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 the striatum, dopamine D(2) receptors are co-localized with adenosine A(2A) receptors on the GABAergic neurons of the striopallidal pathway. Moreover, blockade of A(2A) receptors has been previously shown to suppress parkinsonian-like symptoms (catalepsy, akinesia, muscle rigidity) in rodent and primate models of Parkinson's disease (PD). Since it is believed that main motor symptoms of PD are due to the overactivity of the GABAergic striopallidal pathway, the aim of the present study was to find out whether SCH 58261, a selective antagonist of the adenosine A(2A) receptors, is capable of counteracting both the catalepsy and the enhancement of proenkephalin (PENK) mRNA expression in the rat striatum, induced by haloperidol administered at 1.5 mg/kg s.c. 3 times, every 3 h. Systemic administration of SCH 58261 (5 mg/kg i.p., 3 times, every 3 h, 10 min before haloperidol), partially decreased the haloperidol-induced catalepsy and the increase in the PENK mRNA expression in both dorsolateral and ventrolateral parts of the striatum at all three examined levels. No such changes were seen in the medial striatum and in the nucleus accumbens. Moreover, SCH 58261 given alone did not influence the level of PENK mRNA in any examined part of the striatum. The present results suggest that similarly to other A(2A) receptor antagonists, SCH 58261 normalizes activity of the striopallidal pathway, enhanced by blockade of dopamine D(2) receptors with haloperidol, which may result in recovery of motor functions.
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PMID:SCH 58261, a selective adenosine A2A receptor antagonist, decreases the haloperidol-enhanced proenkephalin mRNA expression in the rat striatum. 1283 87

The possible synergism between caffeine and muscarinic antagonists to inhibit haloperidol-induced catalepsy was investigated with the bar test in rats. Pretreatment with low doses of caffeine (1-3 mg/kg), a non-selective adenosine antagonist, dose dependently reduced the intensity and increased the onset latency of catalepsy induced by haloperidol (0.5-2 mg/kg). Similar effects were produced by the muscarinic antagonists atropine (4.1 mg/kg), and trihexyphenidyl (THP, 0.01-3 mg/kg). THP inhibited catalepsy intensity with an ED(50) of 0.38 mg/kg, and increased its onset latency with an ED(50) of 0.52 mg/kg. The anticataleptic effect of anticholinergics was potentiated when a low dose of caffeine (1 mg/kg) was applied simultaneously. In the presence of caffeine, THP inhibited catalepsy intensity with an ED(50) of 0.19 mg/kg, and prolonged the latency with an ED(50) of 0.30 mg/kg. The synergism was more evident when THP was administered at subthreshold doses that were unable to modify haloperidol-induced catalepsy when applied alone, but produced a clear inhibition of catalepsy when injected with caffeine. To assess whether repeated administration of caffeine could induce tolerance to the synergism with THP, a group of rats was pretreated with three daily doses of caffeine (1 mg/kg) for seven days, and the catalepsy test was performed on the eighth day. In these animals, caffeine was still able to enhance the anticataleptic actions of THP, suggesting that repeated administration of 1 mg/kg caffeine does not induce tolerance to the synergism with anticholinergics. These results indicate that low doses of caffeine enhance the anticataleptic actions of muscarinic antagonists, and leave open the possibility of using caffeine as adjunctive therapy to reduce the doses and the adverse effects of anticholinergics in Parkinson's disease.
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PMID:Caffeine and muscarinic antagonists act in synergy to inhibit haloperidol-induced catalepsy. 1290 10

