exist among striatal projection neuron types in their vulnerability to Huntington's disease (HD). In the present study, we immunolabeled the fibers and terminals of the four main types of striatal projection neuron in their target areas for substance P, enkephalin, or glutamic acid decarboxylase (GAD), and used computer-assisted image analysis to quantify the abundance of immunolabeled terminals in a large sample of HD cases ranging from grade 0 to grade 4 [J. Neuropathol. Exp. Neurol. 44 (1985) 559], normalized to labeling in control human brains. Our goal was to characterize the relative rates of loss of the two striatopallidal projection systems (to the internal versus the external pallidal segments) and the two striatonigral projections systems (to pars compacta versus pars reticulata). The findings for GAD and the two neuropeptides were similar--the striatal projection to the external pallidal segment was the most vulnerable, showing substantial loss by grade 1. Loss of fibers in both subdivisions of the substantia nigra was also already great by grade 1. By contrast, the loss in the striatal projection system to the internal segment of globus pallidus proceeded more gradually. By grade 4 of HD, however, profound loss in all projection systems was apparent. These findings support the notion that the striatal neurons preferentially projecting to the internal pallidal segment are, in fact, less vulnerable in HD than are the other striatal projection neuron types.
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PMID:Differential loss of striatal projection systems in Huntington's disease: a quantitative immunohistochemical study. 1518 1

A leading hypothesis of the cause of neuronal death in Huntington's disease (HD) is excitotoxicity, in which subpopulations of striatal neurons are hypersensitive to glutamate release due to changes in postsynaptic N-methyl-D-aspartate receptors (NMDARs). In the present study we used RT-PCR methods on single cells and tissue to compare the expression of NMDAR subunits, NR1, NR2A and NR2B, in the striatum of R6/2 transgenic mice with their wild-type (WT) littermates at three different age groups corresponding to different symptomatic milestones (19-25 days showing no overt evidence of abnormal behavior, 38-45 days at the onset of the overt phenotype and 78-90 days displaying the full behavioral phenotype). Single-cell RT-PCR studies also examined neurons for the expression of substance P and enkephalin to define different subpopulations of medium-sized projection neurons of the striatum. The results showed a significant decrease in the percentage of cells expressing NR2A at all ages examined. The decrease in expression was not associated with any significant change in expression of NR1 or NR2B. Cells that did not express NR2A contained both enkephalin and substance P, but proportionately more cells containing enkephalin displayed decreases in NR2A. Semi-quantitative RT-PCR studies on striatal tissue in the oldest age group confirmed the significant decrease in NR2A and also showed a decrease in NR2B. These results support the hypothesis that changes in the composition of postsynaptic NMDARs occur in the R6/2 model of HD and this effect occurs early in the expression of the phenotype.
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PMID:Changes in expression of N-methyl-D-aspartate receptor subunits occur early in the R6/2 mouse model of Huntington's disease. 1667 70

Huntington's disease is caused by degeneration or malfunctioning of basal ganglia. Although the exact pathophysiology of this disease is not clear, it seems that abnormal glutamate release is involved in producing movement disorders. Few simulations are done on Huntington's disease. Since a complex movement disorder is seen in this disease, a mathematical model is needed to analyze it. We designed a computational model based on physiological findings. The model block diagram is proposed. The glutamate abnormality of the disease is considered as an environment noise and is designated as a random number generator in the model. To designate inhibitory and excitatory effect of neurotransmitters on each block, we used Hill functions. We designated the internal behavior of blocks using a closed loop system. Proper transfer functions are assumed for each block in our model. In order to separate normal and diseased conditions, we included noise in all glutamate related blocks and put it dependent to a parameter, g. All nominal quantities used in the model are chosen by try and error. The response of the model is presented for different values of g in health and illness states. In this study, we have designated g=1 for healthy and g=10 for illness states. In the healthy state, our model's output is zero. However, it produces an abrupt movement in Huntington's disease, like what is seen in chorea. While reducing g from 10 to 3 causes the size of answer to be reduced, putting the g below 3 will cause cessation of jerky movement. Some of our model's response properties, as the period between each two abrupt movements, size of movement and the shape of movement curve are completely stochastic, being another significant similarity between our model and the real conditions. According to all similarities between the model and Huntington's disease, any change in the model parameters can resemble real changes. We evaluated some parameters, as substance P and GABA levels, in the basal ganglia model and showed that increasing these variables are able to ameliorate the patient's symptoms. We suggest that prescribing drugs such as gabapentin could improve the symptoms. Surely, clinical trials are needed to validate this suggestion.
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PMID:A computational model for the Huntington disease. 1725 71

Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor (Drd1a)+ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P, and dynorphin expression is progressively lost, whereas D2 dopamine receptor (Drd2) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electrographically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in the oral behaviors of sifting and chewing. In line with the limbic seizure profile, cell loss, astrogliosis, microgliosis, and down-regulated dynorphin expression were seen in the hippocampal dentate gyrus. This study specifically implicates Drd1a+ cell loss with tail suspension hindlimb dystonia, hyperactivity, and abnormal oral function. The latter may relate to the speech and swallowing disturbances and the classic sign of tongue-protrusion motor impersistence observed in Huntington's disease. In addition, the findings of this study support the notion that Drd1a and Drd2 are segregated on striatal projection neurons.
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PMID:Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior. 1736 Apr 97

The neuroprotective potential of cannabinoids has been examined in rats with striatal lesions caused by 3-nitropropionic acic (3NP), an inhibitor of mitochondrial complex II. We used the CB1 agonist arachidonyl-2-chloroethylamide (ACEA), the CB2 agonist HU-308, and cannabidiol (CBD), an antioxidant phytocannabinoid with negligible affinity for cannabinoid receptors. The administration of 3NP reduced GABA contents and also mRNA levels for several markers of striatal GABAergic projection neurons, including proenkephalin (PENK), substance P (SP) and neuronal-specific enolase (NSE). We also found reductions in mRNA levels for superoxide dismutase-1 (SOD-1) and -2 (SOD-2), which indicated that 3NP reduced the endogenous antioxidant defences. The administration of CBD, but not ACEA or HU-308, completely reversed 3NP-induced reductions in GABA contents and mRNA levels for SP, NSE and SOD-2, and partially attenuated those found in SOD-1 and PENK. This indicates that CBD is neuroprotective but acted preferentially on striatal neurons that project to the substantia nigra. The effects of CBD were not reversed by the CB1 receptor antagonist SR141716. The same happened with the TRPV1 receptor antagonist capsazepine, in concordance with the observation that capsaicin, a TRPV1 receptor agonist, failed to reproduce the CBD effects. The effects of CBD were also independent of adenosine signalling as they were not attenuated by the adenosine A2A receptor antagonist MSX-3. In summary, this study demonstrates that CBD provides neuroprotection against 3NP-induced striatal damage, which may be relevant for Huntington's disease, a disorder characterized by the preferential loss of striatal projection neurons. This capability seems to be based exclusively on the antioxidant properties of CBD.
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PMID:Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors. 1767 54

Ependymal overexpression of brain-derived neurotrophic factor (BDNF) stimulates neuronal addition to the adult striatum, from subependymal progenitor cells. Noggin, by suppressing subependymal gliogenesis and increasing progenitor availability, potentiates this process. We asked whether BDNF/Noggin overexpression might be used to recruit new striatal neurons in R6/2 huntingtin transgenic mice. R6/2 mice injected with adenoviral BDNF and adenoviral Noggin (AdBDNF/AdNoggin) recruited BrdU(+)betaIII-tubulin(+) neurons, which developed as DARPP-32(+) and GABAergic medium spiny neurons that expressed either enkephalin or substance P and extended fibers to the globus pallidus. Only AdBDNF/AdNoggin-treated R6/2 mice harbored migrating doublecortin-defined neuroblasts in their striata, and the new neurons expressed p27 as a marker of mitotic quiescence after parenchymal integration. AdBDNF/AdNoggin-treated R6/2 mice sustained their rotarod performance and open-field activity and survived longer than did AdNull-treated and untreated controls. Neither motor performance nor survival improved in R6/2 mice treated only with AdBDNF, and intraventricular infusion of the mitotic inhibitor Ara-C completely blocked the performance and survival effects of AdBDNF/AdNoggin, suggesting that the benefits of AdBDNF/AdNoggin derived from neuronal addition. Thus, BDNF and Noggin induced striatal neuronal regeneration, delayed motor impairment, and extended survival in R6/2 mice, suggesting a new therapeutic strategy in Huntington disease.
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PMID:Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. 1788 87

