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)

At the present time, it seems unlikely that progressive neurodegenerative diseases, such as ALS, Parkinson's disease, and dementia of the Alzheimer type, are triggered by environmental agents with excitotoxic potential. These include excitotoxic agents that behave as glutamate agonists or disrupt energy metabolism: both types elicit permanent but self-limiting neuronal diseases with patterns of neuronal deficit that reflect selective chemical exposure (MPP+ and parkinsonism), differential susceptibility to energy dysmetabolism (NPA and dystonia), or the distribution of glutamate-receptors (domoic acid and memory loss). If environmental agents play an etiologic role in progressive neurodegenerative diseases, they are likely to target a critical, irreplaceable neuronal molecule that is required to maintain long-term neuronal integrity.
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PMID:Are human neurodegenerative disorders linked to environmental chemicals with excitotoxic properties? 132 79

The concentrations of 11 amino acids, including the neurotransmitters gamma-aminobutyric acid, glutamate, aspartate, glycine, and taurine, were determined by HPLC in 12 brain regions of genetically dystonic (dtSZ) hamsters and age-matched nondystonic controls. Since dystonia in mutant dtSZ hamsters is transient and disappears after about 70 days of age, amino acids were determined at the age of maximum severity of dystonia (30-40 days) and after disappearance of the disease, to examine which neurochemical changes were related to dystonia. In dtSZ hamsters with the maximum severity of dystonia, significant changes in concentrations of the neurotransmitters gamma-aminobutyric acid, glutamate, aspartate, and taurine were found in several regions involved in motor functions, e.g., cerebellum, thalamus, and corpus striatum. Most of these changes were not permanent but disappeared in parallel with dystonia, implicating a causal relationship between altered aminoacidergic neurotransmission and dystonia in mutant dtSZ hamsters.
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PMID:Abnormalities in amino acid neurotransmitters in discrete brain regions of genetically dystonic hamsters. 135 2

Recent advances in our understanding of the neurochemical anatomy of the pyramidal and extrapyramidal motor systems have led to more logical and effective pharmacotherapies for movement disorders. Our knowledge of the neurochemistry of Parkinson's and Huntington's diseases is the most complete. In the future, the same approaches used in these diseases need to be used on the somewhat less common disorders such as progressive supranuclear palsy, dystonia, Tourette's syndrome, and cerebellar ataxias. Postmortem neurochemical analyses of these diseases should be exciting and will improve our overall understanding of the neurochemistry of movement disorders. The second area that is moving rapidly is investigations of the role of neuropeptides and the excitatory neurotransmitter glutamate. These agents are in high concentrations in motor pathways and projection areas. Further elucidation of their functional roles in the pathogenesis and pathophysiology of basal ganglia diseases should provide new approaches and therapies for motor disorders.
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PMID:Neurochemical anatomy of movement disorders. 615 81

Recent findings of antidystonic effects of NMDA and non-NMDA receptor antagonists in an inbred line of Syrian hamsters with primary generalized dystonia prompted us to investigate the effects of lamotrigine, an inhibitor of veratrine-induced glutamate release, on the severity of dystonia in mutant hamsters. In mutant dystonic hamsters the dystonic attacks which can be induced by mild environmental stimuli or handling are age-dependent with maximum severity between days 30 and 40 of life (maximum period). Thereafter the severity of dystonia slowly declines (post-maximum period) until the susceptibility to induction of dystonia disappears completely at an age of about 70 days. Lamotrigine (5.0, 10.0 or 30.0 mg/kg i.p.) dose dependently decreased the latency to onset of dystonic attacks. Furthermore, at a dose of 30 mg/kg the dystonic attacks were aggravated when lamotrigine was administered during the max and post-max period. Even in mutant hamsters older than 70 days, i.e. after spontaneous remission of dystonia, and in an inbred line of non-dystonic Syrian hamsters with genetic origin similar to the mutant hamsters, lamotrigine (10.0 or 30.0 mg/kg i.p. and 30.0 mg/kg p.o.) provoked dystonic disturbances. In a genetically different outbred line of Syrian hamsters, lamotrigine did not cause dystonic movements. The unexpected finding that lamotrigine exerts prodystonic effects in genetically susceptible hamsters may be due to the lack of selectivity of lamotrigine to block glutamate release. Tentatively, simultaneous inhibition of GABA (gamma-aminobutyric acid) release might be critically involved in the prodystonic activity of lamotrigine.
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PMID:The novel antiepileptic drug, lamotrigine, exerts prodystonic effects in a mutant hamster model of generalized dystonia. 769 75

