Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The concentrations of amino acids in the cerebrospinal fluid (CSF) (n = 20) and serum (n = 20) taken from patients with essential tremor were measured by HPLC and compared with those of controls (n = 10). Reduced concentrations of some amino acids (asparagine, glutamine, glycine, threonine, isoleucine, leucine) were observed in serum taken from patients with tremor. Significant increases were detected in the concentrations of glutamate (p < 0.001) and aspartate (p < 0.01). The general tendency of the changes in CSF and serum was similar; although the highest differences were observed in amino acid concentrations in the serum of patients with essential tremor. Opposite shifts of some amino acids were detected, in the concentrations of aspartate, serine, tyrosine, leucine, and isoleucine, which may indicate the independence of the changes in the serum from those in the CSF. This study raises the possibility that a genetically determined metabolic disorder is involved in the etiology of essential tremor that appears peripherally and, partly, centrally. The slight increase in the concentration of glutamate together with the reduced levels of GABA, glycine, and serine in CSF may form the neurochemical basis of the central oscillation observed in essential tremor.
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PMID:Change in the concentrations of amino acids in CSF and serum of patients with essential tremor. 881 1

Functional models of the circuitry of the basal ganglia have recently been proposed to account for the vast spectrum of motor disorders associated with the loss of anatomical or neurochemical integrity within the basal ganglia. On the basis of these hypothetical models, hypokinetic disorders such as Parkinson's disease, are thought to be associated with excessive tonic and phasic inhibition of the output from the basal ganglia to the thalamus. In the present study we have attempted to determine the validity of the proposed model by measuring neurochemical markers of inhibitory and excitatory neurotransmission in post mortem human brain tissue. We have determined the concentrations of the excitatory neurotransmitters aspartate/glutamate and of the inhibitory neurotransmitter GABA in 18 relevant regions of the thalamocortical circuits of the basal ganglia of patients who had manifested Parkinsonian symptoms, and compared them with controls of individuals who had died without any history of neurological or psychiatric disorders and had no neuropathological abnormalities. Additionally, the receptor subtype for the excitatory amino acid N-methyl-D-aspartate (NMDA) was studied in the same brain tissue in which neurotransmitter concentrations had been analysed as neurochemical markers of post-synaptic excitatory neurotransmission. In patients who had manifested Parkinsonian symptoms, glutamate and aspartate levels were found to be unchanged in all examined brain regions. In contrast, the binding of [3H]MK-801, which identifies the NMDA receptor, was reduced in the head (-42%) and body (-38%) of the caudate nucleus. In parkinsonian patients, GABA levels were diminished by 36% in the centromedial thalamus, compared to control values. These results do not confirm the changes in neurotransmitter concentrations predicted according to the model, although we cannot rule out that the predicted changes might have been observed if the Parkinsonian group had been further subdivided into groups diagnosed on the basis of the patients' clinical picture (akinetic-rigid, tremor-dominant, equivalent type) and compared with the control group.
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PMID:A post mortem study on neurochemical markers of dopaminergic, GABA-ergic and glutamatergic neurons in basal ganglia-thalamocortical circuits in Parkinson syndrome. 900 16

