Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027066 (myoclonus)
 4,275 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we tested whether over-expressing the GABA(B) receptor R1a subtype in transgenic mouse forebrain neurons would be sufficient to induce spontaneous absence seizures. As hypothesized, these transgenic mice develop spontaneous, recurrent, bilaterally synchronous, 3-6 Hz slow spike and wave discharges between 2 and 4 months of age. These discharges are blocked by ethosuximide and exacerbated by baclofen confirming their absence nature. The discharges occur coincident with absence-like behaviors such as staring, facial myoclonus, and whisker twitching. However, in contrast to typical absence epilepsy models, these mice move during the ictal event, display spike and wave discharges in both thalamocortical and limbic circuitry, exhibit impaired hippocampal synaptic plasticity, and display significantly impaired learning ability. Collectively, these features are more characteristic of the less common but more debilitating atypical form of absence epilepsy. Thus, these data support a role for the GABA(B)R1a receptor subtype in the etiology of atypical absence epilepsy.
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PMID:Transgenic mice over-expressing GABA(B)R1a receptors acquire an atypical absence epilepsy-like phenotype. 1736 60

Huntington disease (HD) is a progressive heredoneurodegenerative disease manifested by chorea and other hyperkinetic (dystonia, myoclonus, tics) and hypokinetic (parkinsonism) movement disorders. In addition, a variety of psychiatric and behavioral symptoms, along with cognitive decline, contribute significantly to the patient's disability. Because there are no effective neuroprotective therapies that delay the progression of the disease, symptomatic treatment remains the cornerstone of medical management. Several classes of medications have been used to ameliorate the various symptoms of HD, including typical and atypical neuroleptics, dopamine depleters, antidepressants, antiglutamatergic drugs, GABA agonists, antiepileptic medications, acetylcholinesterase inhibitors, and botulinum toxin. Recently, surgical approaches including pallidotomy, deep brain stimulation, and fetal cell transplants have been used for the symptomatic treatment of HD. The selected therapy must be customized to the needs of each patient, minimizing the potential adverse effects. The primary aim of this article is to review the role of the different therapies, both available and investigational, for the treatment of the motor, psychiatric, behavioral, and cognitive symptoms of HD, and to examine their impact on the patient's functionality and quality of life.
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PMID:Symptomatic treatment of Huntington disease. 1839 62

Hypoxia modifies GABA(A) receptor (GABA(A)R) function and can cause seizures, encephalopathy or myoclonus. To characterize the effects of hypoxia on neuronal GABA(A)Rs, we subjected rat cortical neurons to 1% O2 for 2, 4 or 8h, followed by recovery times of 0-96h, and used whole-cell and perforated patch-clamp recording to assess GABA(A)R currents and pharmacology. Hypoxic exposure for 4h caused downregulation of maximal GABA current immediately following hypoxia and after 48h recovery without changing the EC50 for GABA. Two- and eight-hour hypoxic exposures had inconsistent effects on GABA(A)R currents. Maximal diazepam potentiation was increased immediately following 4h hypoxia, while potentiation by zolpidem was increased after 48h recovery. Pentobarbital enhancement and zinc inhibition of GABA currents were unchanged. Hypoxia also caused a depolarizing shift in the reversal potential of GABA-induced Cl(-) currents after 24h recovery. The L-type voltage-gated calcium channel (L-VGCC) blocker, nitrendipine, during hypoxia or control treatment prevented the reduction in GABA(A)R currents, and increased control currents over baseline. Nitrendipine also prevented the increase in zolpidem potentiation 48h after hypoxia, and blocked the depolarizing shift in Cl(-) reversal potential 24h after hypoxia. The effects of hypoxia on maximal GABA(A)R currents, zolpidem pharmacology and Cl(-) reversal potential thus require depolarization-induced calcium entry via L-VGCCs, and constitutive L-VGCC activity appears to reduce maximal GABA(A)R currents in control neurons via a calcium-dependent process. Calcium-dependent modulation of GABA(A)R currents via L-VGCCs may be a fundamental regulatory mechanism for GABA receptor function.
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PMID:Post-hypoxic changes in rat cortical neuron GABA A receptor function require L-type voltage-gated calcium channel activation. 1867 47