The genetically dystonic hamster is an animal model of idiopathic dystonia that displays sustained abnormal movements and postures either spontaneously or in response to mild environmental stimuli. Previous pharmacological studies have shown that competitive and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists exert potent antidystonic activity in this model, indicating that abnormal NMDA receptor function may be involved in the pathophysiology of this movement disorder. Autoradiographic analysis of NMDA receptor density in 67 brain regions, using the ligand [3H] N-(1-[2-thienyl]cyclohexyl)3,4-piperidine, which binds to the phencyclidine (PCP) site in the ion channel of the NMDA receptor channel complex, revealed that NMDA receptor binding is not substantially altered in dystonic hamster brains compared to age-matched controls. Nevertheless, there was a tendency towards enhanced binding during a dystonic attack in several regions, including a 25% increase in the ventrolateral thalamic nucleus (P < 0.05), which may be associated with altered basal ganglia output. While the data do not indicate widespread abnormalities in the PCP site of the NMDA complex, they do not exclude the possibility of more pronounced changes at other regulatory binding sites of the NMDA complex or other types of glutamate receptors in dystonia.
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PMID:Alterations in N-methyl-D-aspartate receptor binding in dystonic hamster brains. 903 Apr 27

The effects of riluzole (2-amino-6-trifluoromethoxy benzothiazole) on the severity of dystonia were examined in mutant hamsters (dtsz), an animal model of idiopathic dystonia in which dystonic attacks can be age dependently induced by mild stress. Previous studies in hamsters have shown antidystonic activity of various glutamate receptor antagonists whereas lamotrigine, considered as an inhibitor of glutamate release, exerted prodystonic effects. The latter, unexpected, finding prompted us to investigate riluzole which is thought to possess antiglutamatergic properties with mechanisms similar to those of lamotrigine. Riluzole (2, 5, 10 or 20 mg/kg i.p.) dose dependently decreased the latency to onset of dystonic attacks. A dose of 10 or 20 mg/kg significantly increased the severity of dystonia. Even in dtsz hamsters older than 70 days, i.e., after spontaneous remission of age-dependent dystonia, riluzole (10 or 20 mg/kg) provoked severe long-lasting (> 4 h) dystonic attacks. At a dose of 20 mg/kg, riluzole provoked short-lasting (< 1 h) dystonic disturbances also in non-dystonic control hamsters. Electroencephalographic recordings from depth electrodes in the red nucleus, where recent studies have shown abnormal neural activity before and during dystonic attacks in dtsz hamsters, revealed that riluzole (10 mg/kg) tended to cause a further decrease of the total power in dtsz hamsters and significantly reduced the total power in control animals. This finding may indicate that the prodystonic effects of riluzole are related to alterations of rubrospinal activity. With regard to antidystonic effects of glutamate receptor antagonists demonstrated in previous studies, the prodystonic effects of riluzole and, as shown by recent experiments, of lamotrigine also, may be due to the lack of selectivity of these drugs to inhibit glutamate release.
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PMID:Prodystonic effects of riluzole in an animal model of idiopathic dystonia related to decreased total power in the red nucleus? 928 14

The interaction of nigrostriatal dopamine and corticostriatal glutamate plays a critical role in motor output. Recent studies in mutant dystonic hamsters (dt[sz]), an animal model of idiopathic generalized dystonia, revealed antidystonic effects of both N-methyl-D-aspartate (NMDA) receptor antagonists, such as dizocilpine (MK-801), and of neuroleptics, such as haloperidol and clozapine. Whereas the neuroleptics reduced spontaneous locomotion at antidystonic effective doses, MK-801 caused hyperactivity in mutant hamsters. Therefore, the combination of neuroleptics and MK-801 may exhibit synergistic antidystonic effects, while the side effects may be counteracted. In order to prove this assumption, the neuroleptics haloperidol and clozapine were coadministered with MK-801 in dt(sz) hamsters in the present study. The antidystonic effects were potentiated by coadministration of MK-801 and clozapine, but not by the combination of MK-801 and haloperidol. The coadministration of MK-801 and clozapine did not cause severe side effects, such as catalepsy in dystonic hamsters. In contrast to the well-documented reverse of haloperidol-induced catalepsy by MK-801 in rats, in mutant hamsters, catalepsy was increased by coadministration of haloperidol and MK-801. This unexpected finding could be due to pathophysiological brain alterations in dt(sz) hamsters, because in non-dystonic control hamsters, combined treatment with MK-801 and haloperidol did not cause cataleptogenic effects.
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PMID:MK-801 potentiates antidystonic effects of clozapine but not of haloperidol in mutant dystonic hamsters. 937 98

