Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In patients with Parkinson's disease, the therapeutic efficacy of L-DOPA medication is gradually lost over time, and abnormal involuntary movements, dyskinesias, gradually emerge as a prominent side-effect in response to previously beneficial doses of the drug. Here we show that dyskinesia induced by chronic L-DOPA treatment in rats with 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway is critically dependent on the integrity and function of the serotonergic system. Removal of the serotonin afferents, or dampening of serotonin neuron activity by 5-HT1A and 5-HT1B agonist drugs, resulted in a near-complete block of the L-DOPA-induced dyskinesias, suggesting that dysregulated dopamine release from serotonin terminals is the prime trigger of dyskinesia in the rat Parkinson's disease model. In animals with complete dopamine lesions, the spared serotonin innervation was unable to sustain the therapeutic effect of L-DOPA, suggesting that dopamine released as a 'false transmitter' from serotonin terminals is detrimental rather than beneficial. The potent synergistic effect of low doses of 5-HT1A and 5-HT1B agonists to suppress dyskinesia, without affecting the anti-parkinsonian effect of L-DOPA in presence of spared dopamine terminals, suggests an early use of these drugs to counteract the development of dyskinesia in Parkinson's disease patients.
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PMID:Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. 1745 72

The basal ganglia (BG) play a critical role in the pathogenesis and pathophysiology of Parkinson's disease (PD). Recent studies indicate that serotoninergic systems modulate BG activity and may be implicated in the pathophysiology and treatment of PD. The globus pallidus (GP), the rodent homologue of the primate GPe, is the main central nucleus of the basal ganglia, affecting the striatum, the subthalamic nucleus (STN), and BG output structures. We therefore studied the effect of serotonin (5-HT) and specific 5-HT agonists and antagonists on GP neurons from rat brain slices. Using intra- and extracellular recordings of GP neurons we found that serotonin increases the firing rate of GP neurons. Analyzing the effects of specific 5-HT agonists and antagonists on the firing rate of GP neurons showed that the increase in firing rate is due to the activation of 5-HT1B and 5-HT1A receptors. Intracellular recordings in both voltage- and current-clamp modes revealed that serotonin mediates its effect via pre- and postsynaptic mechanisms. The presynaptic effect is mediated by attenuation of gamma-aminobutyric acid release, probably through activation of 5-HT1B receptors. Postsynaptically, serotonin activates a hyperpolarization-activated cation channel, probably via 5-HT1A receptors. Furthermore, serotonin decreases the fast synaptic depression characteristic of the striatal afferent input. The decreased serotonin concentrations in the BG nuclei in PD may contribute to depressed GP activity and enhance the emergence of BG pathological synchronous oscillations. We therefore suggest that future therapeutics of PD should be directed toward restoration of normal serotonin levels in BG nuclei.
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PMID:Pre- and postsynaptic serotoninergic excitation of globus pallidus neurons. 1855 Jul 26

Rotigotine (Neupro) is a non-ergoline dopamine agonist developed for the once daily treatment of Parkinson's disease (PD) using a transdermal delivery system (patch) which provides patients with the drug continuously over 24 h. To fully understand the pharmacological actions of rotigotine, the present study determined its extended receptor profile. In standard binding assays, rotigotine demonstrated the highest affinity for dopamine receptors, particularly the dopamine D3 receptor (Ki=0.71 nM) with its affinities to other dopamine receptors being (Ki in nM): D4.2 (3.9), D4.7 (5.9), D5 (5.4), D2 (13.5), D4.4 (15), and D1 (83). Significant affinities were also demonstrated at alpha-adrenergic (alpha2B, Ki=27 nM) and serotonin receptors (5-HT1A Ki=30 nM). In newly developed reporter-gene assays for determination of functional activity, rotigotine behaved as a full agonist at dopamine receptors (rank order: D3>D2L>D1=D5>D4.4) with potencies 2,600 and 53 times higher than dopamine at dopamine D3 and D2L receptors, respectively. At alpha-adrenergic sites, rotigotine acted as an antagonist on alpha2B receptors. At serotonergic sites, rotigotine had a weak but significant agonistic activity at 5-HT1A receptors and a minor or nonexistent activity at other serotonin receptors. Thus, in respect to PD, rotigotine can be characterized as a specific dopamine receptor agonist with a preference for the D3 receptor over D2 and D1 receptors. In addition, it exhibits interaction with D4 and D5 receptors, the role of which in relation to PD is not clear yet. Among non-dopaminergic sites, rotigotine shows relevant affinity to only 5-HT1A and alpha2B receptors. Further studies are necessary to investigate the contribution of the different receptor subtypes to the efficacy of rotigotine in Parkinson's disease and possible other indications such as restless legs syndrome.
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PMID:The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson's disease. 1870 68

