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)

1 The effects on the high pressure neurological syndrome (HPNS) of drugs which facilitate gamma-aminobutyric acid (GABA) transmission were investigated. Threshold pressures for the onset of the behavioural signs of the HPNS in mice--tremors and convulsions were established. 2 Flurazepam hydrochloride 20 and 10 mg/kg and sodium valproate 800 and 400 mg/kg substantially raised the threshold pressures for both tremor and convulsions. 3 Amino-oxyacetic acid 35 and 25 mg/kg and diaminobutyric acid 600 mg/kg also significantly increased the thresholds. Muscimol 1 mg/kg (and 150 ng i.c.v.) was ineffective at non-toxic doses. 4 These effects paralleled the drugs' ability to raise the convulsion threshold to intravenous infusion of bicuculline in mice. 5 These results demonstrate that drugs with actions more selective than those of the general anaesthetics are effective against the HPNS. It is also possible that there is a GABAergic component to the effects of general anaesthetics on the HPNS.
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PMID:Drugs that increase gamma-aminobutyric acid transmission protect against the high pressure neurological syndrome. 628 24

Intraperitoneal injection of ethanol (1-2 g/kg) and chlordiazepoxide (2-16 mg/kg) suppressed susceptibility to audiogenically induced, clonic-tonic seizures and antagonized forelimb tremor in rats undergoing ethanol withdrawal, 30 min after treatment. However, a smaller dose of ethanol (0.5 g/kg) actually increased clonic seizure frequency, suggesting that ethanol exerts a biphasic proconvulsant/anticonvulsant action. Direct activation of gamma-aminobutyric acid (GABA) receptors by intracisternal administration of GABA (100-1000 micrograms), muscimol (0.3-1.0 micrograms) or 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) (0.3-3.0 micrograms) 5 to 10 min before testing also reduced susceptibility to audiogenic clonic-tonic seizures. In sharp contrast to these anticonvulsant actions, GABA, muscimol and THIP had no effect on withdrawal-induced forelimb tremors. Blockade of GABA uptake with 1-2,4-diaminobutyric acid (300 and 600 mg/kg i.p.) and inhibition of GABA transaminase with aminooxyacetic acid (12.5 and 25.0 mg/kg i.p.) both reduced susceptibility to seizures. However, anticonvulsant doses of these two drugs, unlike GABA, muscimol and THIP, also reduced forelimb tremor. Three other GABA transaminase inhibitors, gamma-vinyl GABA (450 and 900 mg/kg i.p.), gamma-acetylenic GABA (50-150 mg/kg i.p.) and ethanolamine-O-sulfate (250-750 mg/kg i.p.), were inactive against ethanol withdrawal audiogenic seizures and forelimb tremors. These results indicate that direct GABA receptor activation can selectively suppress one type of ethanol withdrawal response (i.e., audiogenic seizure susceptibility) while failing to influence another (forelimb tremors).
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PMID:Differential sensitivity of ethanol withdrawal signs in the rat to gamma-aminobutyric acid (GABA)mimetics: blockade of audiogenic seizures but not forelimb tremors. 631 80

Pretreatment of rats with homotaurine (3 aminopropanesulfonic acid; 3APS), a synthetic gamma-aminobutyric acid (GABA) analog, protected from the convulsant and cytotoxic action of systemically injected kainic acid (KA). Wet dog shaking (WDS) behavior was significantly reduced. Taurine, an inhibitory non-GABA-mimetic amino acid, and muscimol (another direct GABA-agonist) reduced the number of seizures and lesions in the brain but were less effective than homotaurine. Progabide (a GABA-agonist) did not modify kainic acid effects. The neurotoxicity of kainic acid could have been due to repetitive convulsive activity. Activation of GABA-mediated inhibition is an effective, but not the determinant means of preventing KA-induced abnormalities.
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PMID:Homotaurine (3 aminopropanesulfonic acid; 3APS) protects from the convulsant and cytotoxic effect of systemically administered kainic acid. 719 33

