Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One experimental strategy that may offer hope in the neurodegenerative disorder Huntington's disease (HD) has been neural transplantation. In HD, most of the pathological changes occur in the corpus striatum. Fetal human striatal implants will most likely be the first transplant strategy attempted in clinical trials to replace lost neurons and/or prevent the degeneration of neurons destined to die. The temporal expression of neurotransmitters in the developing human corpus striatum is a key factor in determining the optimum age of transplantable tissue. To this end, an immunocytochemical analysis of various neurotransmitters was performed on second trimester human brains. Antibodies against acetylcholine, gamma-aminobutyric acid, enkephalin, neuropeptide-Y and substance P were used in ten human fetal brains ranging from 13 to 21 weeks gestation. The presence and pattern of distribution for these neurotransmitters varied in the different parts of the corpus striatum (globus pallidus, putamen, caudate nucleus). These results are compared to the already existing data for the adult human corpus striatum.
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PMID:Neurotransmitter distribution in the second trimester fetal human corpus striatum. 1121 Apr 25

Recent studies have demonstrated a loss of cannabinoid CB1 receptors in the postmortem basal ganglia of patients affected by Huntington's disease (HD) and in transgenic mouse models for this disease. These studies have led to the notion that substances that increase the endocannabinoid activity, such as receptor agonists or inhibitors of endocannabinoid uptake and/or metabolism, might be useful in the treatment of hyperkinetic symptoms of this disease. In the present study, we employed a rat model of HD generated by bilateral intrastriatal injections of 3-nitropropionic acid (3-NP), a toxin that selectively damages striatal GABAergic efferent neurons. These rats exhibited biphasic motor disturbances, with an early (1-2 weeks) hyperactivity followed by a late (3-4 weeks) motor depression. Analysis of GABA, dopamine, and their related enzymes, glutamic acid decarboxylase and tyrosine hydroxylase, in the basal ganglia proved marked decreases compatible with the motor hyperkinesia. In addition, mRNA levels for CB1 receptor, neuronal-specific enolase, proenkephalin, and substance P decreased in the caudate-putamen of 3-NP-injected rats. There were also reductions in CB1 receptor binding in the caudate putamen, the globus pallidus, and, to a lesser extent, the substantia nigra. By contrast, mRNA levels for tyrosine hydroxylase in the substantia nigra remained unaffected. Interestingly, the administration of AM404, an inhibitor of endocannabinoid uptake, to 3-NP-injected rats attenuated motor disturbances observed in the early phase of hyperactivity. Administration of AM404 also tended to induce recovery from the neurochemical deficits caused by the toxin in GABA and dopamine indices in the basal ganglia. In summary, morphological, behavioral, and biochemical changes observed in rats intrastriatally lesioned with 3-NP acid were compatible with a profound degeneration of striatal efferent GABAergic neurons, similar to that occurring in the brain of HD patients. As expected, a loss of CB1 receptors was evident in the basal ganglia of these rats. However, the administration of substances that increase endocannabinoid activity, by inhibiting the uptake process, allowed an activation of the remaining population of CB1 receptors, resulting in a significant improvement of motor disturbances and neurochemical deficits. These observations might be relevant to the treatment of hyperkinetic symptoms in HD, a human disorder with unsatisfactory symptomatic treatment for most patients.
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PMID:Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibition in a rat model of Huntington's disease. 1184 43

Data obtained from the basal ganglia of postmortem Huntington's disease (HD) brains have revealed that the level of cannabinoid CB1 receptors in striatal efferent neurons decreases in parallel to the dysfunction and subsequent degeneration of these neurons. These findings, and others from rat models of HD generated by lesions with mitochondrial toxins, suggest that the loss of CB1 receptors may be involved in the pathogenesis of the disease. To explore further the changes in the endocannabinoid system, as well as the potential of endocannabinoid-related compounds, we examined the status of CB1 receptors in the HD94 transgenic mouse model of HD. These mice express huntingtin exon 1 with a polyglutamine tract of 94 repeats in a tissue-specific and conditional manner using the tet regulatable system. They develop many features of HD, such as striatal atrophy, intraneuronal aggregates and progressive dystonia. In these animals, we analyzed mRNA levels for the CB1 receptor, in addition to the number of specific binding sites and the activation of GTP-binding proteins by CB1 receptor agonists. mRNA transcripts of the CB1 receptor were significantly decreased in the caudate-putamen of HD transgenic mice compared to age-matched littermate controls. The decrease concurred with a marked reduction in receptor density in both the caudate-putamen and its projection areas such as the globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata. Furthermore, the efficacy of CB1 receptor activation was reduced in the globus pallidus, as determined by agonist-induced [35S]GTPgammaS binding, and tended towards a decrease in the substantia nigra. None of these changes was seen in the cerebral cortex and hippocampus, despite high levels of expression of the mutant protein in these regions. The decrease in CB1 receptor levels was accompanied by a decrease in the proenkephalin-mRNA levels but not in substance P-mRNA levels. Taken together, these results suggest that the loss of CB1 receptor might be preferential to the enkephalinergic CB1 receptor-containing striatopallidal neurons, and further implicate the CB1 receptor to the subsequent HD symptomatology and neuropathology.
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PMID:Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB1 receptors in the basal ganglia of a transgenic model of Huntington's disease. 1186 29

