Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The levels of the neuropeptides Met- and Leu-enkephalin (MET-ENK, LEU-ENK), substance P and neurotensin were measured by a combined high performance liquid chromatography/radioimmunoassay (HPLC/RIA) method in postmortem samples of basal ganglia from Parkinson's disease patients, incidental Lewy body disease patients (pre-symptomatic Parkinson's disease) and matched controls. Dopamine (DA) levels were reduced in the caudate nucleus and putamen in Parkinson's disease, but unaltered in incidental Lewy body disease. The levels of MET-ENK were reduced in the caudate nucleus, putamen and substantia nigra in Parkinson's disease. Met-enkephalin levels were reduced in the caudate nucleus and in the putamen in incidental Lewy body disease. Leu-enkephalin levels were decreased in the putamen and were undetectable in the substantia nigra in Parkinson's disease. Leu-enkephalin levels were unchanged in incidental Lewy body disease, although there was a tendency to a reduction in putamen. Substance P levels were reduced in the putamen in Parkinson's disease. No significant changes in substance P content were observed in incidental Lewy body disease. Neurotensin levels were increased in the substantia nigra in Parkinson's disease. Neurotensin levels in incidental Lewy body disease were not altered significantly, but tended to parallel the changes in Parkinson's disease. The changes in basal ganglia peptide levels in incidental Lewy body disease generally followed a trend similar to those seen in Parkinson's disease, but were less marked. This suggests that they are an integral part of the pathology of the illness and not secondary to DA neuronal loss or a consequence of prolonged drug therapy.
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PMID:Alterations in peptide levels in Parkinson's disease and incidental Lewy body disease. 867 94

Neurotensin is a 13-amino acid hormonal peptide which was first isolated from bovine hypothalamus. It is present in the digestive tract as well as in the central nervous system. It has a variety of biological activities as a central neurotransmitter or neuromodulator, and a peripheral hormone. NT receptors have been characterized in a variety of tissues and cell lines of peripheral and central organs. The physiological functions of NT include stimulation of pancreatic and biliary secretion, stimulation of colonic motility, inhibition of small bowel and gastric motility, trophic effect on numerous tissues of the gastrointestinal tract. NT exerts hypothermic and analgesic effect when injected into the central nervous system. From a clinical standpoint, studies with NT have led to implications of its involvement in schizophrenia, Parkinson's disease and Alzheimer's disease.
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PMID:[Neurotensin--structure, origin and biological function]. 933 84

Sleep disruption and other circadian rhythm disturbances are frequently seen in dementia patients. In this study, we examined the suprachiasmatic nucleus (SCN), the putative site of the hypothalamic circadian pacemaker, to determine the nature and degree of pathologic changes caused by severe dementia. Neuropathologic examination indicated that among 30 patients with a clinical history of severe dementia, 22 had Braak and Braak stage V-VI Alzheimer disease, 3 had combined Alzheimer and Parkinson disease, 3 had Pick disease and 2 had severe hippocampal sclerosis. Comparisons were made with a control group composed of 13 age-matched patients with no clinical or pathological evidence of dementia or other CNS disorders. To determine the pathologic involvement within the SCN, human hypothalami were stained with: Nissl, Bielchowsky silver, thioflavin S and specific antibodies directed against vasopressin (VP), neurotensin (NT), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), beta-amyloid (B/A4) and glial fibrillary acidic protein (GFAP). Pathologic damage was primarily limited to neuronal loss and neurofibrillary tangle formation. Only rare diffuse plaques were noted. The pathologic changes within the SCN were less severe than in the other brain regions. Morphometric analysis was accomplished using a stereological approach to sample the average total number of positively stained neurons and astrocytes in 10 different 0.1mm2 microscopic fields in the dorsal subdivision of the SCN. Patients with Alzheimer disease exhibited a significant decrease in vasopressin (9.75 vs 16.7, p < 0.001) and neurotensin (6.82 vs 9.63, p < 0.002) neurons, as well as a corresponding increase in the GFAP-stained astrocyte/Nissl-stained neuron ratio (0.54 vs 0.10, p < 0.009). These studies provide evidence that both vasopressin and neurotensin neurons are lost in Alzheimer disease, and that the astrocyte/neuron ratio is a reliable indicator of disease-related pathology within the SCN. Taken collectively, our data support the hypothesis that damage to the SCN may be an underlying anatomical substrate for the clinically observed changes in circadian rhythmicity that have been observed in Alzheimer patients.
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PMID:Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. 1006 11

