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 the context of a study of the effects of gamma-vinyl-GABA (GVG) on seizure occurrence and on EEG abnormalities we present three cases with focal epilepsy in which new clinical and EEG paroxysmal manifestations were observed during GVG therapy. At that time, whereas an amelioration or no change in patients' habitual seizures were observed, myoclonic jerks appeared with related changes in the EEG paroxysmal abnormalities, represented by generalized polyspike and wave complexes. An electroclinical correlation was recorded in one case. These data indicate that, although occurring rarely, it is possible to have epileptic myoclonus during GVG treatment. Mechanisms underlying these manifestations are difficult to explain. Probably a shift in the anti/proconvulsant GABAergic balance towards the latter may compromise the therapeutic effect of GVG.
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PMID:Development of myoclonus in patients with partial epilepsy during treatment with vigabatrin: an electroencephalographic study. 773 67

Most drugs used to treat myoclonus are also antiepileptic. The main drugs are the benzodiazepines, valproate, and barbituates. Advances in the understanding of antiepileptic drug mechanisms of action have revealed two main patterns: increasing inhibition either through GABA or glycine, or decreasing excitation due to glutamate. Anticonvulsants such as the benzodiazepines, barbiturates, vigabatrin, tiagabine, or progabide act through GABA. New prototype anticonvulsants such as dizocilpine and remacemide target glutamate receptors or associated ion channels. For some antimyoclonic drugs such as piracetam, many effects are reported but no mechanism of action has been established. Many newer anticonvulsants have not been tested in human myoclonic disorders but efficacy against PTZ-induced seizures suggests antimyoclonic activity. Our ability to improve the treatment of myoclonus requires greater knowledge of the molecular mechanisms of myoclonus and more exact delineation of its relation to epilepsy. Better drugs also will result from refinements from prototype drugs and new concepts about brain function. Most of the discussion has been focused on the use of drugs as symptomatic treatment, but drugs such as glutamate blockers are already having a role in the treatment of degenerative neurological disorders, an important cause of some myoclonic disorders. It also may be possible to improve treatment by focusing on selective regional effects of drugs or drug delivery. The CNS penetration of drugs is often no uniform. For many antimyoclonic and antiepileptic drugs, regional studies have not been performed, especially in humans. Lack of efficacy could therefore be due to lack of drug delivery to myoclonic generators or suppression structures. It is conceivable that drug effects in different brain regions also may be opposing, such as in forebrain and hindbrain structures. Stimulation of the same receptor subtype may have different implications for myoclonus if the sites are pre- or postsynaptically located (as in 5-HTIA sites), or predominantly cerebellar versus hippocampal (as in BDZ I vs II sites). Molecular genetic abnormalities in neurological disease may affect neurotransmission and the action of drug either directly at the receptor site or in other ways such as transduction, translation, or expression. Further insights into these abnormalities may provide new targets for pharmacotherapy. Most antiepileptic and antimyoclonic drugs developed to date have aimed at broad-spectrum treatment of the symptoms, rather than treatment of regional problems such as in the forebrain or the hindbrain. Because of this, the currently available drugs have broad side effects such as cognitive impairment, tremors, teratogenicity, etc. To develop more region-specific and more efficacious drugs, we need to develop a better understanding of local central nervous system problems in myoclonus and epilepsy. The development and application of molecular biological techniques have increased our knowledge of receptors and transporters immensely. It is conceivable that in the near future we will be able to determine whether small mutations affect the structure and function of these molecules. In addition, the glimpses into the process of cell death and sprouting by remaining neurons in the epileptic brain, and perhaps the myoclonic brain, raise the possibility of designing regionally oriented drugs with greater efficacy and fewer side effects. The current developments in the understanding of the central neurons should allow for the development of exciting new pharmacotherapies in the future.
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PMID:Mechanism of action of antiepileptic and antimyoclonic drugs. 884 79