Early-onset torsion dystonia, an autosomal dominant disease associated with the DYT1 locus on 9q34, is the most frequent genetic form of dystonia. Recent work has revealed that the causative mutation in most cases is deletion of a glutamate residue from the carboxy terminal of torsinA, a 332 amino acid protein encoded by the DYT1 gene. To gain insight into how deletion of a single amino acid can produce such a profound movement disorder, we have mapped the expression of the DYT1 gene in normal human postmortem brain. DYT1 mRNA is highly enriched in the dopamine neurons of the substantia nigra pars compacta. Intense expression was also found in the cerebellum and hippocampal subfields. The prominent expression of the DYT1 gene within the substantia nigra pars compacta, which provides dopaminergic innervation to the basal ganglia, implicates a disturbance of dopaminergic function in the pathophysiology of early-onset torsion dystonia.
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PMID:Expression of the early-onset torsion dystonia gene (DYT1) in human brain. 958 64

Niemann-Pick disease Type C (NPC) is a progressive neurovisceral metabolic disorder that is caused in most patients by a defect in a recently found gene, NPC-1. Neurological damage includes visual disorders such as vertical supranuclear gaze palsy, movement disorders such as dystonia and ataxia, dementia, and seizures. So far the biochemical deficit, most likely manifested by delayed intracellular cholesterol transport, has not been correlated with the progressive neurological damage. A mutant Balb/C mouse with a defect in the same gene is used as a model to study NPC. Pathological examination of brain tissue obtained by autopsy from NPC patients or brains of affected NPC mice of different ages, revealed signs of extensive damage throughout the brain, including neurofibrillary tangles and intracellular storage of various compounds. Loss of cerebellar Purkinje cells was the most significant specific damage. The present study examined whether the neurochemical changes present in the NPC mouse brain were related to the pathological changes. The results show major alterations in the levels of serotonin and its main metabolite, 5-hydroxyindoleacetic acid, in the cerebellum and cortex of NPC mice. The levels of the inhibitory amino acid glycine were threefold higher in the cerebellum of NPC mice and those of glutamate and GABA decreased in the cortex. Tyrosine hydroxylase immunoreactivity was present in Purkinje cells, and the levels of L-DOPA increased specifically in the vermis of the cerebellum. These results are the first to indicate changes in neurotransmitters in NPC and that these could be correlated with some of the neuropathology of this disease.
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PMID:Neurochemical alterations in the cerebellum of a murine model of Niemann-Pick type C disease. 967 2

Central cannabinoid receptors are densely located in the output nuclei of the basal ganglia (globus pallidus, substantia nigra pars reticulata), suggesting their involvement in the regulation of motor activity. Furthermore, there is evidence that endogenous cannabinoid transmission plays a role in the manipulation of other transmitter systems within the basal ganglia by increasing GABAergic transmission, inhibiting glutamate release and affecting dopaminergic uptake. Most hyperkinetic and hypokinetic movement disorders are caused by a dysfunction of basal ganglia-thalamo-cortical loops. It has been suggested that an endogenous cannabinoid tone participates in the control of movements and, therefore, the central cannabinoid system might play a role in the pathophysiology of these diseases. During the last years in humans a limited number of clinical trials demonstrated that cannabinoids might be useful in the treatment of movement disorders. Despite the lack of controlled studies there is evidence that cannabinoids are of therapeutic value in the treatment of tics in Tourette syndrome, the reduction of levodopa-induced dyskinesia in Parkinson s disease and some forms of tremor and dystonia. It can be speculated that cannabinoid antagonists might be useful in the treatment of chorea in Huntington s disease and hypokinetic parkinsonian syndromes.
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PMID:Cannabis in movement disorders. 1062 63


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