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 A(2A) receptors (A(2A)R) have received increasing attention for the treatment of L-DOPA-induced dyskinesias in Parkinson disease. In the present study, A(2A)R messenger RNA (mRNA) and receptor-specific binding in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys were studied after treatment with L-DOPA and a selective NR1A/2B NMDA receptor antagonist, CI-1041. Four MPTP monkeys received L-DOPA/benserazide and all developed dyskinesias, whereas among the four MPTP monkeys who additionally received CI-1041, only one developed mild dyskinesias. Four normal monkeys and four MPTP-treated monkeys were also studied. All MPTP monkeys had similar striatal dopamine (DA) denervation. A(2A)R mRNA levels, measured by in situ hybridization, were increased in the rostral lateral caudate and putamen of saline-treated MPTP monkeys as well as in the caudal lateral and medial putamen when compared with those of controls. A(2A)R mRNA levels remained elevated in the rostral caudate and putamen of L-DOPA-treated MPTP monkeys when compared with those of controls. A(2A)R mRNA levels of L-DOPA + CI-1041-treated monkeys were at control levels and decreased in the lateral rostral caudate and caudal putamen when compared with those of L-DOPA-treated and saline-treated MPTP monkeys respectively. No change was measured in the caudal medial putamen and caudate nucleus. A(2A)Rs labeled by autoradiography with [(3)H]SCH-58261 had lower level in the L-DOPA + CI-1041-treated MPTP monkeys compared with saline- or L-DOPA-treated MPTP and control monkeys in the rostral lateral and medial caudate and the putamen. No effect of lesion or L-DOPA treatment was measured on [(3)H]SCH-58261-specific binding. These findings suggest that blockade of NMDA receptors could prevent the development of dyskinesias by altering A(2A)Rs.
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PMID:Prevention of dyskinesia by an NMDA receptor antagonist in MPTP monkeys: effect on adenosine A2A receptors. 1673 15

Preclinical evidence strongly indicate that adenosine A(2A) receptor antagonists represent a promising class of drugs for the treatment of motor deficits associated to Parkinson's disease. The effects of adenosine A(2A) receptor antagonists were here assessed in a rat model of parkinsonian tremor induced by cholinomimetic drugs by evaluating the counteraction of tremulous jaw movements. Systemic administration of the A(2A) antagonist SCH 58261 dose-dependently reduced the magnitude of perioral tremor induced by the acetylcholinesterase inhibitor tacrine (2.5 mg/kg). Furthermore, intrastriatal infusion of SCH BT2 (5 microg/microl), a water-soluble analogue of SCH 58261, antagonized tacrine-induced jaw movements with a maximal effect in the ventrolateral striatum. On the other hand, SCH 58261 (5 mg/kg) was ineffective in blocking tremulous jaw movements stimulated by the direct muscarinic agonist pilocarpine (1 mg/kg). Taken together, these results indicate that A(2A) antagonists reduce parkinsonian tremor stimulated in rats by tacrine and that the striatum is deeply involved in the observed effect. Moreover, the ineffectiveness of SCH 58261 in blocking pilocarpine-stimulated perioral tremor suggests that the antitremorigenic effects of A(2A) antagonists described here are not related to a direct action on muscarinic receptor. The prospective of providing additional antitremor benefits considerably enhances the therapeutic potential of A(2A) antagonists.
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PMID:Dopamine and adenosine receptor interaction as basis for the treatment of Parkinson's disease. 1678 Aug 90

Serotonin 1A (5-HT1A) receptors are distributed throughout the brain with their highest concentrations in the frontal cortex, subthalamic nucleus and entopeduncular nucleus as well as the dorsal and median raphe nucleus. There is growing evidence that 5-HT1A receptor agonists have an antidepressant effect in individuals with major depressive disorders. Recent clinical studies suggest that tandospirone, a highly potent and selective 5-HT1A receptor agonist used clinically as an antidepressant in Japan and China, may act as an antiparkinsonian drug. In the present study, we investigated the effect of tandospirone on contralateral rotational behavior in a unilateral hemiparkinsonian rat model produced with 6-hydroxydopamine (6-OHDA). Tandospirone, as well as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), significantly increased contralateral turnings in a dose-dependent manner (0.5-10 mg/kg). Tandospirone also remarkably potentiated the contralateral turning induced by 0.025 mg/kg of apomorphine. Pretreatment with WAY-100635, a 5-HT1A receptor antagonist, almost completely blocked the contralateral turning behavior evoked by tandospirone and 8-OHDPAT, but not that by apomorphine. SCH-23390, a selective dopamine D1 receptor antagonist, did not affect on the tandospirone-induced rotational behavior. These results suggested that tandospirone could act on postsynaptic 5-HT1A receptors and modulate excitatory amino acid pathways in the basal ganglia. Thus, tandospirone could have therapeutic potential for the treatment of Parkinson's disease by modulating neuronal activities of non-dopaminergic pathways.
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PMID:Tandospirone, a 5-HT1A agonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine-generated lesions. 1688 2

