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)

We have studied dopamine D2 receptor binding by [11C]raclopride positron emission tomography in 14 patients with dopa-responsive dystonia (DRD). Data were compared with 16 levodopa-treated patients with Parkinson's disease (PD) and 26 healthy controls. The results revealed an elevated [11C]raclopride binding index in the putamen and caudate nucleus of DRD patients compared with controls as well as a significant elevation in the caudate nucleus compared with PD patients. The increase of [11C]raclopride binding may be interpreted either as reduced tracer displacement by endogenous dopamine, or as an alteration of the receptor features due to chronic dopamine deficiency. The difference in [11C]raclopride binding in DRD and PD patients in the caudate nucleus suggests that this structure may be of pathophysiological relevance in the presentation of the clinical features of both diseases.
 ...
PMID:D2 receptor binding in dopa-responsive dystonia. 981 31

The present review describes findings and clinical indications for the dopamine D2 receptor scintigraphy. Methods for the examination of D2 receptors are positron emission tomography (PET) using 11C- or 18F-labelled butyrophenones or benzamides or single photon emission tomography (SPECT) using 123l-iodobenzamide (IBZM) respectively. The most important indication in neurology is the differential diagnosis of Parkinsonism: patients with early Parkinson's disease show an increased D2 receptor binding (D2-RB) compared to control subjects. However, patients suffering from Steele-Richardson-Olszewski-Syndrome or Multiple System Atrophy show a decreased D2-RB and are generally non-responsive to treatment. Postsynaptic blockade of D2 receptors results in a drug induced Parkinsonian syndrome, which can be diagnosed by D2 scintigraphy. Further possible indications occur in psychiatry: the assessment of receptor occupancy is useful in schizophrenic patients treated with neuroleptics. Additionally, D2 receptor scintigraphy might help to clarify the differential diagnosis between neuroleptic malignant syndrome and lethal catatonia. The method might be useful for supervising neurobiochemical changes in drug dependency and during withdrawal. Assessment of dopamine D2 receptor binding can simplify the choice of therapy in depressive disorder: patients showing a low D2 binding are likely to improve following an antidepressive drug treatment whereas sleep deprivation is promising in patients with high D2 binding.
 ...
PMID:[Clinical impact of cerebral dopamine-D2 receptor scintigraphy]. 983 Jun 15

Dual probe microdialysis was employed in intact rat brain to investigate the effect of intrastriatal perfusion with selective dopamine D1 and D2 receptor agonists and with c-fos antisense oligonucleotide on (a) local GABA release in the striatum; (b) the internal segment of the globus pallidus and the substantia nigra pars reticulata, which is the output site of the strionigral GABA pathway; and (c) the external segment of the globus pallidus, which is the output site of the striopallidal GABA pathway. The data provide functional in vivo evidence for a selective dopamine D1 receptor-mediated activation of the direct strionigral GABA pathway and a selective dopamine D2 receptor inhibition of the indirect striopallidal GABA pathway and provides a neuronal substrate for parallel processing in the basal ganglia regulation of motor function. Taken together, these findings offer new therapeutic strategies for the treatment of dopamine-linked disorders such as Parkinson's disease, Huntington's disease, and schizophrenia.
 ...
PMID:Functional neuroanatomy of the basal ganglia as studied by dual-probe microdialysis. 986 60

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.
 ...
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

The role of dopamine in the subthalamic nucleus to control motor behaviour was investigated in rats using bilateral microinfusions of the dopamine D1 receptor antagonist SCH23390 and the dopamine D2 receptor antagonist S(-)-sulpiride. Selective blockade of subthalamic D1 receptors, but not of D2 receptors, produced catalepsy. These findings suggest that dopamine D1 receptors within the subthalamic nucleus play a prominent role in the regulation of motor functions. Furthermore, the data point to the possibility that a reduced dopaminergic tone at subthalamic dopamine D1 receptors might contribute to akinesia in Parkinson's disease.
 ...
PMID:Blockade of subthalamic dopamine D1 receptors elicits akinesia in rats. 992 57

