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

Adenosine acts as a neuromodulator through A1 and A2 receptors. The adenosine analogs have been recognized, among other effects, as strong depressors of the locomotor activity by acting on striatal A2 receptors. Moreover, the A2a receptor subtype is exclusively expressed in the striatum. To elucidate at the cellular level the roles of adenosine in the basal ganglia, the anatomical and functional relationships of the A2 receptors with the dopamine D1 and D2 receptors were studied in the rat striatum. In situ hybridization histochemistry was used either in combination with retrograde labeling of striatonigral neurons to determine the projection site of A2a receptor expressing neurons, or on consecutive thin sections to address the putative coexpression of the A2a receptor with the D1 or D2 receptors in individual neurons. The A2a receptor is mainly expressed by neurons projecting to the globus pallidus and expressing also the dopamine D2 receptor and enkephalin, but very sparsely by neurons projecting to the substantia nigra that express the dopamine D1 receptor and substance P. We have further examined the regulatory effect of the A2 receptors on striatal gene expression using in situ hybridization histochemistry and quantitative autoradiography. Rats unilaterally depleted in dopamine by an unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal pathway used as a model of Parkinson's disease subsequently received chronic injections of saline or the adenosine receptor antagonist caffeine. Intact rats were chronically treated with either saline, caffeine alone, caffeine with N-ethyl-carboxamidoadenosine (an equipotent A1 and A2 agonist), or caffeine with cyclohexyladenosine (a more selective A1 agonist).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. 768 65

Experimental and clinical studies indicate that both dopamine D2-like and D1-like receptors are important in reversing the motor symptoms of Parkinson's disease, and therefore stimulation of both D1 and D2 receptors may be advantageous in its treatment. At present, the role of other receptor subtypes, such as the D3 receptor, remains unknown, although in primates the D3 receptor might be of importance because it exists in significant amounts within the caudate-putamen. Both D1 and D2 agonists induce dyskinesias in drug-naive, MPTP-treated primates and provoke dyskinesias in levodopa-primed animals. D1 agonists in low doses, however, might have antiparkinsonian effects without inducing dyskinesias, and on repeated administration perhaps can diminish the intensity of dyskinesias in levodopa-primed, MPTP-treated primates. The production of dyskinesias in Parkinson's disease might reflect an imbalance in the D1-direct and D2-indirect GABAergic output pathways from the caudate-putamen, which colocalize tachykinins and enkephalins, respectively. Destruction of the nigrostriatal pathway decreases the mRNA for substance P but elevates the mRNA for enkephalin. Treatment with levodopa reverses the decrease in substance P mRNA but has either a partial or no effect on mRNA for enkephalin. This suggests that levodopa treatment leads to a new imbalance between output from the striatum through the direct and indirect pathways. In contrast, dopamine agonists appear less able than levodopa to manipulate basal ganglia outflow. This might reflect their decreased ability to reverse parkinsonian motor deficits or the greater ability of levodopa to provoke dyskinesias. Dopamine agonist drugs also might exert neuroprotective actions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The rationale for the use of dopamine agonists in Parkinson's disease. 771 95

Changes in substance P (SP) receptor concentration have been implicated in neuropsychiatric disorders, Parkinson's disease, arthritis, inflammatory bowel disease and asthma. Since, SP and peptide analogs are rapidly metabolized and do not penetrate into the CNS, they are not useful for PET. Recently, a non-peptide SP antagonist, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) was developed. As a prelude to PET studies, this compound was radiolabeled with 11C and biodistribution was determined in hamsters. CP-99,994 was radiolabeled by methylation of tert-Boc, desmethyl CP-99,994 with 11CH3I followed by deprotection and HPLC purification. The time required for the synthesis was 40 min from the end of bombardment. Radiochemical purity of the final product was > 95% and specific activity was routinely > 1000 mCi/mumol [EOS]. The biodistribution of 11C-CP-99,994 was determined in groups of six Syrian hamsters at 5 and 30 min after injection. The results of these studies demonstrated that significant concentrations (%ID/g +/- SEM) of CP-99,994 accumulate in most tissues of the hamster. The highest levels of drug were detected in the lung: 21.04 +/- 1.26 (5 min) and 13.49 +/- 1.71 (30 min). Brain accumulation was: 1.44 +/- 0.06 (5 min), 1.32 +/- 0.05 (30 min). These results indicate that 11C-CP-99,994 can be prepared in high purity and specific activity. This new radiopharmaceutical may be useful for studying both central and peripheral SP receptors by PET.
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PMID:Synthesis of a 11C-labeled NK1 receptor ligand for PET studies. 773 67

Of the five known dopamine receptors, D1A and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D1A receptors expressed by direct output neurons and D2 receptors expressed by indirect output neurons. To further examine the interaction of D1A and D2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D1A receptors (D1A-/-). D1A-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D1A receptor binding was absent in striatal sections from D1A-/- mice. Striatal neurons normally expressing functional D1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D2 receptors, are unaffected. These findings show that D1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway.
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PMID:Altered striatal function in a mutant mouse lacking D1A dopamine receptors. 780 78

