Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peak dose dyskinesia is a major problem in the treatment of parkinsonian patients with levodopa and yet this remains the best pharmacological agent for treating the condition. The hypothesis which this research set out to test was that thalamotomy in the area of the thalamus which receives the input from the medial segment of the globus pallidus would decrease or prevent the dyskinesia. A well established primate model of parkinsonism was used. Eight monkeys (Macaca fascicularis) were rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Regular dosing with levodopa or apomorphine reliably resulted in peak dose dyskinesia. Thalamotomy was carried out using a radiofrequency electrode. To ensure that the appropriate area of the thalamus was targeted, that is the area receiving the pallidal input, an anatomical tracing study was carried out. The anterograde anatomical tracer horseradish peroxidase, covalently bound to wheatgerm agglutinin, was injected into the medial segment of the globus pallidus bilaterally in three monkeys. The target site for thalamotomy was accurately worked out from the tracings obtained. Chorea was usually abolished and always reduced by a thalamotomy in the pallidal terminal territory. This result was obtained after 10 thalamotomies: 4 animals receiving bilateral lesions, with an interval between operations, and 2 animals undergoing unilateral surgery. Lesions in three control sites were carried out and had no permanent effect on chorea. The effect of lesions in other areas was also assessed. Dystonia was not relieved by any thalamic lesion. Thalamotomy is a long established procedure used to help parkinsonian tremor. Appropriately placed thalamotomy should be considered for the relief of disabling peak dose dyskinesia, which is predominantly choreic, in parkinsonian patients on otherwise successful levodopa therapy.
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PMID:The use of thalamotomy in the treatment of levodopa-induced dyskinesia. 158 Jan 97

We examined whether the N-methyl-D-aspartate antagonist MK-801 (dizocilpine) would reverse parkinsonism or potentiate the effects of L-dopa in primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to its effect in rodent models, treatment with MK-801 (0.1 mg/kg) caused bradykinesia and ataxia in parkinsonian primates, but no locomotor stimulation. Coadministration of MK-801 (0.1 mg/kg) with L-dopa (20 mg/kg) induced marked dystonia accompanied by bradykinesia and ataxia. Dystonia was not induced by either treatment given alone. These findings indicate that MK-801 should not be advocated as an adjunct to dopamine agonist therapy in Parkinson's disease.
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PMID:Dystonia induced by combined treatment with L-dopa and MK-801 in parkinsonian monkeys. 164 62

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primates induced a parkinsonian syndrome that could be reversed by levodopa treatment. Animals quickly developed an apparent restlessness ("akathisia") of the lower limbs after as little as five doses. After 4-10 weeks of regular levodopa therapy, animals developed "peak dose" choreiform movements in the lower limbs that spread, with time, to involve the upper limbs and orofacial musculature. With further treatment (5-21 months), animals developed "peak dose" dystonia that variably involved the limbs and orofacial musculature. These conditions represent novel models of levodopa-induced chorea and dystonia in humans. They depend on the same underlying neuropathology and treatment regimen as their human counterparts. It is to be anticipated that these models of dyskinesia will be useful in determining the mechanisms underlying chorea and dystonia in humans and are ideally suited for experimental evaluation of new treatment strategies.
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PMID:Induction of chorea and dystonia in parkinsonian primates. 229 55

The neural mechanisms that mediate dystonia were investigated in a novel experimental primate model of dopamine agonist-induced dystonia. This condition was produced by long-term (15 months) dopamine agonist therapy of a macaque monkey that had been rendered hemiparkinsonian by unilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into the right common carotid artery. The 2-deoxyglucose (2-DG) metabolic mapping technique was applied to the animal during the expression of active unilateral dystonia, and regional brain uptake of 2-DG was assessed autoradiographically. The results demonstrate that dystonia is associated with marked increases in 2-DG uptake in the constituent nuclei of the basal ganglia (caudate nucleus, putamen, medial and lateral segments of the globus pallidus) and in the subthalamic nucleus, but decreased uptake in the structures that receive output of the basal ganglia (ventral anterior/ventral lateral thalamic complex and lateral habenula). Based on these findings it is suggested that dystonia is characterized by increased activity in the putaminopallidal and pallidosubthalamic pathways, and decreased activity in the subthalamopallidal and pallidothalamic pathways.
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PMID:Neural mechanisms of dystonia: evidence from a 2-deoxyglucose uptake study in a primate model of dopamine agonist-induced dystonia. 229 59

