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)

We observed a marked prolongation of the transcranially evoked silent period during continuous intrathecal administration of high doses of the gamma-aminobutyric acid (GABA)B receptor agonist baclofen in a patient with generalized dystonia. Size of motor evoked potentials and central conduction time remained unchanged during intrathecal baclofen administration. The selective prolongation of the silent period during high-dose continuous intrathecal baclofen therapy supports the notion that GABA(B)-ergic intracortical interneurons play a part in the generation of the transcranially evoked silent period.
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PMID:Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia. 1088 14

The effects of the gamma-aminobutyric acid (GABA)-potentiating drug gabapentin (1-(aminomethyl) cyclohexaneacetic acid) on severity of dystonia were examined in a hamster model of idiopathic paroxysmal dystonic choreoathetosis. In the genetically dystonic hamster (dt(sz)) recent pharmacological and neurochemical studies suggested that disturbed GABAergic inhibition is involved in the pathogenesis. In line with a case report of beneficial effects in human paroxysmal dystonic choreoathetosis, gabapentin reduced the severity of dystonia in mutant hamsters at doses of 5 and 10 mg kg(-1) i.p. At higher doses (20 and 100 mg kg(-1)), gabapentin, however, failed to exert antidystonic effects. The GABApotentiating activity of gabapentin could explain the antidystonic effects of low doses, while the loss of efficacy at higher doses may be due to other mechanisms of gabapentin.
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PMID:Gabapentin decreases the severity of dystonia at low doses in a genetic animal model of paroxysmal dystonic choreoathetosis. 1022 72

The pathophysiology of dystonia remains unclear in comparison with other movement disorders. Recent data suggest that there may exist in dystonia an increased thalamic drive to the mesial premotor cortex. To test this hypothesis, we induced overactivity of the motor thalamus by injecting a GABA-A (gamma-aminobutyric acid) antagonist (bicuculline) into the rostral (pallidal) and caudal (cerebellar) ventrolateral nuclei of the thalamus in both hemispheres of one monkey. Dystonic postures were observed in the contralateral limbs and axis. Electromyographic recordings revealed bursts of muscular activation with co-contractions during spontaneous dystonic movements and alterations in muscular patterns during sequential visually guided arm movements. The type of dystonia depended on the site of injections. Rostral thalamic injections induced more severe dystonic postures, whereas myoclonic jerks predominated following caudal injections. We conclude that these two distinct clinical patterns, which are frequently associated in humans, are probably due to a dysfunctioning of segregated thalamic projections to the supplementary motor area (from the rostral part) and to the primary motor cortex (from the caudal part).
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PMID:Bicuculline injections into the rostral and caudal motor thalamus of the monkey induce different types of dystonia. 1076 34

Recent studies in mutant hamsters (dt(sz)), an animal model of primary paroxysmal dystonia, indicated that altered function of the gamma-aminobutyric acid (GABA)ergic system plays a critical role in the pathogenesis of dystonia. In the present study, dt(sz) hamsters were chronically treated with phenobarbital, which has been found to exert antidystonic effects in mutant hamsters after acute administration. In untreated dt(sz) hamsters, the severity of dystonia follows an age-dependent time course with a maximum between the 30th and 40th day of life, followed by a continuous decline of severity until complete remission occurs at the age of about 70 days. In contrast to acute effects, chronic treatment with phenobarbital via drinking water starting at an age of 21 days (i.e., after weaning) worsened dystonia and retarded the spontaneous remission. The unexpected prodystonic effect was more marked after administration of higher doses and when chronic treatment with phenobarbital started at an age of 1 day (neonatal administration via breast milk). After withdrawal of phenobarbital at the age of 70 days, the severity rapidly declined in all treated groups. When phenobarbital was readministered 1 week later, the hamsters again exhibited severe dystonia. The mechanism of these unexpected findings is unknown. Tentatively, activity-dependent GABA-mediated excitation caused by chronic treatment with phenobarbital may be important for the prodystonic effects under pathological conditions in dt(sz) hamsters.
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PMID:Paradoxical aggravation of paroxysmal dystonia during chronic treatment with phenobarbital in a genetic rodent model. 1084 33

Patients with task-specific dystonia (writer's cramp) have impaired cortical inhibition likely arising from striatal dysfunction. However, the levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brains of these patients are not known. In this study, we evaluated 7 patients with right-sided focal, task-specific dystonia and 17 normal control subjects. A novel method using two-dimensional J-resolved magnetic resonance spectroscopy revealed that brain GABA levels are decreased in specific brain regions of the focal dystonia patients compared to normal controls. A significant decrease in GABA level was observed in the sensorimotor cortex and lentiform nuclei contralateral to the affected hand, while there was only a small nonsignificant decrease in the ipsilateral sensorimotor cortex and lentiform nuclei. GABA changes in the posterior occipital region of patients were not significant. The impaired cortical GABA level correlates with prior physiologic studies showing reduced intracortical inhibition. Reduced GABA in the striatum is consistent with striatal dysfunction since GABA is a principal neurotransmitter in that region. The reduction of brain GABA in dystonia patients may explain the clinical symptomatology of focal dystonia. Magnetic resonance spectroscopy may be a useful noninvasive tool in the evaluation of regional brain GABA changes and in monitoring the effects of various therapies.
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PMID:Impaired brain GABA in focal dystonia. 1178 88

