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)

In contrast to antipsychosis drugs which inhibit the dopamine-activated adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] of caudate nucleus, dopaminergic drugs for treatment of Parkinson's disease stimulate this cyclase. Stimulants and inhibitors of cholinergic neurons inhibited this adenylate cyclase activity competitively and specifically. Thus, the mechanism by which dopaminergic medications ameliorate the effects of Parkinson's disease includes activation of the dopamine-sensitive adenylate cyclase. Excessive activation might be present during the psychotic episodes seen in patients with parkinsonism who are overtreated. The enzymatic effects of the drugs that affect cholinergic mechanisms seem to be generally in keeping with the pharmacological reciprocity between psychoses and extrapyramidal function, except for the anticholinergic ones which inhibited this cyclase although they can be hallucinogenic.
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PMID:Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase. 26 41

Dopamine (DA) sensitive adenylate cyclase activity was measured in homogenates of caudate nucleus and putamen from frozen brain of eight Parkinsonian patients and nine controls. In the control group, there was no difference in enzyme activity in respect to sex or age (21--77 years old). Caudate nucleus and putamen exhibited similar mean activity. In the Parkinsonian group, there was a significant decrease in both basal (by 50%) and DA stimulated (by 80%) activities compared with that of control group. This suggests that there may exist a functional disturbance in the postsynaptic (post-DA-nergic) region in the striatum of patients with Parkinson's disease; in addition, the decrease in basal as well as DA stimulated activity as measured in homogenates may not be the biochemical substrate for the hypothetical "denervation supersensitivity" expected to occur in Parkinson's disease.
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PMID:Dopamine-sensitive adenylate cyclase activity in the striatum in Parkinson's disease. 45 31

The morphochemical disposition of the adenylate cyclase-linked dopamine receptor (D1 type) in the rat striatum has been assessed at various time points after a neurotoxic lesion of the dopaminergic afferent pathway to the caudate nucleus. D1 receptor binding sites in the caudate nucleus were determined by in vitro autoradiography of the substituted benzazepine D1 antagonists, [3H]SCH 23390 or [125I]SCH 23982, and contrasted to the pattern of striatal immunohistochemical reactivity of the second messenger compound, cyclic 3',5'-adenosine monophosphate. The results demonstrate that the specific association of this dopamine receptor type with cyclic 3',5'-adenosine monophosphate-stained neurons is abolished at 7 days following chemical interruption of the nigrostriatal pathway, and the receptor disruption is persistent for durations as long as 20 weeks. This investigation suggests that once the postsynaptic receptor pathology is produced by deafferentation, it does not recover the selective morphochemical relationship normally established with the target cell containing the second messenger. This is in contrast to modest biochemical recuperation in D1 dopamine receptor binding seen using this experimental paradigm. This change in D1 dopamine receptor morphochemistry is discussed in relation to the neurochemical deficits produced by dopaminergic denervation and in Parkinson's disease.
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PMID:Long-term changes in striatal D1 dopamine receptor distribution after dopaminergic deafferentation. 253

Somatostatin (SRIF) actions in the brain and pituitary are mediated by specific receptors. Using radioiodinated ligands it has been possible to characterize the kinetics of specific binding sites in the brain and pituitary, and to determine their cellular localization by autoradiography. At the pituitary level, the inhibition of growth hormone, prolactin and thyrotropin secretions induced by SRIF is mediated through a single binding site which is coupled to the inhibition of adenylate cyclase. In the brain, SRIF receptors are localized on neurons and glial cells and are also coupled to adenylate cyclase inhibition. Two sites are differentiated in the brain with an analogue of somatostatin, SMS 201995. In humans, SRIF-binding sites have been related to a number of pathologies. At the pituitary level, it has been shown that the number of binding sites was negatively correlated to growth hormone levels in acromegaly. Furthermore, SRIF-binding sites were undetectable in a patient which did not respond to SMS 201995 therapy. In the brain, meningiomas and gliomas are rich in SRIF binding sites. This suggests a possible role for SRIF on glia. In neurodegenerative diseases, cortical SRIF concentrations are decreased in Alzheimer's and Parkinson's disease associated with dementia while SRIF-binding sites are only affected in Alzheimer's disease. In conclusion, the physiological role of SRIF in the brain and pituitary can be evaluated by studying the receptors of the peptide. Such studies allow to question the implication of SRIF in endocrine and neuropathologies.
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PMID:Somatostatin receptors in brain and pituitary. 256 73