Convergent evidence suggests that serotonin 5-HT1A receptor (5-HT1AR) agonists reduce l-DOPA-induced dyskinesia by auto-regulating aberrant release of l-DOPA-derived dopamine (DA) from raphestriatal neurons. However, recent findings indicate that 5-HT1AR stimulation also modifies D1 receptor (D1R)-mediated dyskinesia and rotations implicating a previously unexplored extra-raphe mechanism. In order to characterize the contribution of the striatum to these effects, rats with medial forebrain bundle DA lesions were tested for abnormal involuntary movements (AIMs) and rotations following striatal microinfusions of the 5-HT1AR agonist +/-8-OH-DPAT and systemic D1R agonist treatment with SKF81297. Additional rats with multi-site striatal DA lesions were tested for motor disability following systemic or intrastriatal +/-8-OH-DPAT with or without systemic SKF81297. In rats with medial forebrain bundle lesions, striatal infusions of +/-8-OH-DPAT dose-dependently reduced AIMs while conversely increasing rotations. In rats with striatal lesions, +/-8-OH-DPAT alone, both systemic and intrastriatal administration, optimally reversed motor disability. Collectively, these results support an important functional interaction between 5-HT1AR and D1R in the striatum with implications for the improved treatment of Parkinson's disease.
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PMID:Striatal 5-HT1A receptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkinsonian rat. 1882 1

The D3 dopamine receptor selective antagonist PG01037 has been evaluated for the ability to attenuate L-dopa-associated abnormal involuntary movements (AIMs) in unilaterally lesioned male Sprague-Dawley rats, which is a model of L-dopa-dependent dyskinesia in patients with Parkinson's Disease. The intrinsic activity of PG01037 was determined using a) a forskolin-dependent adenylyl cyclase inhibition assay with transfected HEK 293 cells expressing either the human D2Long or D3 dopamine receptor subtype and b) an assay for agonist-associated mitogenesis. For the initial experiments, the 5-HT1A receptor selective partial agonist buspirone was used as a positive control to verify our ability to quantitate changes in total AIMs and AIMs minus locomotor scores. Subcutaneous (s.c.) administration of PG01037 was found to have minimal effect on AIMs score. However, it was observed that the in vivo efficacy of PG01037 increased when administered by intraperitoneal (i.p.) injection 15 min after L-dopa/benserazide administration, as compared to a 60 min, 30 min or 0 min pretreatment. It was also found that i.p. administration of PG01037 could inhibit involuntary movements after they had achieved maximum intensity. PG01037 was found to attenuate AIM scores in these animals in a dose dependent manner with IC(50) value equal to a) 7.4 mg/kg following L-dopa/benserazide administration (8 mg/kg each, i.p.) and b) 18.4 mg/kg following the administration of apomorphine (0.05 mg/kg, s.c.). However, PG01037 did not effectively inhibit SKF 81297-dependent abnormal involuntary movements. Rotarod studies indicate that PG01037 at a dose of 10 mg/kg did not adversely affect motor coordination of the unilaterally lesioned rats. Evaluation of lesioned rats using a cylinder test behavioral paradigm indicated that PG01037 did not dramatically attenuate the beneficial effects of L-dopa. These studies suggest that D3 dopamine receptor selective antagonists are potential pharmacotherapeutic candidates for the treatment of L-dopa-associated dyskinesia in patients with Parkinson's Disease.
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PMID:Evaluation of the D3 dopamine receptor selective antagonist PG01037 on L-dopa-dependent abnormal involuntary movements in rats. 1937 85

