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)

A subacute treatment, 500 mg/kg I.P. twice daily during 5 days, by L-methionine provoked an increase in the Bmax of [3H]-spiperone binding in the striatum of the rat. This increase was associated to a decrease in membrane microviscosity. However in these conditions no changes were found in the [3H]-DHA, [3H]QNB bindings or in the brain dopamine sensitive adenylate cyclase activity. L-methionine treatment reduced the accumulation of Dopa after NSD 1015 and antagonized the decrease in striatal acetylcholine provoked by haloperidol. Thus L-methionine might be a new potential drug for Parkinson's disease treatment.
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PMID:A subacute treatment of L-methionine induces an increase in the number of [3H]spiperone binding sites in the striatum of the rat. 684 97

Receptor binding studies with a variety of dopaminergic ligands have confirmed behavioral and biochemical findings that the central nervous system and peripheral nervous system contain several dopamine receptor subtypes. These subtypes can be discriminated on the basis of their agonist-antagonist pharmacological specificities, linkage to adenylate cyclase, cellular location, regulation by guanine neucleotides and ions, and involvement in several human diseases. Although questions remain unanswered, progress is rapidly being made in equating the subgroupings arrived at by these different experimental approaches. Dopamine receptors are regulated by a number of factors. Acutely, guanine nucleotides and some ions regulate agonist but not antagonist binding and are essential for receptor coupling with adenylate cyclase. Chronically, changes in the level of dopaminergic stimulation modulate the number of at least some receptor subtypes, resulting in "up or down regulation." An increase in receptor number appears central to the pathology of Parkinson's disease, tardive dyskinesia, and perhaps schizophrenia. Animal models indicate that it may be possible to exploit inherent capabilities for receptor modulation in clinical therapy. The therapeutic precedents set by the indentification of distinct subtypes of adrenoreceptors. histamine, and cholinergic receptors portends and exciting future for dopamine receptor research.
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PMID:Dopamine receptors: subtypes, localization and regulation. 700 83

Significant reduction in brain weight and in the number of cortical neurons with increase of astroglia in aging brain and SDAT are associated with decreased synthesis and turnover of some neurotransmitters, particularly affecting the DAergic system. Progressive loss of TH activity reaching in SDAT almost the low levels of Parkinson disease is associated with progressive decline in DA concentration in the nigro-striatal system. Increase in MAO-B activity and in the ratio of MAO-B: MAO-A reported by some authors in aging brain and SDAT, however, was not confirmed in human frontal cortex in both Parkinson disease and SDAT. However, the location of both types of MAO in human brain is debatable, since preliminary studies indicate that, unlike in rat brain, MAO-B appears to be the major degradating enzyme of biogenic amines in human brain, while MAO-A might be associated, at least in part, with neuronal structures. Reduction in DAergic parameters in aging brain are also reflected in a decrease of adenylate cyclase activity and of D2 DA receptors. Animal data on decrease of DA-receptor density in the striatum with age were confirmed in human Parkinson disease and Alzheimer disease. These disturbances in neuronal feedback systems may be responsible for pathophysiological and behavioral changes in old age.
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PMID:Morphological and biochemical changes in the aging brain: pathophysiological and possible therapeutic consequences. 715 7

Rats were given powdered diet containing L-DOPA (together with the peripheral decarboxylase inhibitor carbidopa) for a period of 6 months. The estimated daily intake was in the range 20-30 mg/kg. Initially, at 1 week and 1 month, L-DOPA-fed rats exhibited enhanced spontaneous locomotor activity, but this fell to within the control range by 3 and 6 months, although (+)-amphetamine-induced hyperactivity was greater at 6 months in L-DOPA-treated animals than in control rats. Six months after receiving L-DOPA in their diet rats showed enhanced stereotypy scores to a series of dopamine agonists administered acutely including (+)-amphetamine, nomifensine, L-DOPA, apomorphine and piribedil compared with the control animals. In another behaviour test L-DOPA administration reduced the cataleptic potency of both fluphenazine and haloperidol was increased. Biochemically 6 months treatment of rats with L-DOPA was associated with significantly increased plasma concentrations of L-DOPA, enhanced striatal levels of L-DOPA, dopamine and dopamine metabolites, enhanced specific binding (as indicated by increased Bmax values) of [3H] spiroperidol, [3H] ADTN and [3H] 5-HT to striatal membranes, and increased basal and dopamine-stimulated striatal adenylate cyclase activity. The results are discussed in the light of changes of sensitivity of cerebral dopamine receptors, an increase in receptor numbers, and the tolerance to L-DOPA which often develop in the treatment of Parkinson's disease.
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PMID:Behavioural and biochemical changes following chronic administration of L-dopa to rats. 720