The existence of subtypes of dopamine receptors as defined by Kebabian and Calne is now well accepted. The D1 receptor is typically associated with stimulation of adenylate cyclase, while the D2 receptor is either independent of adenylate cyclase or mediates its inhibition. Considerable interest has been generated by the potential physiological and clinical roles of these receptor subtypes. Availability of agonists and antagonists specifically acting at the D1 or D2 receptor site has stimulated research to characterize the functional effects of each receptor subtype. This might facilitate the development of effective compounds to control the signs and symptoms of Parkinson's disease and perhaps prevent the induction of debilitating side effects. Recent evidence indicates that D1 receptor stimulation is required to obtain full expression of the D2 receptor site, which has typically been associated with the clinical benefits of dopaminergic therapy. Both pre- and postsynaptic location of the receptors must also be taken into consideration as well as involvement of other neuronal systems. It appears that in PD, progressive involvement of the dopaminergic pathways is the principal pathological course, however, noradrenergic and serotonergic pathways are likewise involved. This multineuronal involvement suggests that drugs acting specifically at receptor sites, located on both pre- and postsynaptic neurons, might be required at different times during the course of the disease process to control its symptoms and/or the complications occurring after long-term treatment with a given drug.
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PMID:Clinical importance of D-1 and D-2 receptors. 296 Apr 28

The present review focuses on the hypothesized D1/D2 dopamine (DA) receptor classification, originally based on the form of receptor coupling to adenylate cyclase activity. The pharmacological effects of compounds exhibiting putative selective agonist or antagonist profiles at those DA receptors positively coupled to adenylate cyclase activity (D1 DA receptors) are extensively reviewed. Comparisons are made with the effects of putative selective D2 DA receptor agonists and antagonists, and on the basis of this work, the DA receptor classification is critically evaluated. A variety of biochemical, behavioral, and electrophysiological evidence is presented which supports the view that D1 and D2 DA receptors can interact in both an opposing and synergistic fashion. Particular attention is focused on the possibility that D1 receptor stimulation is required to enable the expression of certain D2 receptor-mediated effects, and the functional consequences of this form of interaction are considered. A hypothetical model is presented which considers how both the opposing and enabling forms of interaction between D1 and D2 DA receptors can control behavioral expression. Finally, the clinical relevance of this work is discussed and the potential use of selective D1 receptor agonists and antagonists in the treatment of psychotic states and Parkinson's disease is considered.
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PMID:D1 dopamine receptor--the search for a function: a critical evaluation of the D1/D2 dopamine receptor classification and its functional implications. 297 Dec 73

Antipsychotic drugs, while ameliorating symptoms in schizophrenia, evoke extrapyramidal effects which resemble parkinsonism. We studied the potential of 1- (4,4-bis(4-fluorophenyl)butyl)-4-(4-fluorophenoxy)-1,2,3,6-tetrahydropyr idine d-tartrate to induce extrapyramidal side effects in Rhesus monkeys. This agent shares neurochemical effects of known antipsychotic agents in its ability to antagonize cerebral dopamine action by competing for (3H)-Haloperidol binding of the dopamine receptors and inhibiting limbic and striatal adenylate cyclase in rat brain. The compound was administered orally to monkeys for 18 days, starting at 2 mg/kg and increasing to 20 mg/kg. Additional groups of monkeys received the drug for 29 consecutive days at 5 and 7.5 mg/kg/day. In both studies, extrapyramidal signs were associated with neuropathological changes in the brains of treated monkeys. The findings resemble those reported in Rhesus monkeys and in drug addicts after repeated intravenous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The findings also suggest a structure/activity relationship of tetrahydropyridine analogs with neurologic and associated neuropathologic manifestations produced in monkeys. The experimental model is useful to study the pathogenesis and possibly therapeutic approaches for Parkinson's disease.
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PMID:Parkinson-like syndrome in nonhuman primates receiving a tetrahydropyridine derivative. 348 56