Male Sprague-Dawley rats developed posthypoxic myoclonus following 10-min cardiac arrest and resuscitation. Previous results showed that dysfunction of central GABAergic neurotransmission may contribute to the disease. In current studies, effects of GABA uptake inhibitors, guvacine hydrochloride (1,2,5,6-tetrahydro-3-pyridine carboxylic acid hydrochloride) and (+/-)-cis-4-hydroxynipecotic acid ([+/-]-cis-4-hydroxy-3-piperidine carboxylic acid), in the pathophysiology of posthypoxic myoclonus were investigated. Administration of guvacine (1 or 10 mg/kg, IP) or nipecotic acid (0.5 or 5 mg/kg, IP) significantly attenuated myoclonus scores of the animals. Tolerance to antimyoclonus effects of these two compounds did not develop after chronic administration (twice a day for 14 days) of guvacine (10 mg/kg, IP) or nipecotic acid (5 mg/kg, IP). On the other hand, tolerance was noticed with clonazepam (2.5 mg/kg, IP twice a day for 7 days). The results indicate that guvacine or nipecotic acid may be used in combination with (at reduced doses) or as alternatives to clonazepam to treat patients with the disease so as to reduce tolerance phenomenon usually associated with clonazepam.
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PMID:Effects of GABA uptake inhibitors on posthypoxic myoclonus in rats. 886 96

gamma-Aminobutyric acid type A receptors (GABA(A)-Rs) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system. The beta3 subunit is an essential component of the GABA(A)-R in many brain regions, especially during development, and is implicated in several pathophysiologic processes. We examined mice harboring a beta3 gene inactivated by gene targeting. GABA(A)-R density is approximately halved in brain of beta3-deficient mice, and GABA(A)-R function is severely impaired. Most beta3-deficient mice die as neonates; some neonatal mortality, but not all, is accompanied by cleft palate. beta3-deficient mice that survive are runted until weaning but achieve normal body size by adulthood, although with reduced life span. These mice are fertile but mothers fail to nurture offspring. Brain morphology is grossly normal, but a number of behaviors are abnormal, consistent with the widespread location of the beta3 subunit. The mice are very hyperactive and hyperresponsive to human contact and other sensory stimuli, and often run continuously in tight circles. When held by the tail, they hold all paws in like a ball, which is frequently a sign of neurological impairment. They have difficulty swimming, walking on grids, and fall off platforms and rotarods, although they do not have a jerky gait. beta3-deficient mice display frequent myoclonus and occasional epileptic seizures, documented by electroencephalographic recording. Hyperactivity, lack of coordination, and seizures are consistent with reduced presynaptic inhibition in spinal cord and impaired inhibition in higher cortical centers and/or pleiotropic developmental defects.
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PMID:Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. 910 19

Fluctuating stiffness and paroxysmal spasms of the trunk and legs are the primary features of stiff-man syndrome and it's variants, progressive encephalomyelopathy with rigidity and myoclonus (PERM) and stiff-leg syndrome. The spasms characterized by hyperextension of the back and legs are both spontaneous as well as stimulus-sensitive. They can be excruciatingly painful and are frequently accompanied by symptoms of autonomic dysregulation. Hyperreflexia may be the only pathological finding on the neurological examination. Most patients show psychiatric disturbances suggestive of psychogenic movement disorder and this may cause delays in adequate pharmacotherapy. The disease progresses over the span of months to years rendering many patients wheelchair-bound or bedridden. GABA-mimetics are most effective in treating symptoms, but tolerance and life-threatening withdrawal symptoms are common drawbacks. For therapy-refractory patients, intrathecal baclofen represents a good alternative. The diagnosis is based on clinical, biochemical and electrophysiological findings. Spasmodic reflex myoclonus is observed in nearly all SMS patients. It consists of well-reproduced reflex EMG-activity commencing 50-80 ms after medial or tibial nerve stimulation and lasting several seconds thereafter. The activity is first myoclonic then spasmodic in nature, and commonly begins in the muscles most severely affected before spreading bidirectionally along the neuraxis. Spasmodic reflex myoclonus and the high incidence of antibodies against GAD are suggestive of an autoimmune disorder affecting GABAergic neurons in the spinal cord, but the precise locus of dysfunction remains to be elucidated.
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PMID:Stiff-man syndrome: an overview. 957 75

The GABA-withdrawal syndrome (GWS) is a model of local status epilepticus following the interruption of a chronic GABA infusion into the rat somatomotor cortex. GWS is characterized by focal epileptic electroencephalographic discharges and associated contralateral myoclonus. In neocortical slices obtained from GWS rats, most neurons recorded in the GABA-infused area are pyramidal neurons presenting bursting properties. The bursts are induced by white-matter stimulation and/or intracellular depolarizing current injection and correlate with a decrease of cellular sensitivity to GABA, caused by its prolonged infusion. This effect is related to a calcium influx that may reduce the GABAA receptor-mediated inward current and is responsible for the bursting properties. Here we present evidence for the involvement of calcium- and NMDA-induced currents in burst genesis. We also report modulatory effects of noradrenaline appearing as changes on firing patterns of bursting and nonbursting cells. Complementary histochemical data reveal the existence of a local noradrenergic hyperinnervation and an ectopic expression of tyrosine hydroxylase mRNAs in the epileptic zone.
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PMID:The GABA-withdrawal syndrome: a model of local status epilepticus. 1070 10