Various parameters are currently used for the semi-quantitative assessment of dopamine D2 receptors and differ according to the delineation of the striatal region of interest (ROI) and the choice of the reference ROI. The aim of this study was to assess the value of different ROI approaches in differentiating patients with normal or increased numbers of D2 dopamine receptors (group 1 = Parkinson's disease, n = 8) from patients with decreased dopamine D2 receptors (group 2 = other extrapyramidal syndromes, n = 9) using 123I-iodolisuride SPET (ILIS-SPET). 123I-iodolisuride (190 +/- 31 MBq) and 99Tcm-ethyl cysteinate dimer (99Tcm-ECD) perfusion SPET were performed in the same position, with a dual-headed gamera camera equipped with fan beam collimators. Both a geometric approach (ellipse, circle or rectangle) and an anatomical approach using the CT scan and perfusion SPET as anatomical guides were used to draw striatal and reference ROIs. A total of 33 different parameters were calculated for each patient, indicating the ratio of counts between the striatal and reference ROIs (frontal, occipital cortex or cerebellum) and the asymmetry between the right and left striatum. More significant differences between group 1 and group 2 were found by using geometric ROIs than by using anatomical ROIs. The most discriminant ratios were the caudate/occipital, caudate/frontal and striatum/occipital ratios (P = 0.001, P = 0.002, P = 0.003 respectively). A close correlation was found between the striatum/caudate and striatum/occipital ratios, but not between the striatum/frontal and striatum/occipital ratios or between the striatum/frontal and striatum/caudate ratios. We conclude that the occipital cortex is the best reference for the semi-quantitative evaluation of dopamine D2 receptors as the frontal cortex could include some dopamine D2 receptor-bound radioligand, and that the caudate/occipital ratio is an appropriate parameter for differentiating Parkinson's disease from non-Parkinson extrapyramidal syndrome by 123I-iodolisuride SPET.
 ...
PMID:Effects of the method of drawing regions of interest on the differential diagnosis of extrapyramidal syndromes using 123I-iodolisuride SPET. 994 16

Abnormal involuntary movements, or dyskinesias, plague current symptomatic approaches to the treatment of Parkinson's disease. The neural mechanisms underlying the generation of dyskinesia following repeated l-3,4-dihydroxyphenylalanine (L-DOPA) or dopamine agonist administration in Parkinson's disease remain unknown. However, de novo administration of bromocriptine or lisuride to either l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates or patients can alleviate parkinsonian symptoms without the development of dyskinesia. In this study, we have investigated behavioral responses and alterations in the expression of opioid neuropeptide precursors preproenkephalin-A (PPE-A, encoding methionine- and leucine-enkephalin) and preproenkephalin-B (PPE-B), the precursor encoding dynorphins (dynorphin A1-17 and B1-13, leucine-enkephalin, and alpha-neoendorphin) in striatal output pathways of the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. Expression was assessed following repeated L-DOPA, bromocriptine, or lisuride administration. Given the functional organization of basal ganglia circuitry into anatomically discrete parallel circuits, we investigated alterations in peptide expression with reference to the detailed topography of the striatum. Following repeated L-DOPA administration (6.5 mg/kg, b.d., 21 days) in the 6-OHDA-lesioned rat a rotational response was observed. This became markedly enhanced with repeated treatment. We have previously characterized the pharmacology of this enhanced response and have suggested that it is a useful model for the elucidation of the cellular and molecular mechanisms underlying L-DOPA- and dopamine agonist-induced dyskinesia. In contrast to l-DOPA, de novo administration of bromocriptine (1 or 5 mg/kg, b.d., 21 days) or lisuride (0.01 or 0.1 mg/kg, b.d., 21 days) did not lead to an enhanced behavioral response. In vehicle-treated, 6-OHDA-lesioned animals, PPE-A expression was elevated rostrally and dorsally, while PPE-B expression was reduced in the striatum at all rostrocaudal levels. Repeated l-DOPA administration was accompanied by elevations in striatal PPE-B mRNA levels and a further elevation, above lesion-induced levels, in PPE-A expression. This further elevation was restricted to the dorsolateral striatum. However, following repeated bromocriptine or lisuride administration no increase in PPE-B expression was observed and the lesion-induced increase in PPE-A expression was normalized to prelesion levels. Increased PPE-A and PPE-B levels may, through decreasing GABA and glutamate release, respectively, in output nuclei of the basal ganglia, play a role in the development of L-DOPA- and dopamine-agonist induced dyskinesia in Parkinson's disease. These studies suggest that anti-parkinsonian treatments which are not associated with an elevation in PPE-B and/or normalize elevated PPE-A precursor expression, such as NMDA-receptor antagonists or long-acting dopamine D2 receptor agonists, e.g., cabergoline or ropinirole, may reduce dyskinesia in Parkinson's disease.
 ...
PMID:Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat. 1007 96