Phenocopies of Huntington's disease (HD) are individuals with a family history, clinical symptoms, and occasionally pathological evidence of HD but without an expanded CAG repeat within the HD gene. We report on an HD phenocopy with selective loss of preprotachykinin (PPT) neurons, dysfunction of surviving PPT neurons, preservation of preproenkephalin (PPE) neurons within the striatum, and greater loss of immunohistochemical staining for substance P in terminals of striatal neurons projecting to the substantia nigra, than in those projecting to the internal pallidal segment. This case demonstrates the existence of one type of striatal lesion that may produce a clinical picture similar to HD, and raises the possibility of a rare hereditary disease that mimics HD.
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PMID:Selective loss of striatal preprotachykinin neurons in a phenocopy of Huntington's disease. 1192 Nov 19

Huntington's disease is a neurodegenerative disorder characterized by a selective degeneration of striatal projection neurons, which deal with choreic movements. Neuroprotective therapy could be achieved with the knowledge of the specific trophic requirements of these neuronal populations. Thus, the induction of endogenous trophic response or the exogenous administration of neurotrophic factors may help to prevent or stop the progression of the illness. Excitotoxicity has been implicated in the etiology of Huntington's disease, because intrastriatal injection of glutamate receptor agonists reproduces some of the neuropathological features of this disorder. Activation of glutamate receptors in the striatum differentially regulates the expression of neurotrophins, glial cell line-derived neurotrophic factor (GDNF), neurturin, and their receptors in the striatum and in its connections, cortex, and substantia nigra, showing a selective trophic response against excitotoxic insults. Transplantation of cells genetically engineered to release neurotrophic factors in the striatum has been used to study the neuroprotective effects of neurotrophin and GDNF family members in the excitotoxic model of Huntington's disease. Neurotrophins (brain-derived neurotrophic factor [BDNF], neurotrophin-3, and neurotrophin-4) protected striatal projection neurons against quinolinic or kainic acid treatment. However, GDNF family members showed a more specific action. Neurturin only protected gamma-aminobutyric acid (GABA)/enkephalinergic neurons that project to the external segment of the globus pallidus, whereas GDNF exerts its effects on GABA/substance P positive neurons, which project to the substantia nigra pars compacta and the internal segment of the globus pallidus. In conclusion, the trophic requirements of each population of striatal projection neurons are due to a complex interaction between several neurotrophic factors, such as neurotrophins and GDNF family members, which can be modified, in different pathological conditions. Moreover, these neurotrophic factors may be able to provide selective protection for basal ganglia circuits, which are affected in striatonigral degenerative disorders, such as Huntington's disease or multisystem atrophy.
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PMID:Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington's disease. 1203 Dec 78

Transgenic mouse models of Huntington's disease (HD) were examined following the onset of overt behavioral symptoms. The HD transgenic mice demonstrated profound striatal losses in D1, D2, and D3 dopamine (DA) receptor proteins in comparison with their nonsymptomatic, age-matched littermate controls. In parallel, a robust increase in the striatal D5 DA receptor subtype occurred in the transgenic compared with the wild-type control mice. This receptor elevation was accompanied by heightened cyclic AMP levels, which may be induced by the adenylyl cyclase-linked D5 receptor. This is a unique result; normal striatal D5 protein levels are modest and not thought to contribute substantially to cyclic AMP-mediated DA signaling mechanisms. Simple compensatory up-regulation of D5 DA receptors in response to D1 receptor subtype loss does not explain our findings, because genetic inactivation of the D1 DA receptor does not alter levels of D5 DA receptor expression. Immunofluorescent detection of tyrosine hydroxylase showed that nigrostriatal DA containing terminals were reduced, further supporting that disturbances in DA signaling occurred in HD transgenic models. The substance P-containing striatal efferent pathway was more resistant to the HD mutation than met-enkephalin-producing striatal projection neurons in the transgenics, based on neuropeptide immunofluorescent staining. Analogous findings in multiple transgenic models suggest that these changes are due to the presence of the transgene and are not dependent on its composition, promotor elements, or mouse strain background. These findings suggest modifications in the striatal DA system and that its downstream signaling through cyclic AMP mechanisms is disrupted severely in HD following onset of motor symptoms.
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PMID:Striatal neurochemical changes in transgenic models of Huntington's disease. 1211 32