We have combined genetic and biochemical approaches to analyze the function of the RNA-binding protein Nova-1, the paraneoplastic opsoclonus-myoclonus ataxia (POMA) antigen. Nova-1 null mice die postnatally from a motor deficit associated with apoptotic death of spinal and brainstem neurons. Nova-1 null mice show specific splicing defects in two inhibitory receptor pre-mRNAs, glycine alpha2 exon 3A (GlyRalpha2 E3A) and GABA(A) exon gamma2L. Nova protein in brain extracts specifically bound to a previously identified GlyRalpha2 intronic (UCAUY)3 Nova target sequence, and Nova-1 acted directly on this element to increase E3A splicing in cotransfection assays. We conclude that Nova-1 binds RNA in a sequence-specific manner to regulate neuronal pre-mRNA alternative splicing; the defect in splicing in Nova-1 null mice provides a model for understanding the motor dysfunction in POMA.
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PMID:Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. 1071 79

Alterations in multiple neurochemical systems have been reported in animal and human studies of posthypoxic myoclonus. It is impossible, however, to establish causative relationships between the observed changes and the myoclonic movements from these studies. Therefore, to establish causative links between neurochemical changes and myoclonus, ligands that target neurotransmitter systems that are altered in posthypoxic myoclonus were microinjected into the lateral ventricles of normal rats to identify the changes that can produce myoclonus. Of the ligands that were tested, only the GABA(A) antagonists produced myoclonus after intracerebroventricular administration, suggesting the importance of disinhibition of GABAergic systems in myoclonus. To further examine the role of GABA in myoclonus, GABAergic antagonists were microinjected into the nucleus reticularis of the thalamus (NRT), an area of the brain in which extensive pathologic changes are seen in posthypoxic animals. GABA(A), but not GABA(B), antagonists produced myoclonus after microinjection into the NRT. Earlier investigators have further reported the ability of GABA(A) antagonists to produce myoclonus after microinjection into the caudate. The data therefore suggest that disruption of activity at GABA(A) receptors at any one of a number of levels in the neural axis can produce myoclonus.
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PMID:Involvement of GABA(A) receptors in myoclonus. 1075 72

To explore the possible involvement of glucocorticoids in the previously observed anticonvulsive effect of swim stress, mice were, prior to administration of convulsants, subjected to treatments that diminish or enhance plasma corticosterone levels. Aminoglutethimide, the inhibitor of steroid synthesis, failed to modify convulsant doses of picrotoxin, but enhanced threshold doses of pentylenetetrazole producing myoclonus and death, both in unstressed and stressed animals. The same drug prevented the effect of stress on pentylenetetrazole-induced running bouncing clonus (RB clonus) and abolished the appearance of tonic hindlimb extension (THE). Doses of kainic acid producing convulsions and death were not affected by stress, but they were enhanced by aminoglutethimide. Corticosterone administration could not imitate the effect of swim stress. Finasteride, a 5 alpha-reductase inhibitor, did not interfere with the effect of stress on picrotoxin-induced convulsions. Swim stress failed to modify the binding of the convulsant t[3H]-butylbicycloorthobenzoate [3H]TBOB, to washed mouse forebrain membranes. The results confirmed an anticonvulsant effect of swim stress against convulsions produced by GABA-related convulsants, but they do not support the hypothesis suggesting the involvement of glucocorticoids or neurosteroids in this effect.
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PMID:Anticonvulsive effect of swim stress in mice. 1097 29

Piracetam [2-oxo-1-pyrrolidineacetamide], a cyclic GABA, has been used in Europe for the treatment of patients with cognitive disorders. We investigated the effect of piracetam on urea-induced myoclonus in rats. Myoclonus was induced by intraperitoneal injection of 4.5 g/kg urea, and was recorded with EMG and video apparatus. The incidence of induced myoclonus decreased significantly by intraperitoneal injection of 300 mg/kg piracetam and oral administration of 0.3-10 mg/kg clonazepam. Furthermore, the combined application of 100 mg/kg piracetam and 0.03-0.1 mg/kg clonazepam was effective in ameliorating the myoclonus, although separate administrations were not effective. These findings suggest that piracetam is an effective drug for treating myoclonus, particularly when it is used in combination with clonazepam.
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PMID:[Effect of piracetam on urea-induced myoclonus in rats]. 1106 61


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