Muscarinic receptors regulate a number of important basic physiologic functions including heart rate and motor and sensory control as well as more complex behaviors including arousal, memory, and learning. Loss of muscarinic receptor number or function has been implicated in the etiology of several neurological disorders including Alzheimer's dementia, Down's syndrome, and Parkinson's disease. Muscarinic receptors transduce their signals by coupling with G-proteins, which then modulate the activity of a number of effector enzymes and ion channels. Five subtypes of muscarinic receptors (m1-m5) have been identified by molecular cloning and much has been learned about their distribution, pharmacology, and structure. Less is known about the molecular mechanisms of receptor-effector coupling and the biological role of each receptor subtype. The ectopic expression of genes encoding a single muscarinic receptor subtype in mammalian cell lines has provided an important model system in which to investigate receptor subtype-specific pharmacology and signal transduction. Expression models have revealed that single muscarinic receptor m1, m3, or m5 subtypes can activate multiple signaling effectors simultaneously including phospholipases A2, C, and D, as well as tyrosine kinase and a novel class of voltage-insensitive calcium channels. The m2 or m4 receptors have been shown to augment phospholipase A2 in addition to their established role as inhibitory receptors acting through the attenuation of adenylate cyclase. In addition to allowing investigations of the regulatory mechanisms of muscarinic receptors, expression models provide an excellent tool to investigate receptor-subtype specific physiology and pharmacology.
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PMID:Muscarinic acetylcholine receptors: signal transduction through multiple effectors. 776 53

The effects of co-administration of quinpirole with benzazepine D1 dopamine (DA) agonists possessing full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393 and SKF 75670) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) were investigated in rodent and primate models of Parkinson's disease (PD). In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle, co-administration of SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) strongly potentiated the contralateral circling induced by quinpirole. In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of quinpirole alone increased locomotor activity and reversed motor deficits. Grooming and oral activity were unaltered. Co-administration of SKF 38393 and SKF 75670 inhibited the quinpirole-induced changes in locomotor activity and motor disability. The combined treatment of SKF 80723 or SKF 82958 with quinpirole had no overall effect on locomotor activity or motor disability. In contrast, SKF 83959 extended the duration of the quinpirole-induced increase in locomotor activity with corresponding decreases in motor disability. Co-administration of high doses of SKF 82958 and more especially SKF 83959 and SKF 80723, with quinpirole induced hyperexcitability and seizures. Oral activity and grooming were unaltered following the co-administration of benzazepine derivatives with quinpirole. The ability of some benzazepine D1 DA agonists to prolong the antiparkinsonian effects of quinpirole in the MPTP-treated marmoset may indicate a role for certain D1 DA agonists in the clinical treatment of PD. In general, the behavioural responses to the combined administration of benzazepines with quinpirole in the 6-OHDA lesioned rat and more especially the MPTP-treated marmoset failed to correlate with their ability to stimulate AC. These observations further implicate a behavioural role for D1 DA receptors not linked to AC.
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PMID:The differential behavioural effects of benzazepine D1 dopamine agonists with varying efficacies, co-administered with quinpirole in primate and rodent models of Parkinson's disease. 777 Jun 4

