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)

The baboon Papio papio is the only animal model showing a natural photosensitive epilepsy very similar to that observed in some human epileptic patients. In the baboon, intermittent light stimulation (ILS) induces bilateral and synchronous myoclonic twitches which are associated with paroxysmal discharges (PDs) predominating in the frontal cortex, and can be followed by generalized tonic-clonic seizures. We were able to demonstrate the motor cortical origin of all these manifestations since neuronal generators responsible for paroxysmal discharges are localized there and are activated by visual afferents from the occipital lobe. The corpus callosum is the structure determining the interhemispheric synchronization of PDs. An unbalance of neurotransmitter systems such as GABA or excitatory amino acids should be responsible for the hereditary predisposition of baboons to photosensitive epilepsy. Some Papio papio, either photosensitive or not, may show spontaneous truncular myoclonic twitches, different from those induced by intermittent light stimulation, and resembling the intention myoclonus as observed in some human neurological disorders (post-anoxic syndrome, degenerative encephalopathies such as Ramsay-Hunt syndrome...). Because of the absence of any abnormal electrographic discharge, this myoclonus is considered non epileptic. Until now, we were unable to determine the structure generating this myoclonus. The most probable origin is in the lower brain stem. Experimental data suggest that a local unbalance of the cholinergic neurotransmission could be responsible for the predisposition of baboons to show this type of myoclonus.
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PMID:[Value of the monkey Papio papio for the study of epilepsy]. 218 40

The effect of propranolol was assessed against myoclonus induced by picrotoxin (a known GABA antagonist) in a dose of 3 mg/kg and allylglycine (the inhibitor of GABA synthesis and release) in a dose of 150 mg/kg. A dose-dependent (0.5-2 mg/kg) protective effect was found against both models. Pretreatment of rats with a GABA-reducing dose (100 mg/kg, nonmyoclonic) of allylglycine produced no change in the effect of propranolol against picrotoxin-induced myoclonus. Propranolol thus inhibited myoclonic responses when both the receptor activity and the functional pool of GABA were impaired, suggesting that it produces as antimyoclonic action without the involvement of GABA. However, the drug seems to show a synergistic action with GABA-ergic agents, as greater protection was observed in rats treated concurrently with propranolol and amino-oxyacetic acid, an inhibitor of GABA degradation.
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PMID:The synergistic protective effect of propranolol & aminooxyacetic acid against picrotoxin-induced myoclonus in rats. 234 7

The spatial and temporal EEG features of the epileptogenic syndrome induced by cessation of chronic intracortical GABA infusion in normal rats are described. In the initial stages, the paroxysmal discharges (PDs) induced by withdrawal from unilateral GABA application may appear either unilaterally or bilaterally, although with greater amplitude on the infused side. PDs are transitorily accompanied by behavioral signs of distal myoclonus of the body territory corresponding to the infused area (contralateral hindlimb). Later, the paroxysmal activity becomes more localized, circumscribed to the cannula-infused site and with ipsilateral propagation to anterior cortical areas. The amplitude of PDs decreases progressively while their frequency increases, reaching its maximal value at about 4 h after the first PDs have appeared. In the final stages of the syndrome, which may last several days, clinical manifestations are absent and PDs are activated by slow-wave sleep and reduced during REM sleep and waking. Chronic intracortical applications of taurine failed to induce any electroclinical changes on withdrawal and were unable to inhibit the focus elicited by GABA withdrawal, whereas reinstatement of GABA infusion into the epileptogenic area was effective in blocking the paroxysmal activity. Intracortical infusion of baclofen induced the appearance of an epileptogenic focus that waned on withdrawal. The GABA-withdrawal syndrome appears to be a new model of focal status epilepticus; it may be useful as an experimental model of human partial epilepsy to investigate the role of GABAergic neurotransmission.
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PMID:Electroencephalographic study of the GABA-withdrawal syndrome in rats. 236 74

