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)

A variety of neurotransmitters have been implicated in the pathophysiology of chorea as exemplified by Huntington's chorea. These include dopamine, serotonin, acetylcholine, GABA and a variety of neuropeptides including substance P and somatostatin. Despite biochemical data that suggests that alterations in other neurotransmitters may be of greater significance, pharmacologic data still supports a major role of dopamine in the actual clinical manifestation of chorea.
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PMID:Chorea. 244 58

Substance P concentrations have been found to be reduced in the basal ganglia in Huntington's disease (HD). In order to further examine this finding in the present study we measured substance P-like immunoreactivity (SPLI) in cases of HD which had been graded as to the severity of pathological changes in the striatum. Marked significant reductions of SPLI were found in all striatal nuclei which were significantly correlated with the percentage of neuronal loss in the varying pathologic grades. Similar changes were found in the projection sites of striatal substance P neurons, the globus pallidus interna and the substantia nigra. These changes are consistent with a loss of striatal substance P containing projection neurons in HD. Significant reductions in SPLI were also found in the external pallidum, bed nucleus of the stria terminalis and the subthalamic nucleus. Small significant increases in SPLI (20-30%) were found in 3 frontal cortical regions (Brodmann areas 6, 8 and 9). The finding of neurochemical changes in the subthalamic nucleus is of particular interest since lesions in this nucleus are known to result in chorea and therefore might contribute to the chorea which is a cardinal symptom of HD.
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PMID:A detailed examination of substance P in pathologically graded cases of Huntington's disease. 245 59

We performed a neurochemical study of the brain of two unrelated patients, living in different continents, with neuroacanthocytosis. The levels of monoamines and their metabolites, gamma-aminobutyric acid and substance P, were measured in several brain areas and the monoamine metabolites in cerebrospinal fluid. The binding of 3H-spiperone to striatal membranes and to lymphocytes was also measured. Both patients had a progressive neurological disorder with onset in the third decade of life and characterized by a complex movement disorder, epilepsy, muscular wasting, and changes in behavior. The movement disorder initially manifested with oromandibular dystonia and limb chorea, but at the time of death was characterized by a severe dystonic syndrome. The chemical changes were similar in the two patients. The most important neurochemical findings were a depletion of dopamine and its metabolites in most brain areas, most notably in the striatum, and elevation of norepinephrine levels in the putamen and globus pallidus. Substance P was markedly reduced in the striatum and substantia nigra. Our findings may provide clues to the neurochemical mechanisms underlying dystonia.
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PMID:Neurochemical findings in neuroacanthocytosis. 290 27

Somatostatin, substance P, cyclic AMP and cyclic GMP were determined in the cerebrospinal fluid of patients with Huntington's disease, in first generation relatives of choreic patients and in neurological control patients. Substance P levels were not significantly altered, but somatostatin levels were markedly decreased both in affected patients and symptom-free offspring. Cyclic AMP was decreased only in patients with advanced stages of the disease while cyclic GMP was normal. Evidence is discussed which may support a role of somatostatin deficiency in the pathophysiology of chorea.
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PMID:Huntington's chorea-- measurements of somatostatin, substance P and cyclic nucleotides in the cerebrospinal fluid. 616 83

Chorea-acanthocytosis has been separated as a clinical entity different from Huntington's chorea, mainly based on the clinical findings, but the histopathological and biochemical features of chorea-acanthocytosis, especially of basal ganglia, have not been well established, because only two such autopsy cases have been reported. The case presented here was a 39-year-old man at autopsy, with 10 years duration of typical symptoms and signs of chorea-acanthocytosis. At autopsy, the abnormal histopathological findings in the central nervous system were mainly confined to the striatum, where the caudate nucleus and putamen showed severe and moderate atrophy, respectively. Morphometric evaluation of the numbers of small and large neurons in the striatum with the adjustment for the shrinkage produced in the disease processes was performed. The numbers of small neurons in the caudate nucleus and putamen were 1% and 20% of each control, respectively. On the other hand, the large neurons in the caudate nucleus showed a reduction of diameters without a decrease in number and those in the putamen showed a mild decrease in number. In the biochemical studies, marked decrease of substance P (SP) level without definite decrease of choline acetyltransferase and glutamic acid decarboxylase (GAD) activities in both caudate nucleus and putamen was found. Substantia nigra, where no evident histopathological abnormalities were found, showed definite decrease of GAD activity and SP level. In the peripheral nervous system, the lateral branch of deep peroneal nerve showed mild degree of axonal degeneration. Neurogenic muscular atrophy with severe and mild degrees was found in extensor digitorum brevis and quadriceps femoris muscles, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[An autopsy case of chorea-acanthocytosis. Special reference to the histopathological and biochemical findings of basal ganglia]. 620 44