In the present study, L-prolyl-L-leucyl-glycinamide (1) peptidomimetics 3a-3d and 4a-4d were synthesized utilizing alpha, alpha-disubstituted amino acids. These analogues were designed to explore the conformational effects of constraints at the phi3 and psi3 torsion angles. Constrained conformations were verified by the use of X-ray crystallography and circular dichroism. The effects of Pro-Leu-Gly-NH2 analogues 3a-3d and 4a-4d on enhancing rotational behavior induced by apomorphine in the 6-hydroxydopamine-lesioned animal models of Parkinson's disease were studied. The ability of these peptidomimetics to increase the binding of agonist N-propylnorapomorphine (NPA) to the dopamine D2 receptor was also examined. Extended analogue Pro-Leu-Deg-NH2 was the most active compound of this series. It was 10 times more potent and almost 2 times more effective than 1 in increasing apomorphine-induced rotations (56 +/- 15% at 1.0 mg/kg ip) and in enhancing [3H]NPA specific binding (40%).
 ...
PMID:Synthesis and dopamine receptor modulating activity of novel peptidomimetics of L-prolyl-L-leucyl-glycinamide featuring alpha,alpha-disubstituted amino acids. 1021 30

This paper reviews what is currently known about the redox state of the glutamate synapse and its possible role in modulating synaptic plasticity and thus learning and neurocomputation. The hypothesis is presented that the growth or pruning of the synaptic spine is controlled in part by the balance in the synapse between neurodestructive pro-oxidants (e.g., nitric acid radical and hydrogen peroxide) and neuroprotective antioxidants (e.g., ascorbate and carnosine). In addition, there may be a role for catecholamines, in particular dopamine, related to its role in reinforcement signalling. Activation of the dopamine D2 receptor induces the synthesis of an antioxidant enzyme, possibly catalase. Dopamine may also affect the redox balance in the glutamate synapse directly by diffusion from the adjacent dopaminergic bouton-en-passage. Catecholamines are powerful antioxidants, scavengers of free radicals and iron chelators. Catecholamine-iron complexes are potent dismuters of superoxide ions. Additional agents participating in spine pruning may be neurotoxic catecholamine o-quinones present in the brain. This system may be at fault in schizophrenia and Parkinson's disease. Experiments to test the hypothesis are suggested.
 ...
PMID:Redox mechanisms at the glutamate synapse and their significance: a review. 1032 73

We have previously shown that chronic treatment with the angiotensin-converting enzyme inhibitor perindopril increased striatal dopamine levels by 2.5-fold in normal Sprague-Dawley rats, possibly via modulation of the striatal opioid or tachykinin levels. In the present study, we investigated if this effect of perindopril persists in an animal model of Parkinson's disease, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse. C57BL/6 mice were treated with the neurotoxin (30 mg/kg/day intraperitoneally) for 4 days and then left for 3 weeks to allow the degeneration of striatal dopaminergic terminals. At this time, the mice exhibited a 40% decrease in striatal dopamine content and an accompanying 46% increase in dopamine D2 receptor levels compared with control untreated mice. The dopamine content returned to control levels, and the increase in dopamine D2 receptor levels was attenuated in mice treated with perindopril (5 mg/kg/day orally for 7 days) 2 weeks after the last dose of MPTP. When the angiotensin-converting enzyme inhibitor was administered (5 mg/kg/day for 7 days) immediately after the cessation of the MPTP treatment, there was no reversal of the effect of the neurotoxin in decreasing striatal dopamine content. Our results demonstrate that perindopril is an effective agent in increasing striatal dopamine content in an animal model of Parkinson's disease.
 ...
PMID:Effect of chronic angiotensin-converting enzyme inhibition on striatal dopamine content in the MPTP-treated mouse. 1038 73


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>