We examined the sequential changes in neurotensin receptors in the striatum and substantia nigra of mouse brains lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by receptor autoradiography, in comparison with the alterations in dopamine uptake sites. The mice received four intraperitoneal injections of MPTP (10 mg/kg) at 1-h intervals and then the brains were analyzed at 6 h and 1, 3, 7, and 21 days after the treatments. [3H]Neurotensin and [3H]mazindol were used to label neurotensin receptors and dopamine uptake sites, respectively. [3H]Neurotensin binding was significantly decreased in the striatum from 6 h to 21 days after MPTP treatment. In the substantia nigra, pars reticulata also showed a significant decrease in [3H]neurotensin binding from 3 to 21 days post-MPTP treatment. However, no significant change in [3H]neurotensin binding was observed in the pars compacta even after 21 days. On the other hand, [3H]mazindol binding was markedly decreased in the striatum and substantia nigra from 6 h to 21 days after MPTP treatment. These results indicate that neurotoxin MPTP can produce a severe decrease in neurotensin receptors and dopamine uptake sites in the striatum and substantia nigra of mice. Thus, our findings provide evidence that the dysfunction in neurotensin receptors may be involved in the degenerative processes causing Parkinson's disease.
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PMID:Alteration of neurotensin receptors in MPTP-treated mice. 1047 79

The neurotensin receptor 1 (NTR1) subtype belongs to the family of G protein-coupled receptors and mediates most of the known effects of the neuropeptide including modulation of central dopaminergic transmission. This suggested that nonpeptide agonist mimetics acting at the NTR1 might be helpful in the treatment of Parkinson's disease and schizophrenia. Here, we attempted to define the molecular interactions between neurotensin-(8-13), the pharmacophore of neurotensin, and the rat NTR1. Mutagenesis of the NTR1 identified residues that interact with neurotensin. Structure-activity studies with neurotensin-(8-13) analogs identified the peptide residues that interact with the mutated amino acids in the receptor. By taking these data into account, computer-assisted modeling techniques were used to build a tridimensional model of the neurotensin-(8-13)-binding site in which the N-terminal tetrapeptide of neurotensin-(8-13) fits in the third extracellular loop and the C-terminal dipeptide binds to residues at the junction between the extracellular and transmembrane domains of the receptor. Interestingly, the agonist binding site lies on top of the previously described NTR1-binding site for the nonpeptide neurotensin antagonist SR 48692. Our data provide a basis for understanding at the molecular level the agonist and antagonist binding modes and may help design nonpeptide agonist mimetics of the NTR1.
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PMID:Identification of residues involved in neurotensin binding and modeling of the agonist binding site in neurotensin receptor 1. 1061 22

In the present study we describe the excitatory effects of the bioactive peptide neurotensin on the electrical activity of dopamine neurons (simultaneously recorded) in the substantia nigra pars compacta and the ventral tegmental area. The neurotensin fragment (8-13) induced comparable increases in firing rate of the substantia nigra and ventral tegmental area dopamine neurons (EC50 values 30 and 45 nM, respectively). The neurotensin receptor antagonist SR142948A antagonized the excitatory effects of neurotensin fragment (8-13) (pA2 values 8.4 and 8.2, respectively). Furthermore, it was found that a low concentration of neurotensin fragment (8-13) (1 nM) attenuated the inhibition of the firing rate by the selective dopamine D2 receptor agonist quinpirole in both neuron types (e.g., the effect of 0.01 microM quinpirole was reduced by approximately 60% in the presence of 1 nM neurotensin fragment [8-13]). Antagonism of this neurotensin fragment (8-13) effect by SR142948A confirms that neurotensin receptors can reduce the effect of dopamine D2 receptors at the single-cell level. These results are discussed in the light of possible roles for neurotensin in neurological disorders such as Parkinson's disease and schizophrenia.
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PMID:Neurotensin attenuates the quinpirole-induced inhibition of the firing rate of dopamine neurons in the rat substantia nigra pars compacta and the ventral tegmental area. 1065 21