The specific binding of [3H]neurotensin, [3H]substance P, [3H]D-Ala2-D-Leu5-enkephalin (delta receptors) and [3H]-Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (mu receptors) were studied in membrane preparations of caudate nucleus, putamen, globus pallidus and substantia nigra from patients with Parkinson's disease and from age-matched controls. The density of neurotensin receptors was decreased in globus pallidus (lateral and medial segments) in parkinsonian brain. Substance P receptors were reduced in the putamen (anterior and posterior) and in lateral globus pallidus in Parkinson's disease. There was a reduction in the density of opioid receptors in posterior putamen and in mu receptors in caudate nucleus and putamen (anterior and posterior). No differences in neuropeptide receptor binding were observed in substantia nigra from parkinsonian brains compared with control subjects. The reductions in neuropeptide receptor density were less marked than the decrease in caudate and putamen content of dopamine and its metabolites. This suggests that neuropeptide receptors are only partially localized to striatal dopamine terminals.
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PMID:Neurotensin, substance P, delta and mu opioid receptors are decreased in basal ganglia of Parkinson's disease patients. 796 97

Swollen, bulbous-shaped (dystrophic) neurites are a common pathologic feature of Alzheimer's disease (AD) and represent one of the most abundant neuritic abnormalities within the brains of patients with this disease. In the present study, we sought to determine whether the dystrophic neurites which are observed in association with senile plaques are unique to AD or whether they are characteristic of a more generalized process of neuritic and/or neuronal degeneration which can be observed in other neurodegenerative diseases. To accomplish this, we examined post-mortem brain material from patients with AD, Parkinson's disease (PD), Parkinson's disease with associated AD, Parkinson's disease with dementia yet without AD pathology, Huntington's disease (HD), Pick's disease and normal age-matched controls (NC). Using a battery of antibodies to amyloid beta-protein (A beta P), paired-helical filaments (PHF), tyrosine hydroxylase, substance P, neurotensin, and somatostatin we found that immunolabeled dystrophic neurites of the type characteristically observed in AD, were seen only in cases and in brain regions where A beta P deposition was present. More specifically, brain areas known to display severe afferent and/or local degenerative changes such as the caudate and putamen in all three PD groups, the caudate in the HD cases, and the temporal cortex in the HD and Pick's cases were conspicuously free of these swollen neurites unless A beta P deposition was also present.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alzheimer's disease-like dystrophic neurites characteristically associated with senile plaques are not found within other neurodegenerative diseases unless amyloid beta-protein deposition is present. 809 26

Marked specific and selective changes in the levels of some neuropeptides in age-related diseases, such as senile dementia of the Alzheimer (SDAT) or Lewy body (SDLT) types, Parkinson's disease, Huntington's disease and major depressive disorder, versus normal aging have been noted. However, the levels of most neuropeptides are normal. The only 2 peptides consistently altered in SDAT are somatostatin and corticotrophin-releasing hormone both of which are reduced. In Huntington's disease, the level of substance P in the basal ganglia is reduced suggesting a preferential vulnerability of spiny neurones in this disease. In Parkinson's disease, substance P is attenuated in the basal ganglia while somatostatin is reduced in the neocortex. These and other results suggest that substance P deficits are related to movement disorders while somatostatin deficits are related to cognitive impairment. SDLT is a type of dementia with features common to both SDAT and Parkinson's disease, although the changes in neuropeptides suggest that neurochemically the disease is more closely related to SDAT. In major depressive disorder, the level of corticotrophin-releasing hormone is reduced while there is a reciprocal increase in corticotrophin-releasing hormone receptors suggesting that the neurones remain functional. Potential clinical intervention has been limited by problems such as poor penetration of agents into the brain and the short half-lives of neuropeptide agonists and antagonists. However, some currently available agents may act, at least in part, through modulation of neuropeptide pathways, e.g. carbamazepine and alprazolam both modulate the corticotrophin-releasing hormone system in animals, and both have clinically proven antidepressant activity.
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PMID:Alterations in neuropeptides in aging and disease. Pathophysiology and potential for clinical intervention. 824 6

The striatal expression of substance P (SP) and methionin-enkephalin (met-enk) genes was studied post mortem by in situ hybridization in patients with Parkinson's disease and a group of control subjects. No significant difference in striatal expression of these two neuropeptide messenger RNAs (mRNAs) was found in the patients compared with control subjects. This contrasts with animal models of parkinsonism, where expression of SP mRNA is decreased and met-enk mRNA increased. Possible explanations include: (1) compensatory mechanisms, which may develop during the long term evolution of Parkinson's disease; (2) normalized expression of the two genes resulting from chronic L-DOPA therapy.
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PMID:Striatal expression of substance P and methionin-enkephalin in genes in patients with Parkinson's disease. 857 2

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

To clarify the mechanism of brain impairment in Machado-Joseph disease (MJD), we measured the cerebrospinal fluid (CSF) levels of substance P in 7 patients (mean age 45.7 +/- 12.09 years) with this disease. Four patients had type I and three had type II disease. Findings were compared with those obtained in 14 age-matched controls, 8 patients with Parkinson's disease, 7 patients with multiple system atrophy, and 6 patients with myopathy. The CSF level of substance P was significantly (p = 0.0000) lower in the patients with MJD, being 44.5% of the control value. However, the mean CSF levels of substance P in the patients with Parkinson's disease, multiple system atrophy, or myopathy did not differ significantly from that in the control subjects. The alteration in the CSF level of substance P may be related to the neurological impairment observed in MJD.
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PMID:Decreased cerebrospinal fluid levels of substance P in Machado-Joseph disease. 890 28


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