Three genes (Gabrg3, Gabra5, and Gabrb3) encoding the gamma 3, alpha 5, and beta 3 subunits of the type A gamma-aminobutyric acid receptor, respectively, are known to map near the pink-eyed dilution (p) locus in mouse chromosome 7. This region shares homology with a segment of human chromosome 15 that is implicated in Angelman syndrome, an inherited neurobehavioral disorder. By mapping Gabrg3 on a panel of p-locus deletions, we have determined that the order of genes within this cluster is centromere-p(D15S12h)-Gabrg3-Gabra5-Gabrb3-telom ere. Like Gabrb3, neither the Gabra5 nor Gabrg3 gene is functionally imprinted in adult mouse brain. Mice deleted for all three subunits die at birth with a cleft palate, although there are rare survivors (approximately 5%) that do not have a cleft palate but do exhibit a neurological abnormality characterized by tremor, jerky gait, and runtiness. We have previously suggested that deficiency of the beta 3 subunit may be responsible for the clefting defect. Most notably, however, in this report we describe mice carrying two overlapping, complementing p deletions that fail to express the gamma 3 transcript, as well as mice from another line that express neither the gamma 3 nor alpha 5 transcripts. Surprisingly, mice from both of these lines are phenotypically normal and do not exhibit any of the neurological symptoms characteristic of the rare survivors that are deleted for all three (gamma 3, alpha 5, and beta 3) subunits. These mice therefore provide a whole-organism type A gamma-aminobutyric-acid receptor background that is devoid of any receptor subtypes that normally contain the gamma 3 and/or alpha 5 subunits. The absence of an overt neurological phenotype in mice lacking the gamma 3 and/or alpha 5 subunits also suggests that mutations in these genes are unlikely to provide useful animal models for Angelman syndrome in humans.
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PMID:Phenotypic consequences of deletion of the gamma 3, alpha 5, or beta 3 subunit of the type A gamma-aminobutyric acid receptor in mice. 814 95

The mouse pink-eyed cleft-palate (p(cp)) mutation is characterized by hypopigmentation associated with cleft palate, neurological disorders and runting. Most p(cp) homozygotes are born with cleft palate and die shortly after birth, presumably as a result of feeding problems. A few exceptional p(cp) mutants live beyond this stage but display tremor and jerky gait. We report here that the genes encoding the gamma-aminobutyric acid type A (GABAA) receptor subunits alpha 5 (originally described as alpha 4; ref. 4), beta 3 and gamma 3 are disrupted by a deletion in p(cp) mice. We also show that the alpha 5 and gamma 3 genes are located between the p and beta 3 genes on mouse chromosome 7. The p(cp) deletion leads to alterations of binding properties of the GABAA receptors in the brain, providing an in vivo model system for studying GABAA receptor function. The human homologue of the region deleted in p(cp) mice is associated with Angelman syndrome. Thus, p(cp) mice may be useful in defining the region containing the gene(s) for this syndrome.
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PMID:A cluster of three GABAA receptor subunit genes is deleted in a neurological mutant of the mouse p locus. 839 62

Tiagabine is a gamma-aminobutyric acid (GABA) uptake inhibitor which is structurally related to nipecotic acid but has an improved ability to cross the blood-brain barrier. Clinical trials have shown that tiagabine is effective as add-on therapy in the management of patients with refractory partial epilepsy. In short term studies of this indication, tiagabine < or = 64 mg/day for 7 to 12 weeks reduced the complex partial and simple partial seizure frequency by > or = 50% in 8 to 31 and 28.2 to 37% of patients, respectively. Tiagabine appeared to produce a sustained reduction in seizure frequency in studies of up to 12 months' duration. Data from preliminary studies are currently insufficient to confirm the usefulness of tiagabine when used as monotherapy or in the treatment of children with epilepsy. Further studies are, therefore, necessary to more fully elucidate the efficacy of the drug in these settings. Adverse events associated with tiagabine are primarily CNS-related and include dizziness, asthenia, nonspecific nervousness and tremor. Skin rash or psychosis occurred with similar frequencies among tiagabine- and placebo-treated patients. With long term administration (> or = 1 year for many patients), the profile and incidence of adverse events was similar to that for short term therapy. Tiagabine does not appear to affect the hepatic metabolism of other drugs such as carbamazepine and phenytoin. Possible disadvantages of tiagabine include its short plasma elimination half-life, necessitating 2 to 4 times daily administration, and its inducible hepatic metabolism. Thus, tiagabine is a new antiepileptic agent with a novel mechanism of action, which has demonstrated efficacy in the adjunctive treatment of patients with refractory partial epilepsy. Further investigation of the efficacy of tiagabine is expected to provide a clearer definition of its place in the treatment of epilepsy and its relative merits in relation to other antiepileptic drugs.
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PMID:Tiagabine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy. 953 May 48