A panel of novel D2 and D3 dopamine receptor selective antagonists, partial agonists and full agonists have been evaluated for the ability to attenuate L-dopa-associated abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA) unilaterally lesioned male Sprague Dawley rats, which is an animal model of L-dopa-induced dyskinesia (LID). LID is often observed in patients with Parkinson's Disease following chronic treatment with L-dopa. The intrinsic activity of these dopaminergic compounds was determined using a forskolin-dependent adenylyl cyclase inhibition assay with transfected HEK 293 cells expressing either the human D2Long or D3 dopamine receptor subtype. For the initial experiments the 5-HT1A receptor selective partial agonist buspirone was used to verify our ability to quantitate changes in total AIMs and AIMs minus locomotor scores. Two D2 dopamine receptor selective antagonists, SV 156 and SV 293, were evaluated and found to minimally attenuate AIM scores in these animals. Four members of our WC series of D3 dopamine receptor selective compounds of varying intrinsic activity at the D3 dopamine receptor subtype, WC 10, WC 21, WC 26 and WC 44, were also evaluated and found to attenuate AIM scores in a dose dependent manner. The in vivo efficacy of the compounds increased when they were administered simultaneously with L-dopa, as compared to when the compounds were administered 60 min prior to the L-dopa/benserazide. It was also found that the D3 receptor antagonist WC 10 could inhibit the involuntary movements after they had achieved maximum intensity. Unlike the D1-like dopamine receptor selective agonist SKF 81297 and the D2-like dopamine receptor agonist bromocriptine which can precipitate abnormal involuntary movements in these unilaterally lesioned animals, abnormal involuntary movements were not observed after administration of our D3 receptor selective agonist WC 44. In addition, we evaluated the effect of these four D3 dopamine receptor selective compounds for their effect on a) spontaneous locomotion and b) coordination and agility using a rotarod apparatus. We also used a cylinder test to assess the effect of L-dopa on spontaneous and independent use of each of the rat's forelimbs in the presence or absence of test compound. The results of these studies suggest that substituted phenylpiperazine D3 dopamine receptor selective compounds are potential pharmacotherapeutic agents for the treatment of L-dopa-associated dyskinesia in patients with Parkinson's Disease.
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PMID:Evaluation of D2 and D3 dopamine receptor selective compounds on L-dopa-dependent abnormal involuntary movements in rats. 1937 86

This review gives an overview of those in vivo imaging studies on synaptic neurotransmission, which so far have been performed on patients with movement disorders and/or dementia. Thereby, the focus is on disease-related deficiencies within the functional entity of the dopaminergic, serotonergic, cholinergic, glutamatergic, GABAergic or opioid synapse. In vivo investigations have yielded highly consistent results on the dysfunction of synaptic constituents in the majority of diseases covered by this overview. Findings show presynaptic dysfunctions in idiopathic as well as early-onset Parkinson's disease with decreases in striatal dopamine synthesis (57 out of a total of 59 reports on both types of Parkinson's disease), storage (nine out of nine reports), release (two out of three reports) and transporter binding (95 out of 95 reports). In contrast, the "Parkinson plus" syndromes multiple system atrophy and progressive supranuclear palsy are characterized by both pre- and postsynaptic deficiencies with reductions in striatal dopamine synthesis (11 out of a total of 11 reports on both types of "Parkinson plus" syndromes), storage (four of four reports), and transporter binding (27 out of 27 reports) as well as D1 (two out of two reports) and D2 receptor binding (34 out of 36 reports). This does not hold for the "Parkinson plus" syndromes dementia with Lewy bodies and corticobasal degeneration. For these diseases, for the time being, firm evidence of alterations in D1 and/or D2 receptor binding is lacking. In patients with Huntington's disease, mainly postsynaptic dysfunctions with reductions of striatal D1 (six out of six reports) and D2 receptor binding (15 out of 15 reports) were observed. Alzheimer's disease is characterized by both pre-and postsynaptic deficiencies of the cholinergic system with decreases of cortical acetylcholine storage (one out of two reports) and both musarinic (seven out of 10 reports) and nicotinic cholinergic receptor binding (three out of six reports). Moreover, reductions in cortical (one out of three reports) and limbic 5-HT1A (three out of three reports) and cortical (four out of four reports) and limbic 5-HT2A receptor binding (one out of two reports) were observed. Moreover, there is evidence for a cortical (four out of six reports) and cingulate (three out of three reports) increase of peripheral benzodiazepine receptor binding indicative of microglial activation. In the majority of investigations on patients with Alzheimer's disease, no alterations of presynaptic dopamine function were found, whereas all other forms of dementia including corticobasal degeneration, dementia with Lewy bodies, Parkinson's disease dementia and frontotemporal dementia were characterized by presynaptic dopaminergic deficiencies with reductions in striatal dopamine synthesis (10 out of a total of 10 reports on these types of dementia), storage (four out of four reports) and transporter binding (29 out of 29 reports). Taken together, in vivo imaging methods can be employed for the diagnosis of idiopathic and early-onset Parkinson's disease as well as "Parkinson plus" syndromes and Huntington's disease. Moreover, differentiation is feasible between, firstly, Parkinson's disease and the "Parkinson plus" syndromes multiple system atrophy and progressive supranuclear palsy, secondly, multiple system atrophy/progressive supranuclear palsy and the other "Parkinson plus" syndromes dementia with Lewy bodies and corticobasal degeneration, and, thirdly, Alzheimer's disease and other forms of dementia.
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PMID:In vivo imaging of synaptic function in the central nervous system: I. Movement disorders and dementia. 1952 90