To evaluate the possible role of central free amino compounds in pediatric opsoclonus-myoclonus syndrome (OMS), 21 cerebrospinal fluid (CSF) amino compounds were measured by an amino acid analyzer or mass spectroscopy in 74 anesthetized children, 54 with OMS and 20 age-matched neurological controls. In OMS, only phosphoethanolamine was increased compared to controls; OMS severity and duration had significant converse effects on alanine and phosphoethanolamine. In contrast, corticotropin (ACTH) treatment was associated with increased alanine and phenylalanine, and decreased taurine compared to controls and untreated OMS, and increased glutamine, lysine, ornithine, and tyrosine compared to untreated OMS. Other than low taurine, these effects were not found with corticosteroid treatment, and non-steroidogenic immunotherapy had no effect. The ACTH dose-association was most apparent for alanine and phosphoethanolamine, but lysine and ornithine were also higher in the high-dose ACTH group. There were no significant disease- or treatment-associated perturbations in GABA, glycine, or other amino acids. These data suggest a unique pattern of ACTH effects on non-neurotransmitter CSF amino compounds, for the most part not shared by steroids.
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PMID:Neurometabolic effects of ACTH on free amino compounds in opsoclonus-myoclonus syndrome. 1899 Nov 96

Zolpidem and diazepam are widely used drugs acting via benzodiazepine binding sites on GABA(A) receptors. While diazepam is non-selective, zolpidem has a high affinity for alpha1-, and no affinity for alpha5-containing receptors. Several studies suggested that behavioral effects of zolpidem might be more similar to classical benzodiazepines than previously thought. To compare the sedative and anticonvulsant properties of these drugs and to evaluate the importance of GABA(A) receptor subunits for development of tolerance during chronic treatment, we tested the effects of acute and repeated administration of zolpidem and diazepam on ambulatory locomotor activity (a measure of sedation) and on the threshold for myoclonic, clonic and tonic seizures in response to i.v. infusion of pentylenetetrazole (PTZ). Both drugs given acutely in doses 0.3, 1 and 3 mg/kg reduced locomotion, and in doses 1 and 3 mg/kg elevated the threshold for PTZ-induced seizures. The effects of zolpidem and diazepam on the tonic seizure threshold were greater than on myoclonus and clonic seizure threshold. Diazepam and zolpidem (3 mg/kg), given 18 or 42 h after repeated drug treatment (10 days, 5 mg/kg, twice daily), decreased the PTZ seizure threshold and increased the locomotor activity as compared to control mice, indicating development of tolerance to their anticonvulsant and sedative effects. After repeated treatment the PTZ seizure threshold was not different between the two drugs, while differences in sedation became larger than after the acute treatment. The results suggest that alpha5-containing GABA(A) receptors are not crucial for the development of sedative and anticonvulsant tolerance.
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PMID:Effects of acute and repeated zolpidem treatment on pentylenetetrazole-induced seizure threshold and on locomotor activity: comparison with diazepam. 1934 34

Propofol, a GABA-mediated inhibitor of excitatory neurotransmitter, is a popular intravenous agent for general anesthesia and sedation. Its side effects reportedly include opisthotonus, seizures, and myoclonus, and are usually manageable. We present a patient who developed propofol-induced delayed-onset refractory myoclonic seizures that resisted antiepileptic drugs.
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PMID:A case of propofol-induced delayed-onset refractory myoclonic seizures. 1951 84

Infantile spasms syndrome (ISS) is a catastrophic pediatric epilepsy with motor spasms, persistent seizures, mental retardation, and in some cases, autism. One of its monogenic causes is an insertion mutation [c.304ins (GCG)(7)] on the X chromosome, expanding the first polyalanine tract of the interneuron-specific transcription factor Aristaless-related homeobox (ARX) from 16 to 23 alanine codons. Null mutation of the Arx gene impairs GABA and cholinergic interneuronal migration but results in a neonatal lethal phenotype. We developed the first viable genetic mouse model of ISS that spontaneously recapitulates salient phenotypic features of the human triplet repeat expansion mutation. Arx((GCG)10+7) ("Arx plus 7") pups display abnormal spasm-like myoclonus and other key EEG features, including multifocal spikes, electrodecremental episodes, and spontaneous seizures persisting into maturity. The neurobehavioral profile of Arx mutants was remarkable for lowered anxiety, impaired associative learning, and abnormal social interaction. Laminar decreases of Arx+ cortical interneurons and a selective reduction of calbindin-, but not parvalbumin- or calretinin-expressing interneurons in neocortical layers and hippocampus indicate that specific classes of synaptic inhibition are missing from the adult forebrain, providing a basis for the seizures and cognitive disorder. A significant reduction of calbindin-, NPY (neuropeptide Y)-expressing, and cholinergic interneurons in the mutant striatum suggest that dysinhibition within this network may contribute to the dyskinetic motor spasms. This mouse model narrows the range of critical pathogenic elements within brain inhibitory networks essential to recreate this complex neurodevelopmental syndrome.
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PMID:A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10+7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment. 2012 36