Chronic subthalamic nucleus high frequency stimulation (STN HFS) improves motor function in Parkinson's disease. However, its efficacy on cognitive function and the mechanisms involved are less known. The aim of this study was to assess the effects of STN HFS in hemiparkinsonian awake rats performing different specific motor tests and a cognitive operant task. Unilateral STN HFS applied in unilaterally DA-depleted rats decreased the apomorphine-induced circling behaviour and reduced catalepsy induced by the neuroleptic haloperidol. DA-depleted rats exhibited severe deficits in the operant task, among which the inability to perform the task was not alleviated by STN HFS. However, in a few animals showing less impairment, STN HFS significantly reduced the contralateral neglect induced by the lesion. These results are the first to demonstrate a beneficial effect of STN HFS applied in awake rats on basic motor functions. However, STN HFS appears to be less effective on impaired cognitive functions.
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PMID:High frequency stimulation of the subthalamic nucleus has beneficial antiparkinsonian effects on motor functions in rats, but less efficiency in a choice reaction time task. 1292 21

Catalepsy of animals represents a condition of akinesia and high rigidity of muscles. Catalepsy is a model for Parkinson's disease. The activity of spiny projection neurons in the striatum is correlated with different groups of muscles in rats or primates. Burst activity is a typical characteristic of spiny projection neurons in the state of Parkinson's disease. Rats were treated with 0.5 mg/kg haloperidol to induce a cataleptic state for 180 s. Spiny projection neuronal activity in striatum was measured to detect changes in spike frequency. Triggers were set manually when the rats increased their muscle tone superimposed on the already existing tetanus of the forelimb muscles. The results showed a clear correlation of the occurring triggers and the burst activity in the striatum. During such a burst event, rats did not move but showed this typical superimposed muscle tetanus. A possible explanation is that the intention to move is encoded in the burst activity of spiny projection neurons in the striatum while the execution of the movement is blocked. But also bursts that are not correlated with the short-term superimposed muscle tetanus occurred.
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PMID:Burst activity of spiny projection neurons in the striatum encodes superimposed muscle tetani in cataleptic rats. 1451 87

An intensification of catalepsy has been observed upon repeated testing in rats with permanent neurodegeneration of substantia nigra. Here, the question is addressed whether the rate of development of intensification of catalepsy upon repeated testing in the same context is dependent on dopamine level in the basal ganglia. Rats were lesioned with 2 microg or 6 microg of 6-hydroxydopamine in the median forebrain bundle to produce dopamine depletion in substantia nigra in two different proportions. Both groups were exposed to catalepsy tests for 7 successive days in the same context, and the context was changed on day 8. On day 9 the catalepsy test was repeated with the old context. After the completion of the behavioral experiments, various regions of basal ganglia were analyzed for dopamine and its metabolites 3,4-dihydroxyphenylacetic acid, 3-methyl tyronine, and homovanillic acid. Lesions with 6 microg of 6-hydroxydopamine produced strong dopamine depletion (78%) and akinetic response in the catalepsy test on day 1. Repeated exposure of this group to the catalepsy tests in the same context produced intensification of cataleptic response. Changing the context on day 8 reduced catalepsy. Performing the experiments again with the old context on day 9 produced an intensified response. Lesions with 2 microg of 6-hydroxydopamine produced partial dopamine depletion (46%) without any motor disturbances. However, repeated exposure and context changes produced a similar pattern of catalepsy as in the 6 microg lesioned animals. These results indicate that the rate of building up of intensification of catalepsy is not dependent on the degree of dopamine depletion. It signifies the importance of context in the expression and augmentation of parkinsonian symptoms during the course of the disease to subjects with subthreshold dopaminergic neurodegeneration that could not produce motor disturbances alone. Prevention of context-dependent intensification of catalepsy could be beneficial in the treatment of Parkinson's disease.
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PMID:Intensification of cataleptic response in 6-hydroxydopamine-induced neurodegeneration of substantia nigra is not dependent on the degree of dopamine depletion. 1466 19