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor have been reported to potentiate the antiparkinsonian action of levodopa and reverse levodopa-induced motor fluctuations in animal models of Parkinson's disease. To evaluate the effect of NMDA receptor blockade on dyskinesias complicating the response to long-term levodopa therapy, we studied the selective antagonist LY235959 in six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. Drugs were administered subcutaneously, LY235959 at doses of 0.5, 1.0, 3.0, and 5.0 mg/kg and levodopa/benserazide at doses that produced moderate dyskinesias while almost totally reversing parkinsonian signs. Compared with vehicle control injections, LY235959 (3.0 mg/kg) abolished oral dyskinesias and diminished choreic dyskinesias by 68% (p < 0.01). Lower doses had smaller effects, although still significant, on oral dyskinesias (55% reduction at 1.0 mg/kg, p < 0.05). The highest LY235959 dose (5.0 mg/kg) prolonged oral dyskinesia suppression, but tended to increase dystonia severity. LY235959 had no effect on motor function when given alone and did not reduce the antiparkinsonian response to levodopa. These findings suggest that NMDA receptor blockade may ameliorate the dyskinetic complications of long-term levodopa therapy, without diminishing the beneficial effects on parkinsonian signs.
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PMID:Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsonian monkeys. 861 38

The pathophysiology of dystonia is unclear, but several clues implicate striatal dopamine dysfunction. In contrast, the causal relationship between striatal dopamine deficiency and parkinsonism is well defined. We now suggest that parkinsonism or dystonia may occur following striatal dopamine deficiency. Baboons treated with intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed transient hemidystonia prior to hemiparkinsonism. The day after MPTP treatment, most animals had spontaneous ipsilateral turning. Within a few days, all developed contralateral hemidystonia, with the arm and leg extended and externally rotated. This transient dystonia preceded hemiparkinsonism with flexed posture, bradykinesia, and postural tremor that persisted for up to 1.5 years. Dystonia corresponded temporally with a decreased striatal dopamine content and a transient decrease in D2-like receptor number. The time course of dystonia and parkinsonism is analogous to lower limb dystonia as the first, frequently transient, symptom of Parkinson's disease in humans. The association of striatal dopamine deficiency with dystonia and parkinsonism implies that other factors influence clinical manifestations.
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PMID:MPTP induces dystonia and parkinsonism. Clues to the pathophysiology of dystonia. 937 34

Carbon disulfide toxicity is well characterized. The principal target organ is the nervous system, although cardiovascular, reproductive, ophthalmologic, and other effects are also recognized. The neurotoxicity manifests in three ways: encephalopathy, peripheral and cranial nerve dysfunction, and movement abnormalities. This report describes a case of olivopontocerebellar atrophy, a form of multiple system atrophy, developing in an adult after over 30 years of occupational exposure to carbon disulfide. The patient presented with the insidious onset of balance problems, impotence, and irritability, without tremor, cogwheel rigidity, bradykinesia, or changes in facial expression. Over the next few years severe ataxia developed, and the clinical diagnosis was confirmed with computed tomography and magnetic resonance imaging scans. The patient experienced multiple medical complications and died approximately 9 years after diagnosis. This case is consistent with a large body of clinical and experimental literature, much of it 50 years old, showing that carbon disulfide can cause movement disorders. It also serves as a reminder that movement disorders, ranging from parkinsonism to dystonia, are associated with a variety of toxic exposures such as manganese, carbon monoxide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and medications.
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PMID:Multiple system atrophy following chronic carbon disulfide exposure. 1070 37