The reticular thalamic nucleus consists of densely packed neurons containing the neurotransmitter GABA. It surrounds the lateral border of the thalamus, has extensive reciprocal connections with thalamocortical neurons, and is thought to be involved in attentional processes. The reticular thalamic nucleus also receives direct and indirect inputs from the basal ganglia, suggesting that it may be involved in relaying motor information to the thalamus and cortex. We examined the possibility that decreased dopaminergic transmission in the basal ganglia indirectly affects the reticular thalamic nucleus. Rats received unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta and were killed two or three weeks after the lesion. Sections of the reticular thalamic nucleus were processed for in situ hybridization histochemistry at the single cell level with RNA probes for both isoforms of glutamate decarboxylase (M(r) 65,000: glutamate decarboxylase 65 and M(r) 67,000: glutamate decarboxylase 67), the rate limiting enzyme of GABA synthesis. Unilateral nigrostriatal dopaminergic lesions induced a topographically specific, bilateral increase in glutamate decarboxylase 67 messenger RNA in neurons of the lateral and ventral reticular thalamic nucleus. A much smaller increase in glutamate decarboxylase 65 messenger RNA was observed which was significant only ipsilateral to the lesion. Short- (seven day) and long-term (eight month) treatments with the antipsychotic drug haloperidol, in regimens that preferentially block D2 dopamine receptors, induced catalepsy and orofacial dyskinesia, respectively, but did not alter glutamate decarboxylase 67 messenger RNA levels in the reticular thalamic nucleus. Thus, loss of dopaminergic terminals, but not blockade of D2 dopamine receptors, induced the effects observed in the reticular thalamic nucleus. The results reveal a novel bilateral effect of unilateral dopamine depletion. In view of the role of the reticular thalamic nucleus in tremor and attentional processes, which are altered in Parkinson's disease, this effect may contribute to the clinical manifestations of nigrostriatal dopamine depletion.
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PMID:Unilateral nigrostriatal lesions induce a bilateral increase in glutamate decarboxylase messenger RNA in the reticular thalamic nucleus. 905 94

Four experiments were conducted to investigate the role of pallidal and nigral GABA in the generation of tremulous jaw movements in rats. In these experiments, tremulous jaw movements were induced by i.p. injections of the anticholinesterase tacrine (5.0 mg/kg). Previous work has shown that the tremulous jaw movements induced by cholinomimetics and dopamine depletion are dependent upon striatal mechanisms. Thus, the present study investigated potential striatal output pathways that could be involved in the generation of these movements. Because there are GABAergic projections from neostriatum to entopeduncular nucleus (medial globus pallidus) and substantia nigra pars reticulata, the GABA agonist muscimol was injected directly into these structures to study the effects of GABA stimulation on tacrine-induced jaw movements. Injections of muscimol into the entopeduncular nucleus (25-100 ng) failed to have any significant effects on tacrine-induced vacuous jaw movements. However, injections of muscimol (12.5-50 ng) into the substantia nigra pars reticulata blocked the jaw movements induced by tacrine. In the third experiment, it was again demonstrated that 25.0 ng of muscimol injected directly into the substantia nigra pars reticulata blocked the jaw movements induced by tacrine; in addition, it was shown that injections of this dose 2.0 mm dorsal to the substantia nigra pars reticulata failed to affect tacrine-induced tremulous jaw movements. It was shown in the fourth experiment that injections of muscimol into a more medial portion of the substantia nigra pars reticulata also reduced tacrine-induced tremulous jaw movements. These results indicate that stimulation of GABA(A) receptors in substantia nigra pars reticulata can block tacrine-induced tremulous jaw movements. This finding is consistent with the notion that striatonigral GABA projections are involved in the generation of tremulous jaw movements. It is also possible that striatonigral GABA mechanisms are involved in human clinical phenomena such as parkinsonian tremor.
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PMID:Involvement of pallidal and nigral GABA mechanisms in the generation of tremulous jaw movements in rats. 928 55

The effects of the administration of two doses (1,000 and 1,500 mg kg-1) of gamma-vinyl-GABA (GVG), have been tested in pubescent rats, systemically injected with kainic acid (KA). The changes in spontaneous behaviour before KA injection, the behavioural and epileptic manifestations (Wet Dog Shakes, Limbic Seizures and Status Epilepticus) and the lethality rate caused by KA were taken into account and compared to those observed in controls and in carbamazepine (CBZ) or phenytoin (PHT) treated animals. While GVG appeared to reduce the incidence of the epileptic manifestations and the subsequent mortality, particularly when higher doses of the drug were used, CBZ exerted a proconvulsant action and PHT did not substantially modify the parameters considered. Moreover, GVG, but not CBZ and PHT, induced remarkable sedative effects which disappeared within 48 h. The different anticonvulsant profile of GVG, CBZ and PHT were correlated to their different modes of action, since GVG acts by enhancing the inhibitory GABA-mediated processes, while CBZ and PHT act by reducing the excitatory processes.
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PMID:Vigabatrin versus carbamazepine and phenytoin in kainic acid-treated pubescent rats. 934 35