Noradrenaline has been shown to control dopamine turnover and release in rat brain. Noradrenergic lesion with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) decreases dopamine release in the striatum and enhances catalepsy in experimental models of Parkinson's disease. However, in due course, sprouting of remaining noradrenergic axons, to compensate for the decreased noradrenaline is said to occur in specific brain regions. Though this is to some extent understood, the longstanding effects of noradrenergic lesion on dopaminergic neurons of the basal ganglia and in Parkinsonian behavior is not known. Here the question is addressed, whether locus coeruleus lesion with DSP-4 in rats alters dopamine concentration of the basal ganglia and influences Parkinsonian behavior in a long term (6 months). Parkinsonian behavior was assessed by catalepsy and activity cage after challenging with subthreshold dose of haloperidol (0.2 mg/kg), on 7, 30, 90, 120 and 180 days after DSP-4 lesion. The concentrations of noradrenaline and dopamine and its metabolites were estimated by HPLC. 6 months after DSP-4 lesion, increased concentration of noradrenaline was found in prefrontal cortex and hippocampus. Other regions remain unaffected. The concentration of dopamine remained unchanged. However, dopamine turnover appeared to be increased in prefrontal cortex and reduced in striatum and nucleus accumbens. Catalepsy and hypoactivity were observed in DSP-4 lesioned animals after haloperidol challenge on 7th, 30th and 60th day. Though dopamine turnover was reduced after 6 months in the striatum, haloperidol-induced catalepsy was not observed after 60 days. These results indicate a gradual functional recovery, perhaps hyperinnervation of noradrenergic neurons after DSP-4 treatment and the reversal of its effects on dopaminergic neurons and on Parkinsonian symptoms.
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PMID:Functional recovery of locus coeruleus noradrenergic neurons after DSP-4 lesion: effects on dopamine levels and neuroleptic induced-parkinsonian symptoms in rats. 1471 12

The complex I inhibitor rotenone is a neurotoxin that has been proposed to induce Parkinson-like degeneration. As the mechanisms of rotenone toxicity are not fully understood, the present study addresses the question of whether rotenone induces NO production and lipid peroxidation-like products, that is, thiobarbituric acid reactive substances (TBARS). Rotenone at a dose of 1.5 mg kg(-1) i.p. was administered to rats daily for 10, 20, 30, and 60 days, and NO and TBARS were measured in the frontal cortex and in the striatum. On the 1st and 10th day, there were no increases in NO and TBARS levels, after 20 days, the NO and TBARS levels were increased in the striatum. After 30 and 60 days, NO and TBARS levels were increased in striatum and frontal cortex. Behaviorally, on days 30 and 60, the rats exhibited akinesia and rigidity in the catalepsy test. These results show that chronic administration of rotenone over a long period is capable of increasing NO and TBARS in the cortex and striatum and mimics Parkinson's disease (PD)-like behavioral symptoms that are akinesia and rigidity in rats.
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PMID:Chronic administration of rotenone increases levels of nitric oxide and lipid peroxidation products in rat brain. 1502 59

Rotenone (an inhibitor of mitochondrial complex I) has been proposed as a model of Parkinson's disease (PD) as it induces nigrostriatal degeneration associated with alpha-synuclein inclusions. So far, only peripherally administered rotenone has been used as a model of PD. There has not been any investigation on the neurobehavioral changes induced by bilateral lesions of dopaminergic neurons by rotenone in rats. In the present study, rotenone (3 microg) was administered bilaterally stereotaxically into the medial forebrain bundle (MFB) to produce parkinsonian symptoms. Behavioural and biochemical data showed a strong increase in catalepsy, a decrease in locomotor activity and a significant depletion of dopamine levels in the striatum as compared to sham-lesioned animals. If the locomotor deficits are caused by the depletion of dopaminergic neurons, then L-DOPA should counteract motor deficits because L-DOPA therapy reverses mostly all motor deficits in human Parkinsonian patients. To examine the effectiveness of L-DOPA in reversing the motor deficit in rats, two different doses of L-DOPA (5 and 10 mg/kg) in combination with the peripheral amino acid decarboxylase inhibitor benserazide were daily administrated intraperitonially for a period of 31 days lesioned animals. L-DOPA plus benserazide counteracted catalepsy dose-dependently and increased locomotor activity. The results indicate that rotenone infused into the MFB destroys dopaminergic neurons, induces pakinsonian symptoms that are reversed by the clinically effective anti-parkinsonian drug L-DOPA. Therefore, sterotaxically infused rotenone may be useful for screening drugs for the treatment of PD.
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PMID:The neurobehavioral changes induced by bilateral rotenone lesion in medial forebrain bundle of rats are reversed by L-DOPA. 1508 27