Within 10 minutes of intraperitoneal injection of penitrem A (3 mg/kg), rats develop severe generalized tremors and ataxia that persist for up to 48 hours. These are accompanied by a three- to fourfold increase in cerebellar cortical blood flow. Mitochondrial swelling occurs in cerebellar stellate and basket cells within 30 minutes of dosing and persists for more than 12 hours without leading to cell death. From 2 hours, Purkinje cell dendrites show early cytoplasmic condensation accompanied by fine vacuolation of smooth endoplasmic reticulum and enlargement of perikaryal mitochondria. From 6 hours, many Purkinje cells develop intense cytoplasmic condensation with eosinophilia that resembles "ischemic cell change," and from 12 hours, many other Purkinje cells show marked watery swelling. Astrocytes begin to swell from 0.5 hours after injection and show hypertrophy of organelles from 6 hours. Also from 6 hours onward, discrete foci of necrosis appear in the granule cell layer, while permeability of overlying meningeal vessels to horseradish peroxidase becomes evident at 8 hours. All changes are more severe in vermis and paravermis. Despite widespread loss of Purkinje cells, the animals' behavior becomes almost normal within a week. While tremor occurs with doses of 1.5 and 0.5 mg/kg, cellular damage is minimal. The tremor mechanism differs from that of harmaline since destruction of inferior olivary nuclei abolishes neither the tremor response to penitrem A nor the cellular damage. No morphological changes are found in other brain regions. The affinities of penitrem A for high-conductance calcium-dependent potassium channels and for gamma-aminobutyric acid receptors with the probability of resultant excitotoxity are considered to be important underlying factors for these changes.
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PMID:The effects of the tremorgenic mycotoxin penitrem A on the rat cerebellum. 954 35

Tiagabine exerts its antiepileptic drug (AED) activity by selectively inhibiting the uptake of gamma-aminobutyric acid (GABA) onto the transporter molecules, and thus, increasing extracellular concentrations of GABA in the brain. The absorption and elimination of tiagabine follow linear pharmacokinetics. Tiagabine is metabolized by hepatic cytochrome P450 enzymes and enzyme-inducing AEDs increase tiagabine clearance by 50-65%. Tiagabine has shown no clinically important interactions with other drugs, including oral contraceptives. In the perforant pathway stimulation model of status epilepticus, tiagabine reduced the seizure number and severity, and also prevented the loss of pyramidal cells in the hippocampus as well as alleviated impairment of the spatial memory impairment associated with hippocampal damage. Tiagabine has both antiepileptogenic and anticonvulsant effects in the kindling model of epilepsy. Based on the data from the short- and long-term add-on studies, tiagabine is effective adjunctive therapy for all partial seizure types in adolescents and adults. Conversion to tiagabine monotherapy has been also possible in substantial amount of patients with partial seizures in three trials. Tiagabine is generally well-tolerated. The most common adverse events in controlled studies involve the central nervous system; for example, dizziness, asthenia, nervousness, tremor, depressed mood and emotional lability. Special safety analyses with formal neuropsychological testing suggest that tiagabine does not adversely affect cognition or mood. Tiagabine represents an important new therapeutic option for patients with treatment-refractory partial seizures. The role of tiagabine in the management of partial epilepsy of patients with intellectual disability is especially emphasized since tiagabine has a low side-effect profile in the cognitive area.
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PMID:Tiagabine: a new therapeutic option for people with intellectual disability and partial epilepsy. 1003 Apr 35

Four major components of the mechanism of action have been identified for the antiparkinsonian drug budipine up to now. 1) The primary action of budipine is an indirect dopaminergic effect as shown by facilitation of dopamine (DA) release, inhibition of monoamine oxidase type B (MAO-B) and of DA (re) up-take and stimulation of aromatic L-amino acid decarboxylase (AADC), which in sum might be responsible for enhancing the endogenous dopaminergic activity. 2) Radioligand and functional studies at the N-methyl-D-aspartate (NMDA) type glutamate receptor characterize budipine as a low-affinity, uncompetitive antagonist with fast kinetics and moderate voltage-dependency at the phencyclidine (PCP) binding site, comparable to that observed with amantadine, thereby counteracting an increased excitatory glutamatergic activity. 3) The antimuscarinic action of budipine, verified by functional and binding studies at native muscarinic M1-M3 and human recombinant m1-m5 receptor subtypes in vitro, is up to 125-fold weaker than that of biperiden and corresponds to its approximately 100-fold lower potency to cause experimentally-induced peripheral antimuscarinic effects and explains only part of its high potency, which equals biperiden, to suppress cholinergically evoked tremor. 4) An additional inhibition of striatal gamma-aminobutyric acid (GABA) release by budipine may be beneficial to suppress an increased striatal GABAergic output activity. The contribution of other observed effects to the therapeutic action of budipine, i.e. weak stimulation of noradrenaline and serotonin release, binding to brain sigma1 receptors and blockade of histamine H1 receptors, is not yet clear. By means of these multiple mechanisms, budipine might correct the imbalance of striatal output pathways by restoring DA levels in the striatum, and positively influence the secondary changes in other transmitter systems (glutamate, acetylcholine, GABA) observed in Parkinson's disease.
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PMID:Multiple mechanisms of action: the pharmacological profile of budipine. 1037 Sep 4

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


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