Clonazepam is a potent anticonvulsant 1,4-benzodiazepine that controls some types of myoclonus. Its primary mode of action is to facilitate GABAergic transmission in the brain by a direct effect on benzodiazepine receptors. GABA receptors lie on the cell bodies of dorsal raphe neurons, and GABA acts to inhibit raphe cell firing, an action potentiated by benzodiazepines. Clonazepam does not alter 5-HT synthesis but decreases 5-HT utilization in brain and blocks the egress of 5-HIAA from the brain. It is not known whether the actions of clonazepam in altering 5-HT function are responsible for its antimyoclonic action, since these are observed only after large doses. Also, the effects of clonazepam are the exact opposite of those predicted from the beneficial effects of 5-HTP in human myoclonic disorders. Finally, why clonazepam, more than other benzodiazepines, is of benefit in the treatment of myoclonus is not clear. This may be due to some pharmacokinetic feature of the drug in conjunction with its potency at benzodiazepine receptors.
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PMID:Mechanism of action of clonazepam in myoclonus in relation to effects on GABA and 5-HT. 241 52

The convulsant potency of bicuculline, a GABA antagonist, was shown to be greater in Short-Sleep (SS) mice than in Long-Sleep (LS) mice. LS mice, selectively bred for lengthy ethanol-induced narcosis, had longer latencies to myoclonus and clonus following administration of bicuculline and picrotoxin than did ethanol-resistant SS mice. SS mice were also more susceptible to pentylenetetrazol-induced myoclonus, but not clonus. F1 hybrids showed bicuculline seizure sensitivity intermediate to the two parent lines. Ethanol weakly inhibited bicuculline-induced myoclonus in both LS and SS mice. Clonus was clearly antagonized by ethanol in both lines, but to a similar degree. These data provide evidence for a GABAergic role in genotype-dependent sensitivity to ethanol.
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PMID:Convulsant properties of GABA antagonists and anticonvulsant properties of ethanol in selectively bred long- and short-sleep mice. 250 97

The antiseizure activities of glial or neuronal GABA uptake inhibitors and GABA agonists were compared following intracerebroventricular administration in 2 acute models of chemoconvulsion in rats. The glia-selective GABA uptake inhibitor, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO), given at doses of 100-750 micrograms, i.c.v., protected against maximal pentylenetetrazol (PTZ) seizures and increased the latency to isonicotinic acid hydrazide (INH) seizures for at least 1 h following central administration. THPO failed to increase PTZ seizure thresholds. In contrast, the more potent partly glia-selective GABA uptake inhibitor, cis-4-hydroxynipecotic acid (30-300 micrograms), which is also a substrate for neuronal and glial transport systems, protected only 33% of rats against PTZ-induced tonic extension and had no effect on INH seizure latency. The neuron-selective uptake inhibitor L-2,4-diaminobutyric acid (DABA) at 1500 micrograms exhibited anti-PTZ activity initially and then, after a delay, produced proconvulsant behavior and spontaneous myoclonus in some animals. Intracerebroventricular injection of the GABA receptor agonist, muscimol, at toxic doses, gave rise to mixed anticonvulsant (INH seizures) and proconvulsant (PTZ seizure thresholds) effects. The results suggest that THPO, of the 4 compounds tested, possesses significant anticonvulsant activity. Its ability to suppress tonic but not generalized minor seizures suggests that it may block seizure spread.
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PMID:Anticonvulsant activity of intracerebroventricularly administered glial GABA uptake inhibitors and other GABAmimetics in chemical seizure models. 252 32

The present study investigates whether clonazepam exerts its antimyoclonic action through a GABA independent mechanism. We have studied the antimyoclonic effect of clonazepam and compared it with that of aminooxyacetic acid (AOAA), a GABA transaminase inhibitor, against myoclonus induced by picrotoxin, a GABA receptor antagonist and allylglycine, a drug which inhibits synthesis and release of GABA. We have also investigated the effect of clonazepam against picrotoxin-induced myoclonus in rats pretreated with either AOAA or submyoclonic dose of allylgylycine. Clonazepam pretreatment inhibited both picrotoxin and allylglycine-induced myoelonus whereas AOAA was effective in inhibiting only picrotoxin-induced myoclonus. The protective effect of clonazepam against picrotoxin-induced myoclonus was potentiated by AOAA pretreatment. Moreover, clonazepam afforded protection against picrotoxin-induced myoclonus in rats pretreated with a submyoclonic GABA reducing dose of allylglycine. These findings indicate that a GABA independent mechanism may also be involved in the antimyoclonic action of clonazepam.
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PMID:The antimyoclonic action of clonazepam through a GABA--independent mechanism. 262 Sep 67