In the Weaver mutant mouse (wv/wv), an animal model for hereditary cerebellar ataxia, electrophysiological experiments have revealed a disorganized output of cerebellar Purkinje cells (the latter using GABA as an inhibitory transmitter) which, by a cascade of mechanisms, was thought to be the cause of the poor motor abilities. In Purkinje cell degeneration mice (pcd/pcd) lacking nearly all Purkinje cells and displaying milder motor deficiencies than wv, in comparison to wild-type mice, a strong increase in parvalbumin- and (co-localized with parvalbumin) glycine-immunopositive somata in the deep cerebellar and vestibular nuclei has recently been found. It was therefore intriguing to investigate whether motor performance in weaver mutants could be ameliorated by applying cerebellar lesions to eliminate the faulty output and to look for a change in transmitter weighting, indicated by a strong increase in parvalbumin-positive somata in areas (the respective target areas) which were formerly devoid of it. Ten Weaver mutants were subjected to cerebellar lesions. After removal of the vermis a total abolition of tremor, a definite improvement in the balance of affected body parts, an increase in locomotor activity when tested in an open-field matrix, and a strong increase in parvalbumin expression in Weaver mutant deep cerebellar and vestibular nuclei in comparison to wild-types have indeed been found. Increase in motor activity (or explorative behaviour) has been placed in relation to learning mechanisms. The increase in parvalbumin expression and the observed improvement in motor abilities and mechanisms probably related to learning underline the hypothesis that any change in the physiological equilibrium of the brain function by removal of input or output related to an assembly of nerve cells leads to a cascade of changes at the transmitter and neuronal level in near or distant connected brain structures.
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PMID:Vermectomy enhances parvalbumin expression and improves motor performance in weaver mutant mice: an animal model for cerebellar ataxia. 1033 81

Parkinson's disease (PD) is characterized by progressive neuronal loss associated with Lewy bodies in many subcortical nuclei leading to multiple biochemical and pathophysiological changes of clinical relevance. Loss of nigral neurons causing striatal dopamine deficiency is related to both the duration and clinical stages (severity) of the disease. The clinical subtypes of PD have different morphological lesion patterns: a) The akinetic-rigid type shows more severe cell loss in the ventrolateral part of substantia nigra zona compacta (SNZC) that projects to the dorsal putamen than the medial part projecting to caudate nucleus and anterior putamen, with negative correlation between SNZC cell counts, severity of akinesia-rigidity, and dopamine loss in the posterior putamen. Reduced dopaminergic input causes overactivity of the GABA ergic inhibitory striatal neurons projecting via the "indirect loop" to SN zona reticulata (SNZR) and medial pallidum (GPI) leading to inhibition of the glutamatergic thalamo-cortical motor loop and reduced cortical activation. b) The tremor-dominant type shows more severe neuron loss in medial than in lateral SNZC and damage to the retrorubral field A8 containing only few tyrosine hydroxylase and dopamine transporter immunoreactive (IR) neurons but mainly calretinin-IR cells. A8 that is rather preserved in rigid-akinetic PD (protective role of calcium-binding protein?) projects to the matrix of dorsolateral striatum and ventromedial thalamus. Together with area A10 it influences the strial efflux via SNZR to thalamus and from there to prefrontal cortex. Rest tremor in PD is associated with increased metabolism in the thalamus, subthalamus, pons, and premotor-cortical network suggesting an increased functional activity of thalamo-motor projections. In essential tremor, no significant pathomorphological changes but overactivity of cerebello-thalamic loop have been observed. c) In the akinetic-rigid forms of multisystem atrophy, degeneration is more severe in the lateral SNZC with severe loss of calbindin-IR cells reflecting initial degeneration of the striatal matrix in the caudal putamen with transsynaptic degeneration of striatonigral efferences that remain intact in PD. This fact and loss of striatal D2 receptors--as in advanced stages of PD--are reasons for negative response to L-dopa substitution. These data suggest different pathophysiological mechanisms of the clinical subtypes of PD that have important therapeutic implications. d) Involvement of extranigral structures in PD includes the mesocortical dopaminergic system, the noradrenergic locus coeruleus, dorsal vagal nucleus and medullary nuclei, serotonergic dorsal raphe, nucleus basalis of Meynert and other cholinergic brainstem nuclei, e.g. Westphal-Edinger nucleus (controlling pupillomotor function), posterolateral hypothalamus and the limbic system, e.g. amygdaloid nucleus, part of hippocampal formation, limbic thalamic nuclei with prefrontal projections, etc. Damage to multiple neuronal systems by the progressing degenerative process causing complex biochemical changes may explain the variable clinical picture of PD including vegetative, behavioural and cognitive dysfunctions, depression, pharmacotoxic psychoses, etc. Future comparative clinico-morphological and pathobiochemical studies will further elucidate the pathophysiological basis of specific clinical symptoms of PD and related disorders providing a broader basis for effective treatment strategies. Parkinson's disease (PD) is characterized by progressive degeneration of the nigrostriatal dopaminergic system and other subcortical neuronal systems leading to striatal dopamine deficiency and other biochemical deficits related to the variable clinical signs and symptoms of the disorder. (ABSTRACT TRUNCATED)
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PMID:Post mortem studies in Parkinson's disease--is it possible to detect brain areas for specific symptoms? 1037 Sep 1