Bromocriptine is an ergopeptine derivative and dopamine agonist that predominantly stimulates the striatal D2 non-adenyl cyclase-linked dopamine receptors. Bromocriptine, unlike other dopamine agonists, has mixed "agonist-antagonist" properties at these receptors. The striatal dopamine receptors exist in two different affinity states: a low and a high affinity state. Bromocriptine, unlike other dopamine agonists, does not differentiate between the low and the high affinity state of the D2 receptors, and bromocriptine does not induce a conformational change in these receptors. Bromocriptine, in low doses, is effective in patients with mild to moderate Parkinson's disease, while bromocriptine in higher doses is needed in patients with advanced disease. Both in low doses and in high doses, bromocriptine combined with levodopa is usually more effective than bromocriptine alone. The efficacy of low dose (5-30 mg/day) and high dose (31-100 mg/day) bromocriptine alone and with levodopa was examined in 27 studies encompassing 790 patients. Forty-six % of the studies were done in a double blind manner. In four studies of 79 patients, low dose bromocriptine (16 mg/day) without levodopa resulted in improvement in 58% of the patients. Only 9% of the patients experienced adverse effects. Most of the patients (63%) and mild or moderate Parkinson disease. In seven studies of 143 patients, high dose bromocriptine (56 mg/day) without levodopa resulted in improvement in 62% of patients, but with 27% having adverse effects. Most of these patients (77%) had mild or moderate disease. Diurnal oscillations in performance, the "wearing off" or "on-off" effect, were not seen during treatment with bromocriptine alone. In nine studies of 201 patients, low dose bromocriptine (23 mg/day) and levodopa resulted in improvement in 71% of patients with 26% having adverse effects. Most of these patients (66%) had advanced disease, and many had diurnal oscillations in performance. In seven studies of 367 patients, high dose bromocriptine (48 mg/day) and levodopa resulted in improvement in 58% with 37% having adverse effects. Most of these patients (85%) had advanced disease. The increased effectiveness of bromocriptine in combination with levodopa may be explained as follows. Bromocriptine by itself does not discriminate between the low and the high affinity states of the dopamine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Bromocriptine in Parkinson disease. 390 Oct 46

In order to elucidate the mechanism of interaction of a peptide L-prolyl leucyl-glycinamide (PLG) with dopamine receptors, we have studied the action of PLG on dopamine receptors in various brain regions. The results support the hypothesis that specific PLG binding sites exist in the central nervous system and these binding sites (receptors) have a modulatory effect on the sensitivity of dopamine receptors. It is also suggested that PLG and its active analogues warrant further vigorous and systematic clinical trials to establish their therapeutic efficacy in Parkinson's disease, neuroleptic drug induced tardive dyskinesia and related extrapyramidal motor disorders. Studies carried out on solubilized dopamine receptors and adenylate cyclase suggest that dopamine receptors sites coupled to neurolic drug action and adenylate cyclase linked receptor sites might be closely interrelated. The preliminary results on lymphocyte dopamine binding sites suggest an increase in binding in schizophrenic patients, however, receptor criteria (stereospecific binding, saturation, etc.) could not be met for these binding sites (see Rotstein et al., 1983, for details).
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PMID:CNS dopamine receptors: effect of prolyl-leucyl-glycinamide and solubilization. 615 23

This paper reviews and correlates three separate recent findings that implicate the one-carbon cycle in neuropsychiatric disease: (i) the demonstration by kinetic studies that the Vmax of methionine adenosine transferase (MAT) is reduced in some schizophrenics and depressives and is increased in some manics, and that the activity of serine hydroxymethyltransferase (SHMT) is reduced in a further subpopulation of schizophrenics; (ii) the demonstration that S-adenosylmethionine (the product of MAT) is an effective clinical antidepressant; and (iii) the reports that L-methionine is an effective treatment for certain of the symptoms of Parkinson's disease. These clinical findings may be correlated with recent findings that transmethylation reactions (lipid and carboxymethylation) play an important role in synaptic events (coupling of receptors to adenylate cyclase and release of neurotransmitters).
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PMID:The role of the one-carbon cycle in neuropsychiatric disease. 632 30


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