The aim of this study was to achieve a better understanding of the integration in striatal medium-sized spiny neurons (MSNs) of converging signals from glutamatergic and dopaminergic afferents. The review of the literature in the first section shows that these two types of afferents not only contact the same striatal cell type, but that individual MSNs receive both a corticostriatal and a dopaminergic terminal. The most common sites of convergence are dendritic shafts and spines of MSNs with a distance between the terminals of less than 1-2 microns. The second section focuses on synaptic transmission and second messenger activation. Glutamate, the candidate transmitter of corticostriatal terminals, via different types of glutamate receptors can evoke an increase in intracellular free calcium concentrations. The net effect of dopamine in the striatum is a stimulation of adenylate cyclase activity leading to an increase in cAMP. The subsequent sections present information on calcium- and cAMP-sensitive biochemical pathways and review the regional and subcellular distribution of the components in the striatum. The specific biochemical reaction steps were formalized as simplified equilibrium equations. Parameter values of the model were chosen from published experimental data. Major results of this analysis are: at intracellular free calcium concentrations below 1 microM the stimulation of adenylate cyclase by calcium and dopamine is at least additive in the steady state. Free calcium concentrations exceeding 1 microM inhibit adenylate cyclase, which is not overcome by dopaminergic stimulation. The kinases and phosphatases studied can be divided in those that are almost exclusively calcium-sensitive (PP2B and CaMPK), and others that are modulated by both calcium and dopamine (PKA and PP1). Maximal threonine-phosphorylation of the phosphoprotein DARPP requires optimal concentrations of calcium (about 0.3 microM) and dopamine (above 5 microM). It seems favourable if the glutamate signal precedes phasic dopamine release by approximately 100 msec. The phosphorylation of MAP2 is under essentially calcium-dependent control of at least five kinases and phosphatases, which differentially affect its heterogeneous phosphorylation sites. Therefore, MAP2 could respond specifically to the spatio-temporal characteristics of different intracellular calcium fluxes. The quantitative description of the calcium- and dopamine-dependent regulation of DARPP and MAP2 provides insights into the crosstalk between glutamatergic and dopaminergic signals in striatal MSNs. Such insights constitute an important step towards a better understanding of the links between biochemical pathways, physiological processes, and behavioural consequences connected with striatal function. The relevance to long-term potentiation, reinforcement learning, and Parkinson's disease is discussed.
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PMID:Postsynaptic integration of glutamatergic and dopaminergic signals in the striatum. 783 76

Corticotropin-releasing factor (CRF) plays a major role in coordinating the endocrine, autonomic, behavioral and immune responses to stress through actions in the brain and the periphery. CRF receptors identified in brain, pituitary and spleen have comparable kinetic and pharmacological characteristics, guanine nucleotide sensitivity and adenylate cyclase-stimulating activity. Differences were observed in the molecular mass of the CRF receptor complex between the brain (58,000 Da) and the pituitary and spleen (75,000 Da), which appeared to be due to differential glycosylation of the receptor proteins. The recently cloned CRF receptor in the pituitary and the brain (designated as CRF1) encodes a 415 amino acid protein comprising seven putative membrane-spanning domains and is structurally related to the calcitonin/vasoactive intestinal peptide/growth hormone-releasing hormone subfamily of G-protein-coupled receptors. A second member of the CRF receptor family encoding a 411 amino acid rat brain protein with approximately 70% homology to CRF1 has recently been identified (designated as CRF2); there exists an additional splice variant of the CRF2 receptor with a different N-terminal domain encoding a protein of 431 amino acids. In autoradiographic studies, CRF receptors were localized in highest densities in the anterior and intermediate lobes of the pituitary gland, olfactory bulb, cerebral cortex, amygdala, cerebellum and the macrophage-enriched zones and red pulp regions of the spleen. CRF can modulate the number of CRF receptors in a reciprocal manner. For example, stress and adrenalectomy increase hypothalamic CRF secretion which, in turn, down-regulates CRF receptors in the anterior pituitary. CRF receptors in the brain and pituitary are also altered as a consequence of the development and aging processes. In addition to a physiological role for CRF in integrating the responses of the brain, endocrine and immune systems to physiological, psychological and immunological stimuli, recent clinical data implicate CRF in the etiology and pathophysiology of various endocrine, psychiatric, neurologic and inflammatory illnesses. Hypersecretion of CRF in the brain may contribute to the symptomatology seen in neuropsychiatric disorders, such as depression, anxiety-related disorders and anorexia nervosa. Furthermore, overproduction of CRF at peripheral inflammatory sites, such as synovial joints may contribute to autoimmune diseases such as rheumatoid arthritis. In contrast, deficits in brain CRF are apparent in neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, as they relate to dysfunction of CRF neurons in the brain areas affected in the particular disorder. Strategies directed at developing CRF-related agents may hold promise for novel therapies for the treatment of these various disorders.
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PMID:Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. 883 89