Six patients undergoing stereotactic procedures for essential tremor received microinjections of muscimol (a gamma-aminobutyric acid-A [GABA(A)] agonist) into the ventralis intermedius thalamus in areas where tremor-synchronous cells were identified electrophysiologically with microelectrode recordings and where tremor reduction occurred with electrical microstimulation. Injections of muscimol but not saline consistently reduced tremor in each patient. The effect had a mean latency of 7 minutes and lasted an average of 9 minutes. We propose that GABA-mediated thalamic neuronal inhibition may represent a mechanism underlying the effectiveness of surgery for tremor and that GABA analogues could potentially be used therapeutically.
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PMID:Tremor arrest with thalamic microinjections of muscimol in patients with essential tremor. 1044 91

Tiagabine is a new antiepileptic drug which acts by blocking neuronal and glial GABA uptake and it is indicated in the treatment of partial epilepsies. Its pharmacokinetics is lineal, being extensively metabolized in the liver by means of CYP3A4 isoenzyme. Plasma elimination half life ranges between 5-8 hours in healthy volunteers, being markedly reduced when the drug is administered concomitantly with enzyme-inducing antinconvulsants. Tiagabine does not induce nor inhibit hepatic enzymes and, consequently, it does not modify the kinetics of simultaneously prescribed antiepileptic drugs. No relevant kinetic differences have been observed between adults and elderly subjects. Renal impairment does not alter the pharmacokinetic profile of tiagabine; hepatic disease, however, significantly reduces tiagabine elimination and lower daily doses of the drug are necessary in these patients. Although tiagabine elimination half life is short, it has been ascertained that therapeutic efficacy is similar when administered in 2 or 4 divided doses. Tiagabine is usually well tolerated; its most frequent side effects include dizziness, asthenia, nervousness, tremor, diarrhea and depressed mood.
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PMID:[Clinical implications of pharmacology and pharmacokinetics of tiagabine]. 1071 5

Initial observations in patients with tremor treated with deep brain stimulation (DBS) of the thalamus suggested that application of high-frequency stimulation (HFS) had a lesion-like effect. New clinical information from patients treated with DBS of the subthalamic nucleus (STN) and globus pallidus internus (GPi) suggested a more complex mechanism of action. Recent experiments in the rat have shown that HFS of the STN was accompanied by increased release of glutamate and dopamine in the substantia nigra and striatum, respectively. Observations made in the GPi of parkinsonian patients during surgery suggest that stimulation may excite GABA release in axons from afferent connections. Therefore, although depolarization block may remain a major mechanism of action, generation of action potentials and release of neurotransmitters may also be involved in the therapeutic effects of DBS in Parkinson's disease.
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PMID:Mechanism of action of deep brain stimulation. 1118 68


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