In Parkinson's disease, besides the dopaminergic neurodegeneration, locus coeruleus noradrenergic neurons degenerate as well. Noradrenergic neurons have potential anti-parkinsonian, neuromodulatory and neuroprotective properties. Presently, an animal model with dopaminergic lesion has been used as a standard model of Parkinson's disease. The behavioral effects of dopaminergic agents in a Parkinson's animal model with additional noradrenergic lesions has not been studied so far. Here, the behavioral effects of dopaminergic agents L-DOPA (15 mg/kg) and D-amphetamine (4 mg/kg) in two different pathophysiological conditions have been explored; One group involving only dopaminergic deficiency with 6-hydroxydopamine (6-OHDA) and the other group with both dopaminergic and noradrenergic deficiency with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). DSP-4 specifically depleted noradrenaline from locus coeruleus terminal fields. 6-OHDA lesion depleted dopamine and its metabolites DOPAC, HVA and 3-MT in the regions of basal ganglia and it was potentiated by additional locus coeruleus denervation. Dopaminergic lesion produced catalepsy and hypoactivity. Hypoactivity in openfield was potentiated by additional noradrenergic denervation of locus coeruleus neurons. L-DOPA produced effective anticataleptic activity in group with both dopaminergic and noradrenergic lesions and D-amphetamine was found to be more effective in group only with dopaminergic lesions, indicating increased dopaminergic neurodegeneration after noradrenergic lesions. L-DOPA produced hyperactivity in dual neurodegenerated group indicating its differential activity in an animal model with noradrenergic and dopaminergic lesions. These findings indicate the neuroprotective and symptomatic role of noradrenergic neurons. It implicates the importance of noradrenergic pathophysiology in Parkinson's disease and its treatment and need for a more relevant animal model.
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PMID:Behavioral and neurochemical effects of noradrenergic depletions with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine in 6-hydroxydopamine-induced rat model of Parkinson's disease. 1508 35

The most effective treatment of Parkinson's disease (PD) is, at present, the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA), however a number of disadvantages such as a loss of drug efficacy and severe side-effects (psychoses, dyskinesias and on-off phenomena) limit long-term effective utilisation of this drug. Recent experimental studies in which selective antagonists of adenosine A(2A) receptors were used, have shown an improvement in motor disabilities in animal models of PD. The A(2A) antagonist [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine] (SCH 58261) potentiated the contralateral turning behavior induced by a threshold dose of L-DOPA or direct dopamine receptor agonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, an effect accompanied by an increase in Fos-like-immunoreactivity in neurons of the lesioned striatum. Likewise, other A(2A) receptor antagonists such as (3,7-dimethyl-1-propargylxanthine) (DMPX), [E-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] (KF 17837) and [E-1,3-diethyl-8(3,4-dimethoxystyryl-7-methyl-3,7-dihydro-1H-purine-2,6-dione] (KW 6002) antagonized catalepsy induced by haloperidol or reserpine in the rat, whereas in non-human primate models of PD, KW 6002 reduced the rigidity and improved the disability score of MPTP-treated marmosets and cynomolgus monkeys. Moreover, in contrast to L-DOPA, selective A(2A) receptor antagonists administered chronically did not produce dyskinesias and did not evoke tolerance in 6-OHDA and MPTP models of PD. An additional therapeutic potential of adenosine A(2A) antagonists emerged from studies showing neuroprotective properties of these compounds in animal models of cerebral ischemia and excitotoxicity, as well as in the MPTP model of PD. Adenosine A(2A) receptor antagonists by reversing motor impairments in animal models of PD and by contrasting cell degeneration are some of the most promising compounds for the treatment of PD.
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PMID:Adenosine A(2a) receptor antagonists: potential therapeutic and neuroprotective effects in Parkinson's disease. 1511 Dec 44


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