Sex steroids can influence seizures. Estrogen (E(2)), progesterone (P(4)), and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), in particular, have received much attention for exerting these effects. Typically, it is thought that E(2) precipitates seizures, and progestogens, such as P(4) and 3alpha,5alpha-THP, attenuate seizures. However, E(2) may also have antiseizure effects, perhaps in part through its enhancement of the formation of 3alpha,5alpha-THP, which has GABA(A)/benzodiazepine receptor agonist-like actions. To test this hypothesis, male and female, castrated or ovariectomized, wild-type and 5alpha-reductase knockout mice were implanted with Silastic capsules of E(2) or vehicle and then administered pentylenetetrazol (85 mg/kg, ip). Wild-type, but not 5alpha-reductase knockout, mice administered E(2) had significantly longer latencies to myoclonus and increased levels of 3alpha,5alpha-THP in the hippocampus. Thus, some of the anticonvulsive effects of E(2) may involve formation of 3alpha,5alpha-THP in the hippocampus.
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PMID:Estrogen increases latencies to seizures and levels of 5alpha-pregnan-3alpha-ol-20-one in hippocampus of wild-type, but not 5alpha-reductase knockout, mice. 1978 46

Zolpidem is a widely used hypnotic drug acting via benzodiazepine binding sites on GABA(A) receptors. Several studies suggested that zolpidem might have better anticonvulsant potency than previously thought. To compare the sedative and anticonvulsant potency of this drug, we studied in male mice the influence of zolpidem (0.1-10 mg/kg i.p.) on ambulatory locomotor activity (a measure of sedation) and on the threshold for myoclonus, clonic and tonic seizures, as well as death, in response to i.v. infusion of pentylenetetrazole (PTZ, 4.4 mg/min). Because older people take zolpidem more often than young people and have a higher incidence of epilepsy, we also compared the sedative and anticonvulsant properties of low doses of this drug (0.1 and 1 mg/kg i.p.) between adult (3 months) and aged (13 months) mice. Zolpidem in doses of 0.3-10 mg/kg decreased locomotion, as quantified by recording interruptions of infrared beams during 10 min, and in doses of 1-10 mg/kg increased the threshold for PTZ-induced seizures and death. The effect of zolpidem against tonic seizures was greater than against two other seizure components and death. In control aged mice the threshold for PTZ-induced myoclonus, clonic seizures and death was lower than in adult mice, while the locomotor activity was not different. In adult and in aged mice zolpidem in a dose of 1 mg/kg decreased locomotion and elevated the threshold for PTZ-induced seizures and death. Neither of these effects was age-dependent. The results suggest that in addition to strong sedative activity zolpidem has potent anticonvulsant properties.
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PMID:Zolpidem is a potent anticonvulsant in adult and aged mice. 1991 23

Unverricht-Lundborg disease (ULD) is the most common progressive myoclonic epilepsy. Its etiology has been identified in a defect of a protease inhibitor, cystatin B (CSTB), but the mechanism(s) by which this defect translates in the clinical manifestations of the disease are still obscure. We tested the hypothesis that ULD is accompanied by a loss of cortical GABA inhibition in a murine model (the CSTB knockout mouse) and in a human case. Cortical GABA signaling has been investigated measuring VGAT immunohistochemistry (a histological marker of the density of GABA terminals), GABA release from synaptosomes and paired-pulse stimulation. In CSTB knockout mice, a progressive decrease in neocortex thickness was found, associated with a prevalent loss of GABA interneurons. A marked reduction in VGAT labeling was found in the cortex of both CSTB knockout mice and an ULD patient. This implicates a reduction in GABA synaptic transmission, which was confirmed in the mouse model as reduction in GABA release from isolated nerve terminals and as loss of electrophysiologically measured GABA inhibition. The alterations in VGAT immunolabeling progressed in time, paralleling the worsening of myoclonus. These results provide direct evidence that loss of cortical GABA input occurs in a relevant animal model and in a case of human ULD, leading to a condition of latent hyperexcitability that favors myoclonus and seizures. These findings contribute to the understanding of the pathogenic mechanism of ULD and of the neurobiological basis of the effect of currently employed drugs.
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PMID:Loss of cortical GABA terminals in Unverricht-Lundborg disease. 2253 21


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