So far, no clear correlation has been found between the effects of dopamine D1 receptor agonists on motor behavior in primate models of Parkinson's disease and their ability to stimulate adenylate cyclase in rats, the benzazepine SKF 83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H- 3-benzazepine) being the most striking example. Since this discrepancy might be attributed to: (A) the different species used to study these effects or (B) the interaction of SKF 83959 with other catecholamine receptors, the aims of this study were: (1) to study the ability of SKF 83959 to stimulate adenylate cyclase in cultured human and monkey glial cells equipped with dopamine D1 receptors and (2) to evaluate the affinity for and the functional interaction of SKF 83959 with other catecholamine receptors. Binding studies revealed that SKF 83959 displayed the highest affinity for the dopamine D1 receptor (pKi=6.72) and the alpha2-adrenoceptor (pKi=6.41) and moderate affinity for the dopamine D2 receptor and the noradrenaline transporter. In monkey and human cells, SKF 83959 did not stimulate cyclic adenosine monophosphate (cAMP) formation to a significant extent, but antagonized very potently the dopamine-induced stimulation of cAMP formation in both cell types. The compound stimulated basal dopamine outflow and inhibited depolarization-induced acetylcholine release only at concentrations > 10 microM. Finally, SKF 83959 concentration dependently increased electrically evoked noradrenaline release, indicating that it had alpha2-adrenoceptor blocking activity and interfered with the noradrenaline transporter. In conclusion, SKF 83959 is a potent dopamine D1 receptor and alpha2-adrenoceptor antagonist. Thus, the anti-parkinsonian effects of SKF 83959 in primates are not mediated by striatal dopamine D1 receptors coupled to adenylate cyclase in a stimulatory way.
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PMID:The alleged dopamine D1 receptor agonist SKF 83959 is a dopamine D1 receptor antagonist in primate cells and interacts with other receptors. 992 Jan 82

Recent advances in molecular biology, biochemistry, cell biology and behavioral pharmacology together with the development of more selective ligands to the various adenosine receptors have increased our understanding of the functioning of central adenosine A(2A) receptors. The A(2A) receptor is one of four adenosine receptors found in the brain. Its expression is highest in striatum, nucleus accumbens and olfactory tubercles, although it also occurs in neurons and microglia in most other brain regions. The receptor has seven transmembrane domains and couples via Gs to adenyl cyclase stimulation. Antagonistic interactions between A(2A) receptors and dopamine D(2) receptors have been described, as stimulation of the A(2A) receptor leads to a reduction in the affinity of D(2) receptors for D(2) receptor agonists. The A(2A) receptor is thought to play a role in a number of physiological responses and pathological conditions. Indeed, A(2A) receptor antagonists may be useful for the treatment of acute and chronic neurodegenerative disorders such as cerebral ischemia or Parkinson's disease. A(2A) receptor agonists may treat certain types of seizures or sleep disorders. This review discusses the characteristics, distribution, pharmacochemical properties and regulation of central A(2A) receptors, as well as A(2A) receptor-mediated behavioural responses and their potential role in various neuropsychiatric disorders.
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PMID:Central adenosine A(2A) receptors: an overview. 1061 96


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