Common marmosets show parkinsonian motor deficits following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration and develop dyskinesias during chronic L-dopa exposure. The D1 agonists A-77636 [(1R, 3S) 3-(1'-adamantyl)-1-aminomethyl-3, 4-dihydro-5, 6-dihydroxy-1H-2-benzopyran HCl] and A-86929 [(-)-trans 9, 10-hydroxy-2-propyl-4, 5, 5a, 6, 7, 11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride] possess potent antiparkinsonian activity in the MPTP-treated marmoset and we now assess their influence on L-dopa-induced dyskinesias. MPTP-treated marmosets with stable motor deficits were treated with L-dopa plus carbidopa for 28 days to induce dyskinesias. Subsequently, they received A-86929 for 10 days, initially at 0.5 micromol/kg and then at 1.0 micromol/kg for a further 5 days. Several months later, L-dopa 12.5 mg/kg plus carbidopa 12.5 mg/kg was given orally twice daily for 7 days, followed by A-77636 1 micromol/kg for 10 days, and then both A-77636 and L-dopa plus carbidopa were given concurrently for 3 further days. In these L-dopa-primed animals, A-86929 effectively reversed akinesia and produced dose-dependent dyskinesias which were significantly less intense than those produced by L-dopa administration. A degree of behavioral tolerance was encountered, but antiparkinsonian activity was preserved and elicited behaviour was free of hyperkinesis and stereotypy and more naturalistic than that seen with L-dopa. After a week of twice-daily L-dopa dosing, administration of the long-acting D1 agonist A-77636 initially dramatically enhanced locomotion and reproduced dyskinesia with prominent dystonia, but after repeated administration of A-77636, dyskinesia and in particular chorea, gradually disappeared. Tolerance to locomotor stimulation greater than with A-86929 occurred, although activity remained significantly above baseline levels. There was a marked reduction in L-dopa-induced climbing, stereotypy and hyperkinesis and behaviour more closely resembled that of normal unlesioned marmosets. Upon reintroduction of L-dopa concurrently with continued A-77636 administration, dystonic, but virtually no choreic dyskinesias appeared and behaviour was once again free of stereotypy and hyperkinesis, contrasting dramatically with the presence of these behaviours along with abundant chorea when L-dopa is given alone. These results show a lesser liability of A-86929 and A-77636 to reproduce dyskinesia in L-dopa-primed MPTP-lesioned subjects while maintaining effective antiparkinsonian activity and producing a more naturalistic motor response. The differential effects of A-77636 on chorea and dystonia, with suppression of chorea and stereotypy on co-administration with L-dopa, may reflect an altered balance of activity in the direct and indirect striatofugal pathways. These results suggest a possible role for D1 agonists in the treatment of Parkinson's disease.
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PMID:Actions of the D1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated L-dopa-primed common marmosets. 1010 82

Although the basal ganglia have been implicated in the development of movement disorders since the 1940s, the exact role played by these structures has remained elusive. The development of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-monkey model of parkinsonism, and the recent resurgence of surgical therapy for the treatment of hypokinetic and hyperkinetic movement disorders has, however, led to an improved understanding of the pathophysiological mechanisms that underlie their development. In this article, we review the functional organization and examine the changes in neuronal activity that occur in the basal ganglia thalamocortical 'motor' circuit in these disorders. An alternative to the classic 'rate' model for Parkinson's disease is presented that incorporates the observed changes in neuronal activity, as well as additional neuronal pathways that contribute to these changes. Based on studies in animal models and humans with hyperkinetic movement disorders, it is postulated that dyskinesias develop as the result of a combination of excessive reductions in the mean discharge rate, altered patterns and increased synchronization of neurons in the internal segment of the globus pallidus. It is further postulated that the particular type of involuntary movement which develops also depends on the relative change in neuronal activity in the direct, indirect and alternative pathways. Support for these postulates is examined, and models for drug-induced dyskinesia, hemiballismus and dystonia are proposed.
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PMID:Physiology of hypokinetic and hyperkinetic movement disorders: model for dyskinesia. 1076 40

We conducted a new chronic sequential 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3NP) intoxication paradigm in two female monkeys in order to reproduce the striatonigral degeneration type of levodopa-unresponsive parkinsonism. A comparison was made with MPTP-, 3NP-intoxicated and control monkeys. A levodopa-responsive parkinsonism emerged in all MPTP-treated monkeys. During subsequent 3NP intoxication, one of the two MPTP +3NP monkeys exhibited hindlimb dystonia concomitantly with a reduced levodopa response. All MPTP-monkeys had severe cell loss in the substantia nigra pars compacta (>70%), but 3NP-induced discrete lesioned areas and cell loss predominantly in the putamen appeared only in the dystonic and levodopa-unresponsive animal. We propose that the appearance of dystonia after 3NP intoxication following dopaminergic striatal denervation is the key symptom predictive of the loss of dopaminergic response.
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PMID:Dystonia is predictive of subsequent altered dopaminergic responsiveness in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine+3-nitropropionic acid model of striatonigral degeneration in monkeys. 1245 36


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