1. Evidence relating to the role of GABA in the pathogenesis of epilepsy is reviewed. 2. Impaired GABAergic function appears to contribute to seizure susceptibility in a variety of genetically-determined syndromes in animals, e.g. genetically epilepsy prone rats showing sound-induced seizures, gerbils with genetically determined epilepsy, and baboons, Papio papio, with photosensitive epilepsy. 3. In epilepsy secondary to a cerebral insult there is some morphological and biochemical evidence for impaired GABAergic function in experimental situations, but little definitive evidence in man. 4. Pharmacological approaches to enhancing GABAergic inhibition include the use of GABA agonists (or prodrugs), GABA-transaminase inhibition, GABA uptake inhibition, and action at the GABA/benzodiazepine allosteric site. 5. Experimental data suggest that the best prospect for potent anticonvulsant action with fewest side effects (myoclonus, sedation, ataxia) is at present offered by GABA-transaminase inhibitors or novel agents acting on the benzodiazepine receptor site.
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PMID:GABAergic mechanisms in the pathogenesis and treatment of epilepsy. 266 5

The most potent agents currently available for suppressing myoclonic activity in animals and humans act to enhance GABA-mediated inhibition and/or to diminish amino acid-induced excitation. Postsynaptic GABA-mediated inhibition plays an important role at the cortical level, diminishing the effect of augmented afferent activity and preventing pathologically enhanced output. Enhancement of GABAergic inhibition, principally at the cortical level but also at lower levels, by clonazepam and by valproate appears to be a predominant element in their antimyoclonic action. Studies in various animal models, including photically induced myoclonus in the baboon, P papio, indicate the value of other approaches to enhancing GABA-mediated inhibition. Among such approaches meriting evaluation in humans are inhibition of GABA-transaminase activity by gamma-vinyl GABA and action at some of the benzodiazepine receptors to enhance the action of GABA, as by the novel anticonvulsant beta-carbolines. Excitatory transmission mediated by dicarboxylic amino acids appears to play a role in myoclonus, especially at the spinal level, but also in the brainstem, cerebellum, basal ganglia, and cortex. Among various novel agents that act at the postsynaptic receptor site to antagonize such excitation, those specifically blocking excitation induced by aspartate and/or NMDA prevent myoclonic activity in a wide range of animal models. Further research is required before such agents can be evaluated in humans.
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PMID:Drugs acting on amino acid neurotransmitters. 286 23

Stimulus sensitive myoclonus is a prominent symptom of uremia in both man and animals. Intravenous injection of urea into cats had been previously reported to produce spike and sharp wave electrical discharges in the medullary reticular formation which correlated with the myoclonic movements. In the present investigations, intraperitoneal injections of 2 g/kg urea every 15 minutes for 4 injections produced myoclonus in rats accompanied by brain urea concentrations of 6.8 X 10(-2)M, which is sevenfold higher than normal. 10(-2) and 10(-1) M urea significantly reduced 3H-strychnine binding to rat medulla membranes by 30% and 43% respectively. Urea inhibition of 3H-strychnine binding was reversible and binding kinetics revealed that 10(-1)M urea decreased Bmax by 65% with no effect on the affinity. Brain glycine levels did not change after urea injections and urea had no effect on synaptosomal uptake of 3H-glycine. Urea did not alter 3H-GABA, 3H-glutamate and 3H-QNB receptor binding but decreased 3H-diazepam receptor binding in the medulla. Mannitol also reduced 3H-diazepam binding but had no effect on 3H-strychnine binding. Stereotaxic injection of the glycine receptor antagonist, strychnine, into the rat medullary reticular formation produced myoclonus, whereas Ro 15-1788, a benzodiazepine antagonist, had no effect. Urea may produce myoclonus by blockade of glycine receptors in the medullary reticular formation.
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PMID:Urea-induced myoclonus: medullary glycine antagonism as mechanism of action. 298 63


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