The dopaminergic system plays a major role in neurological and psychiatric disorders such as Parkinson's disease, Huntington's disease, tardive dyskinea and schizophrenia. Knowledge on altered dopamine synthesis, receptor densities and status are important for understanding the mechanisms underlying the pathogenesis and therapy of diseases. PET provides a non-invasive tool to investigate these features in vivo, provided the availability of suitable radiopharmaceuticals. To investigate presynaptic function, PET-tracers have been developed to measure dopamine synthesis and transport. For the former the most commonly used tracers are 6-[(18)F]FDOPA and 6-[(18)F]FMT, whereas for the latter several (11)C/(18)F-labeled tropane analogues are being clinically used. Postsynaptically, dopamine exerts actions through several subtypes of the dopamine receptor. The dopamine receptor family consists of 5 subtypes D(1)-D(5). In order to investigate the role of each receptor subtype, selective and high-affinity PET-radioligands are required. For the dopamine D(1)-subtype the most commonly used ligand is [(11)C]SCH 23390 or [(11)C]NNC 112, whereas for the D(2)/D(3)-subtype [(11)C]raclopride is a common tracer. [(18)F]Fallypride is a suitable PET-tracer for the investigation of extrapyramidal D(2)-receptors. For the other subtypes no suitable radioligands have been developed yet. This paper gives an overview of the current status on dopamine PET-tracers and the development of new lead compounds as potential PET-tracers by medicinal chemistry.
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PMID:PET tracers for imaging of the dopaminergic system. 1691 44

In rats lesioned neonatally with 6-hydroxydopamine (6-OHDA), repeated treatment with SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol), a dopamine D(1)/D(5) receptor agonist, produces robust stereotyped and locomotor activities. The gradual induction of dopamine D(1) receptor supersensitivity is known as a priming phenomenon, and this process is thought to underlie not only the appearance of vacuous chewing movements in humans with tardive dyskinesia, but also the onset of motor dyskinesias in L-dihydroxyphenylalanine (L-DOPA)-treated Parkinson's disease patients. The object of the present study was to determine the possible influence of the histaminergic system on dopamine D(1) agonist-induced activities. We found that neither imetit (5.0 mg/kg i.p.), a histamine H(3) receptor agonist, nor thioperamide (5.0 mg/kg i.p.), a histamine H(3) receptor antagonist/inverse agonist, altered the numbers of vacuous chewing movements in non-primed-lesioned rats. However, in dopamine D(1) agonist-primed rats, thioperamide alone produced a vacuous chewing movements response (i.e., P < 0.05 vs SKF 38393, 1.0 mg/kg i.p.), but did not modify the SKF 38393 effect. Notably, both imetit and thioperamide-induced catalepsy in both non-primed and primed 6-OHDA-lesioned rats, comparable in magnitude to the effect of the dopamine D(1)/D(5) receptor antagonist SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.5 mg/kg i.p.). Furthermore, in primed animals both imetit and thioperamide intensified SCH 23390-evoked catalepsy. In vivo microdialysis established that neither imetit nor thioperamide altered extraneuronal levels of dopamine and its metabolites in the striatum of 6-OHDA-lesioned rats. On the basis of the present study, we believe that histaminergic systems may augment dyskinesias induced by dopamine receptor agonists, independent of direct actions on dopaminergic neurons.
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PMID:Histamine H3 receptor agonist- and antagonist-evoked vacuous chewing movements in 6-OHDA-lesioned rats occurs in an absence of change in microdialysate dopamine levels. 1705 81

Antagonism of the adenosine A2A receptor offers great promise in the treatment of Parkinson's disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.
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PMID:Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines. 1723 62

In this study, we examined the combination effects of L-DOPA and adenosine receptor antagonists on rotational behaviors in a hemi-Parkinsonian mouse model induced by unilateral 6-hydroxydopamine (6-OHDA) injection. The adenosine A(2A) antagonist SCH-58261, but not the A(1)-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine or A(2B)-receptor antagonist alloxazine, synergistically potentiated the L-DOPA-induced rotational behaviors in the 6-OHDA-lesioned mice. In addtion, the 6-OHDA-induced lesions of the dopaminergic system did not affect the in vivo binding of an adenosine A(2A)-receptor tracer [(11)C]SCH-442416 in the striatatum. These findings suggest that adenosine A(2A) antagonists are extremely useful for pharmacotherapy of L-DOPA in Parkinson's disease patients.
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PMID:Synergistic effects of adenosine A2A antagonist and L-DOPA on rotational behaviors in 6-hydroxydopamine-induced hemi-Parkinsonian mouse model. 1734 41