Huntington's disease is a progressive degenerative neurological disorder which produces a characteristic movement disorder termed chorea. Although chorea is associated with dysfunction of the basal ganglia, the underlying mechanisms by which dyskinesias such as chorea are produced, are poorly understood. Recent studies in primates have led to experimental models of chorea with postulated involvement of specific neural pathways. In the present study we attempted to determine the validity of the experimental models by measuring concentrations of gamma-aminobutyric acid (GABA), glutamate, substance P and met-enkephalin in the basal ganglia of Huntington's disease patients who manifested either chorea or rigidity/bradykinesia within 6 months of death. We also characterized changes in the Huntington's disease patients according to pathological grade, since this may be a confounding factor. We analysed post-mortem brain tissue from 12 controls, and 11 grade 3 and 12 grade 4 Huntington's disease patients. The grade 3 and 4 cases consisted of eight adult-onset choreic, nine adult-onset rigid and six juvenile-onset rigid patients. We also analysed the putamen and globus pallidus from 11 grade 2 adult onset choreic Huntington's disease patients. A model of chorea based on experimental studies in primates proposes that a loss of striatal GABAergic inhibitory projections to the globus pallidus externa leads to increased activity of the inhibitory globus pallidus externa GABAergic neurons which project to the subthalamic nucleus. It is believed that the loss of GABAergic inputs to the globus pallidus externa precedes a loss of GABAergic input to the globus pallidus interna, which occurs later in the disease and is associated with the development of rigidity and bradykinesia. In the choreic Huntington's disease patients whom we studied, there was a greater loss of GABA in the globus pallidus externa than in the globus pallidus interna, and the globus pallidus interna: globus pallidus externa GABA ratio was significantly increased compared with rigid patients. There were also increases in GABA in the subthalamic nucleus in the choreic patients, although this did not reach significance. A differential loss of met-enkephalin in the globus pallidus externa compared with substance P loss in the globus pallidus interna was not observed in either the choreic patients with advanced disease or the grade II patients. There was a significant increase in GABA concentrations in the ventroanterior nucleus of the thalamus in the choreic patients compared with rigid/bradykinetic patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurochemical substrates of rigidity and chorea in Huntington's disease. 769 98

Huntington's Disease (HD) is a progressive degenerative disorder of the central nervous system inherited as an autosomal dominant trait. Clinically, the disorder is characterized by choreoathetosis (with age of onset typically in the late thirties or early forties) and neuropsychiatric disturbance. The striatum is particularly vulnerable to the degenerative disease process, with selective loss of medium spiny neurons and decreased levels of associated neurotransmitters, including substance P. GABA, met-enkephalin and dynorphin. Although the underlying pathophysiology is unknown, recent theories concerning pathogenesis have involved mitochondrial abnormalities and excitotoxin-mediated damage. The gene for HD has recently been discovered and characterized as an unstable CAG trinucleotide repeat sequence on the short arm of chromosome 4 (now known as IT15). The direct test now available for the HD gene has facilitated disease diagnosis, particularly for those with unclear family history or chorea of uncertain origin; presymptomatic testing is also available. Management of affected individuals is unsatisfactory as only symptomatic control is available. However, as the effect of the genetic abnormality may soon be known, specific treatment of the disorder may become available in the near future.
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PMID:Huntington's disease: recent advances in diagnosis and management. 775 74

Gamma-aminobutyric acid (GABA)/substance P (SP) neurons and GABA/enkephalin (Enk) neurons in the striatum exert opposing influence on the regulation of movement. The loss of GABA/SP neurons results in hypokinetic disorders (parkinsonism), whereas the loss of GABA/Enk neurons results in hyperkinetic disorders (e.g. chorea). The present study determined age-related changes in the beta-preprotachykinin (the precursor of SP) and preproenkaphalin (the precursor of Enk) messenger RNA (mRNA) ratio in the postmortem human putamen using the reverse transcription-polymerase chain reaction (RT-PCR). The ratio of beta-preprotachykinin to preproenkephalin mRNA expression decreased with age. The reduction in the beta-preprotachykinin/preproenkephalin mRNA ratio was more marked in cases with multiple small infarcts (status lacunaris) in the putamen. These findings may in part explain the susceptibility of the elderly, particularly of those with ischemic changes in the striatum to hypokinetic disorders.
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PMID:Reduction in the ratio of beta-preprotachykinin to preproenkephalin messenger RNA expression in postmortem human putamen during aging and in patients with status lacunaris. Implications for the susceptibility to parkinsonism. 936 4

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

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


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