Parkinson's disease is a neuropathological disorder involving the degeneration of dopamine neurons in the substantia nigra, with the resultant loss of their terminals in the striatum. This dopamine loss causes most of the motor disturbances associated with the disease. One animal model of Parkinson's disease involves destruction of the nigrostriatal pathway with a neurotoxin (6-hydroxydopamine) injected into this pathway. In unilaterally lesioned animals, injection of D-amphetamine causes rotation towards the lesioned side, while injection of apomorphine acting upon supersensitive postsynaptic dopamine receptors causes rotation away from the lesioned side. In this study, we tested the effects of acute and subchronic injection of a neurotensin analog (NT69L) on the rotational behavior induced by D-amphetamine (5 mg/kg) or apomorphine (600 microg/kg) in unilaterally 6-hydroxydopamine lesioned rats. Pretreatment of animals with intraperitoneal injections of NT69L (1 mg/kg) resulted in a significant reduction of apomorphine-induced contralateral rotation and D-amphetamine-induced ipsilateral rotation in these lesioned rats with an ED(50) of 40 and 80 microg/kg, respectively. After three daily injections of NT69L, its effects on this rotational behavior were unchanged, suggesting that no tolerance develops to this effect of NT69L.
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PMID:Antiparkinson-like effects of a novel neurotensin analog in unilaterally 6-hydroxydopamine lesioned rats. 1167 40

This review will be an update, focusing on the central nervous system (CNS) roles of the neurotransmitter, neurotensin. We will provide a summary of current knowledge about neurotensin, why it is an important peptide to study, and where the field is heading. Special emphasis is placed on the development of neurotensin analogs, which has been a major effort of our group, the potential role of neurotensin in Parkinson's disease, and the interaction of neurotensin with other neurotransmitters as evidenced by microdialysis studies.
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PMID:Neurotensin analogs indications for use as potential antipsychotic compounds. 1184 95

The tridecapeptide neurotensin has been demonstrated to increase glutamate release in discrete rat brain regions, leading to the hypothesis of a possible involvement of the peptide in neurodegenerative pathologies. The role of neurotensin in modulating glutamate excitotoxicity and the possible neuroprotective action of the neurotensin receptor antagonist SR48692 were investigated in primary cultures of mesencephalic neurons by measuring [(3)H]dopamine uptake and tyrosine hydroxylase immunocytochemistry 24 hr after glutamate treatment. The exposure to glutamate (30 and 100 microM, 10 min) decreased [(3)H]dopamine uptake into mesencephalic neurons. Neurotensin (10 and 100 nM), added before glutamate (30 microM) exposure, significantly enhanced the glutamate-induced reduction of [(3)H]dopamine uptake. In addition, the peptide (10 nM) also significantly enhanced the effect of 100 microM glutamate. The effects of neurotensin were counteracted by the neurotensin receptor antagonist SR48692 (100 nM) and by the protein kinase C inhibitor calphostin C. The exposure to 100 microM, but not 30 microM, glutamate significantly reduced the number of tyrosine hydroxylase-immunoreactive cells, and neurotensin (10 nM) significantly enhanced this effect. SR48692 (100 nM) prevented the neurotensin-induced action. These findings support the view of a possible pathophysiological role of neurotensin in mesencephalic dopamine neuronal function. Furthermore, selective neurotensin antagonists in combination with conventional drug treatments could provide a novel therapeutic approach for the treatment of neurodegenerative disorders, such as Parkinson's disease.
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PMID:Neurotensin enhances glutamate excitotoxicity in mesencephalic neurons in primary culture. 1244 98

Neurotensin (NT) is a neuropeptide found in the central nervous system and gastrointestinal tract. It is closely associated with dopaminergic and other neurotransmitter systems, and evidence supports a role for NT in various neuropsychiatric disorders. Because NT is readily degraded by peptidases, our group has developed various NT agonists that can be injected systemically, cross the blood brain barrier (BBB), yet retain the characteristics of native NT. The most widely studied and successful of these compounds, called NT69L, holds promise as a therapeutic agent for Parkinson's disease, schizophrenia, psychostimulant abuse and nicotine dependence, and serves as a tool to study the cellular and molecular effects of NT.
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PMID:Current topics: brain penetrating neurotensin analog. 1451 64


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