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are second only to Alzheimer's disease (AD) in frequency. In particular it is evident that up to 80% of people with PD will develop dementia towards the end of their life. While the neurobiology of movement disorder has been well studied in PD, much less attention has been given to mechanisms underlying the cognitive and behavioural symptoms associated with DLB and PDD. To date, the best correlate of cognitive impairment appears to be cortical Lewy bodies; however, new emphasis has been placed on small aggregates of synuclein. Furthermore, very few studies have attempted to investigate the neurochemical correlates of behavioural disorders in DLB/PDD and whether these are similar or distinct from AD. Aggregated alpha-synuclein forms the core component of Lewy bodies, a major pathological feature of Parkinson's-related conditions. The 26S proteasome is an ATP-dependent protease that catalyses the breakdown of alpha-synuclein. Previous studies have implicated alterations in the proteasome in PD. Furthermore, proteasome inhibitors have been reported to induce alpha-synuclein aggregation and Lewy body-like inclusions, resulting in neuronal loss both in vitro and in vivo. Our preliminary results indicate that selective alterations in the expression of proteosome sub-units are a feature of both DLB and PDD, while changes in activity are restricted to PDD. Depression is a common symptom in DLB/PDD, yet the evidence base for standard treatment with SSRIs is limited. In contrast to previous studies of AD, our results indicate that there is no association between depression and the 5-HT transporter, while there was a significant increase in the number of 5-HT1A receptors in those DLB/PDD patients with depression. These data may provide an insight into the lack of success of current treatments and suggest alternative approaches.
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PMID:Biochemical and pathological correlates of cognitive and behavioural change in DLB/PDD. 1971 Nov 17

L-DOPA-induced dyskinesia in Parkinson's disease is associated with large increases in brain dopamine (DA) levels following drug dosing, but the precise significance of this phenomenon is not understood. Here we compare DA efflux and metabolism in the striatum and the substantia nigra in dyskinetic and non-dyskinetic animals following a standard dose of L-DOPA. Rats with 6-hydroxydopamine lesions were treated chronically with L-DOPA, monitored on the abnormal involuntary movements scale, and then subjected to intracerebral microdialysis under freely-moving conditions. Following s.c. L-DOPA injection, peak extracellular DA levels in both striatum and substantia nigra were about twice as large in dyskinetic animals compared to non-dyskinetic rats. This effect was not attributable to differences in DOPA levels or DA metabolism. The larger DA efflux in dyskinetic animals was blunted by 5-HT1A/5-HT1B receptor agonists and tetrodotoxin infusion, reflecting release from serotonin neurons. Striatal levels of serotonin and its main metabolite, 5-hydroxyindolacetic acid were indeed elevated in dyskinetic animals compared to non-dyskinetic rats, indicating a larger serotonergic innervation density in the former group. High DA release was, however, not sufficient to explain dyskinesia. The 'abnormal involuntary movements output' per unit concentration of striatal extracellular DA was indeed much larger in dyskinetic animals compared to non-dyskinetic cases at most time points examined. The present results indicate that both a high DA release post-L-DOPA administration and an increased responsiveness to DA must coexist for a full expression of dyskinesia.
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PMID:L-DOPA-induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson's disease: temporal and quantitative relationship to the expression of dyskinesia. 2005 Sep 78

Partial D(2/3) dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease (PD) that may avoid common dopaminergic side-effects, including dyskinesia and psychosis. The present study focussed on the in vivo pharmacological and therapeutic characterisation of the novel D(2/3) receptor partial agonist and full 5-HT(1A) receptor agonist pardoprunox (SLV308; 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monochloride). Pardoprunox induced contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED=0.03mg/kg; po). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, pardoprunox dose-dependently increased locomotor activity (MED=0.03mg/kg; po) and decreased motor disability (MED=0.03mg/kg; po). The effects of pardoprunox were reversed by the D(2) antagonist sulpiride. In contrast pardoprunox attenuated novelty-induced locomotor activity (MED=0.01mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED=0.3mg/kg; po) and apomorphine-induced climbing (MED=0.6mg/kg; po) in rodents. Pardoprunox also induced 5-HT(1A) receptor-mediated behaviours, including flat body posture and lower lip retraction (MED=0.3mg/kg; po) and these were reversed by the 5-HT(1A) receptor antagonist WAY100635. Collectively, these findings demonstrate that pardoprunox possesses dopamine D2/3 partial agonist effects, 5-HT1A agonist effects and reduces parkinsonism in animal models. functional DA D(2) receptor partial agonist activity and is effective in experimental models predictive of efficacy in PD. The presence of functional 5-HT(1A) agonist activity might confer anti-dyskinetic activity and have effects that control neuropsychiatric components of PD.
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PMID:An in vivo pharmacological evaluation of pardoprunox (SLV308)--a novel combined dopamine D(2)/D(3) receptor partial agonist and 5-HT(1A) receptor agonist with efficacy in experimental models of Parkinson's disease. 2043 90


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