The underlying mechanisms of idiopathic dystonias are poorly understood. The dystonic phenotype in the dt(sz) mutant hamster, a model of paroxysmal dystonia, has been suggested to be based on a deficit of gamma-aminobutyric acid (GABA)ergic interneurons and changes of the GABA(A)-benzodiazepine receptor complex in the striatum. In order to confirm and extend previous observations, the effects of compounds which bind to different sites of the GABA(A) receptor on the severity of dystonia were determined after striatal microinjections in comparison to systemic treatments in dt(sz) mutants. The GABA(A) receptor agonist (muscimol) and the benzodiazepine (flurazepam) reduced the severity of dystonia after striatal and systemic injections. The antidystonic effects of the barbiturate phenobarbital were less marked both after striatal and intraperitoneal administration of drugs. Intrastriatal injections of GABA delayed the onset of dystonic attacks. Striatal and systemic treatments with the GABA(A) receptor antagonist, bicuculline, and with pentylenetetrazole, which reduces GABAergic function, accelerated the onset of dystonia at subconvulsant doses. The benzodiazepine receptor antagonists flumazenil aggravated dystonia after systemic and intrastriatal injections. In all, the present data substantiate the relevance of striatal GABAergic disinhibition in the pathogenesis of paroxysmal dystonia in dt(sz) mutants.
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PMID:Effects of striatal injections of GABA(A) receptor agonists and antagonists in a genetic animal model of paroxysmal dystonia. 1204 93

The dt(sz) hamster is a well-established animal model of idiopathic paroxysmal dystonia. Previous investigations of this mutant have indicated dysfunctions of the gamma-aminobutyric acid (GABA)-ergic system within the basal ganglia. Systemic administration of the central stimulant pentylenetetrazole (PTZ) aggravated dystonia at subconvulsant doses, whereas GABA-mimetic drugs have beneficial effects in dt(sz) hamsters. GABA mimetics also provide clinical benefit in humans with idiopathic paroxysmal dystonia. The spontaneous discharge rates of substantia nigra pars reticulata (SNr) neurons was unaltered in anesthetized dt(sz) hamsters, but systemic application of subconvulsant doses of PTZ caused significantly greater increases of discharge rates in dystonic hamsters compared with nondystonic controls. The present study tested the hypothesis that SNr neurons are more sensitive to local application of PTZ in dt(sz) hamsters than in nondystonic hamsters. PTZ applied locally by pressure injection at 2, 3, and 5 mM to the SNr during in vivo single unit recordings revealed a dose-dependent increase of SNr discharge rates in mutants and controls relative to predrug rates, with a significantly greater increase in mutants at 3 mM PTZ. To examine the functional relevance of the increased susceptibility of SNr neurons to PTZ in mutants, the effects of PTZ on severity of dystonia were investigated after microinjections into the SNr of freely moving dt(sz) hamsters. Bilateral nigral microinjection of 40 ng PTZ did not aggravate dystonia but exerted moderate antidystonic effects. Therefore, the previous findings of prodystonic effects of systemic administration of PTZ in dt(sz) hamsters are related to extranigral effects rather than to the elevation of nigral discharge rates in response to systemic, or locally applied, PTZ. The greater susceptibility of neurons within the SNr to PTZ suggests dysfunctions of the GABA(A) receptor in dt(sz) mutants.
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PMID:Effects of locally administered pentylenetetrazole on nigral single unit activity and severity of dystonia in a genetic model of paroxysmal dystonia. 1211 49

Previous studies suggested an involvement of gamma-aminobutyric acid (GABA)-mediated excitation by an enhanced efflux of bicarbonate ions in addition to retarded development of GABAergic inhibition in the syndrome of dt(sz) mutant hamsters, a model of paroxysmal dyskinesia in which dystonic episodes occur in response to stress. Acetazolamide blocks bicarbonate regeneration in neurons and can thereby reduce GABA-mediating excitation without affecting GABA-mediated inhibition. In the present study, the effects of acetazolamide (15-60 mg/kg, i.p.) on severity of dystonia were therefore examined in dt(sz) hamsters. Acetazolamide significantly reduced the severity of dystonia at a dose of 60 mg/kg. These data are in line with several case reports from patients with paroxysmal dystonia, suggesting that acetazolamide can be useful in the treatment of this movement disorder. The mechanism of the antidystonic efficacy of acetazolamide has to be examined by further studies.
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PMID:The carbonic anhydrase inhibitor acetazolamide exerts antidystonic effects in the dt(sz) mutant hamster. 1546 95

In the dtsz mutant hamster, a model of paroxysmal dyskinesia in which dystonic episodes occur in response to stress, previous studies suggested that retarded development of gamma-aminobutyric acid (GABA)ergic inhibition plays a critical role in the pathogenesis. In the present study, we therefore examined the effects of selective GABA uptake inhibitors on severity of dystonia in dtsz hamsters. R(-)N-(4,4-di(3-methylthien-2-yl)-but-3-enyl) nipecotic acid hydrochloride (tiagabine, 5-20 mg/kg i.p.) and 1-[2-[[(diphenylmethylene) imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-711, 1-10 mg/kg i.p.) significantly reduced the severity of dystonia. These data suggest that GABA uptake inhibitors may provide novel therapeutic approaches for paroxysmal dyskinesias.
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PMID:Antidystonic efficacy of gamma-aminobutyric acid uptake inhibitors in the dtsz mutant. 1618 56

Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABA(A) receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.
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PMID:Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice. 1638 Jul 13


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