Evidence obtained in rodent and primate models of Parkinson's disease (PD) and preliminary clinical trials, indicates that adenosine A(2A) receptor antagonists might represent a promising nondopaminergic therapeutic tool for the treatment of PD. Those studies demonstrated the ability of adenosine A(2A) receptor antagonists to potentiate l-dopa-mediated motor improvement, whereas very little is known about counteraction of specific motor deficits and on the effects of these compounds when administered alone. To this aim we evaluated the effects of different adenosine A(2A) receptor antagonists on initiation of movement deficits, gait impairment and sensory-motor deficits, induced in rats by a unilateral 6-hydroxydopamine lesion of dopaminergic nigrostriatal neurons. The following tests were used: (1) initiation time of stepping; (2) adjusting step (stepping with forelimb was measured as the forelimb was dragged laterally); (3) vibrissae-elicited forelimb placing (as index of sensory-motor integration deficits). Acute administration of the A(2A) receptor antagonists SCH 58261 (5 mg/kg i.p.) and ST 1535 (20 mg/kg i.p.) similarly to l-dopa (6 mg/kg i.p.) counteracted the impairments in the initiation time of stepping test, in the adjusting step and in the vibrissae-elicited forelimb placing induced by the lesion. The intensity of the effect was l-dopa > SCH 58261 > ST 1535. The results provide the first evidence that blockade of A(2A) receptors is effective in antagonizing specific motor deficit induced by DA neuron degeneration, such as initiation of movement and sensory-motor integration deficits, even without l-dopa combined administration.
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PMID:Adenosine A2A receptor antagonists improve deficits in initiation of movement and sensory motor integration in the unilateral 6-hydroxydopamine rat model of Parkinson's disease. 1747 84

Glioma cell line C6, transfected with tyrosine hydroxylase (TH) cDNA under the control of the glial fibrillary acid protein promoter (C6-THA cells), elicited a reduction in the apomorphine-induced turning behavior when they are implanted in Parkinson's disease models. Nevertheless, dopamine (Da) release has not been explicitly demonstrated nor has a possible mechanism of release been implicated. In this study, the in vitro Da release by C6 and C6-THA cells after chemical stimulation with KCl or glutamate was quantified using HPLC. Modifications in intracellular calcium levels in response to KCl stimulation and participation of Da receptor-mediated feedback in calcium regulation were also studied using FLUO 3 as a calcium concentration indicator. C6-THA cells release dopamine in basal conditions, and increase its release after KCl or glutamic acid stimulation. In a fraction of C6 and C6-THA cells, a transient intracellular calcium increase was observed after KCl stimulation, but C6-THA cells demonstrated a faster rate of calcium removal. C6 cells express mRNA from all five subtypes of Da receptors as demonstrated by real time PCR. D1 receptors were most abundant in C6 cells and its expression was further increased in C6-THA cells. Blocking D1-like receptors in C6-THA cells with the specific antagonist drug SCH-23390 induced a decrease in intracellular calcium removal rate, resembling non-manipulated C6 cells' calcium clearance. Da release by C6-THA cells could be related to calcium dependent mechanisms. Furthermore, production of Da by C6-THA cells seems to upregulate the expression of D1 receptors' mRNA.
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PMID:Dopamine release modifies intracellular calcium levels in tyrosine hydroxylase-transfected C6 cells. 1768 96

Rats with unilateral lesion of the substantia nigra pars compacta (SNpc) have been used as a model of Parkinson's disease. Depending on the lesion protocol and on the drug challenge, these rats rotate in opposite directions. The aim of the present study was to propose a model to explain how critical factors determine the direction of these turns. Unilateral lesion of the SNpc was induced with 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Separate analysis showed that neither the type of neurotoxin nor the site of lesion along the nigrostriatal pathway was able to predict the direction of the turns these rats made after they were challenged with apomorphine. However, the combination of these two factors determined the magnitude of the lesion estimated by tyrosine-hydroxylase immunohistochemistry and HPLC-ED measurement of striatal dopamine. Very small lesions did not cause turns, medium-size lesions caused ipsiversive turns, and large lesions caused contraversive turns. Large-size SNpc lesions resulted in an increased binding of [(3)H]raclopride to D2 receptors, while medium-size lesions reduced the binding of [(3)H]SCH-23390 D1 receptors in the ipsilateral striatum. These results are coherent with the model proposing that after challenged with a dopamine receptor agonist, unilaterally SNpc-lesioned rats rotate toward the side with the weaker activation of dopamine receptors. This activation is weaker on the lesioned side in animals with small SNpc lesions due to the loss of dopamine, but stronger in animals with large lesions due to dopamine receptor supersensitivity.
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PMID:Hemiparkinsonian rats rotate toward the side with the weaker dopaminergic neurotransmission. 1832 80


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