In the Presidential Lecture, I looked back my 28 years' history of researches on Huntington's disease (HD). In the first 3-4 years, I worked predominantly in the field of the neuro-anatomy, elucidating the fine distribution of the inhibitory neurotransmitter, GABA, in the human substantia nigra, elucidating the existence of a hitherto unknown subthalamo-nigral pathway in rat, and demonstrating the presence of the excitatory substance P-ergic striatonigral pathway in rat. In the middle 16-17 years, I preferentially worked in the field of neurochemical pharmacology, suggesting a mechanism of chorea in HD to be a result of hyperactivity of remaining presynaptic dopaminergic system in the striatum by making a 'choreic' model in monkey using excitotoxic kainic acid and levodopa. In the last 7-8 years, we began to be involved in the analysis of huntington gene of patients and protein chemistry of intranuclear inclusion bodies appeared in culture cells, based on the concept that HD is a CAG repeat disease. We found that the forming process of inclusion bodies was unexpectedly rapid. In addition, we found that inclusion bodies not only contain huntington itself but also contain histones, splicosomes, and ubiquitin. The recruitment of those biologically important proteins into the inclusion bodies could give neurons serious damages for living normally, even if not directly to a catastrophe, a neuronal death.
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PMID:[On what I learned from researches on Huntington's disease]. 1223 89

Methamphetamine (METH) is an addictive substance that also causes extensive neural degeneration in the central nervous system. Because METH augments striatal substance P (SP) levels, we hypothesized that this neuropeptide plays a role in methamphetamine-induced toxicity and neural damage in the striatum. In this study we present evidence demonstrating that signaling through the neurokinin-1 (NK-1) receptor by SP plays an important role in methamphetamine-induced toxicity in the striatum. We tested the effects of the selective NK-1 receptor antagonists WIN-51,708 and L-733,060 on several markers of dopaminergic terminal toxicity in the mouse striatum. Administration of NK-1 receptor antagonist prevented the loss of dopamine transporters assessed by autoradiography and western blotting, the loss of tissue dopamine assessed by high-pressure liquid chromatography, and the loss of tyrosine hydroxylase, as well as the induction of glial fibrillary acidic protein determined by western blotting. Pre-treatment with NK-1 receptor antagonist had no effect on METH-induced hyperthermia. Pre-exposure of mice to either of the NK-1 receptor antagonists alone was without effect on all of these neurochemical markers. These results provide the first evidence that tachykinins, particularly SP, acting through NK-1 receptors, play a crucial role in the pathogenesis of nigrostriatal dopaminergic terminal degeneration induced by METH. This finding could lead to novel therapeutic strategies to offset drug addictions as well as in the treatment of a number of disorders including Parkinson's and Huntington's diseases.
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PMID:Neurokinin-1 (NK-1) receptor antagonists abrogate methamphetamine-induced striatal dopaminergic neurotoxicity in the murine brain. 1239 May 23

In early adult-onset Huntington's disease (HD), enkephalinergic striatopallidal projection neurons show preferential loss, reduced preproenkephalin (PPE) expression in surviving striatopallidal neurons, and loss of fibers in their projection target area. We examined PPE and PPT (preprotachykinin) gene expression in striatal projection neurons and in striatal projection fibers immunoreactive for the PPE product enkephalin (ENK) and the PPT product substance P (SP) in a transgenic HD model, the R6/2 mouse, to see if changes occur in these neuron types similar to those seen in early adult-onset HD. The results show that PPE mRNA level, the number of striatal neurons expressing PPE, and the staining intensity of fibers immunoreactive for ENK in the pallidum were all decreased. By contrast, the SP-containing striatal projection systems to the pallidum and substantia nigra were relatively normal in R6/2 mice. The selective reduction in striatal PPE in R6/2 mice is reminiscent of adult-onset HD, but the preservation of the striatonigral projection system is not. Thus, R6/2 mice do not strictly mimic adult-onset HD in their striatal pathology.
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PMID:Differential changes in striatal projection neurons in R6/2 transgenic mice for Huntington's disease. 1258 47

Huntingtin is the protein whose mutation leads to Huntington's disease (HD). The protein is heterogeneously distributed in the telencephalon, and not consistently correlated with cell vulnerability in HD [Fusco, F.R., Chen, Q., Lamoreaux, W.J., Figueredo-Cardenas, G., Jiao, Y., Coffman, J.A., Surmeier, D.J., Honig, M.G., Carlock, L.R., and Reiner, A., J. Neurosci., 19 (1999) 1189-1202]. The aim of our study was to investigate a possible preferential distribution of huntingtin among the two main striatal output pathways, namely, the striatonigral and the striatopallidal circuit. Dual label immunofluorescence by means of confocal microscopy was used to detect the presence of huntingtin among striatal projection neurons identified by their cellular content of Substance P, Enkephalin, CB1 receptor, and D1a dopamine receptor. Our data showed that striatopallidal neurons co-containing SP and D1a [Surmeier, D.J., Song, W.J., and Yan, Z., J. Neurosci., 16 (1996) 6579-6591] co-localized with huntingtin in a higher proportion than striatonigral neurons.
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PMID:Huntingtin distribution among striatal output neurons of normal rat brain. 1261 99


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