We report the first autopsy case of genetically confirmed, autosomal-dominant chorea-acanthocytosis (AD-ChAc), showing a heterozygous mutation (G-A) at nucleotide position 8,295 in exon 57 of VPS13A. The patient was a 36-year-old Japanese man and the duration of his illness was 11 years. Neuropathologically, the patient showed marked atrophy and neuronal loss, particularly small and medium-sized neurons, with astrocytic gliosis in the caudate nucleus, putamen and globus pallidus. These findings were similar to previous autopsy reports of autosomal-recessive ChAc (AR-ChAc) with mutations of VPS13A. The broad distribution of atrophic neurons and astrocytosis throughout the whole brain was unique in our AD-ChAc patient and has not been described in AR-ChAc. The neuronal density of the dorsal caudate nucleus was lower than that of the ventral side in this patient as well as in three Huntington's disease (HD) patients. The neuronal densities in both the rostral and caudal sides were lower than that in the middle region at the anterior commissure level, while in the three HD patients, the neuronal densities of the caudate nucleus were more decreased in the caudal side. This ChAc patient showed faint immunoreactivity in the caudate nucleus and globus pallidus with antibodies against the striatal neurotransmitters, methionine-enkephalin, leucine-enkephalin and substance P. The difference in patterns of neuronal vulnerability could reflect those in the mechanisms of neurodegeneration between ChAc and HD.
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PMID:A neuropathological study of autosomal-dominant chorea-acanthocytosis with a mutation of VPS13A. 1866 Nov 37

Huntington's disease (HD) is a disease of the basal ganglia which results in a major loss of the striatal GABAergic medium spiny neurons containing enkephalin and substance P. These neurons project principally to the globus pallidus (GP) and substantia nigra pars reticulata (SNr). Both GABA(A) and GABA(B) receptors are localised postsynaptically on neurons in the GP and SNr, and cannabinoid (CB(1)) receptors are localised presynaptically on the axon terminals of the medium spiny projection neurons in the GP and SNr. The aims of this project were to investigate the changes in the distribution of CB(1), GABA(A), and GABA(B) receptor subunits, as well as enkephalin and substance P in the GP in the HD brain compared to the normal brain. The results of this study have shown firstly, that in the HD brain there is a dramatic loss of enkephalin and CB(1) receptor immunoreactivity (IR) in the external segment of the globus pallidus (GPe) and a major loss of substance P and CB(1) receptor-IR from the internal segment of the globus pallidus (GPi). Secondly, the degeneration of these striatal efferent neurons results in the upregulation of the various subunits of both GABA(A) (alpha(1), beta(2,3) and gamma(2)) and GABA(B) (R(1)) receptors in the GP in HD. Detailed double labelling confocal microscopy studies show that in HD the increased GABA(A) and GABA(B) receptor-IR is distributed not just in punctate "synaptic" regions, but throughout all dendritic and somal membranes of pallidal neurons. These results provide the first comprehensive description of the changes of CB(1), GABA(A) and GABA(B) receptor subunits in the HD basal ganglia. The upregulation of both GABA(A) and GABA(B) receptors may serve to increase the sensitivity of pallidal neurons to the decreased levels of GABA that occurs in the GP in HD. The loss of CB(1) receptors in HD is also thought to be a compensatory mechanism due to evidence that endocannabinoids modulate the reuptake of GABA in the GP. These findings show the high degree of plasticity of CB(1), GABA(A) and GABA(B) receptors and provide a better understanding of the GABAergic modulation of basal ganglia neurons in the normal and diseased human brain.
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PMID:Cannabinoid (CB(1)), GABA(A) and GABA(B) receptor subunit changes in the globus pallidus in Huntington's disease. 1948 Oct 11

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