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)

Two potent glutamate antagonists, NBQX and GYKI 52466, that act selectively on non-NMDA receptors, have been tested for anticonvulsant activity in 3 models of reflex epilepsy (sound-induced seizures in DBA/2 mice and in genetically epilepsy-prone rats and photically-induced myoclonus in Papio papio) and in amygdala kindled rats. Both compounds potently but transiently suppress reflexly-induced epileptic responses. GYKI 52466 also reduces behavioral seizures and afterdischarge duration in amygdala kindled rats, but with a lower potency than it suppresses reflex epilepsy. These data are similar to earlier results with antagonists acting selectively on NMDA receptors; they do not support a specific involvement of enhanced AMPA receptor sensitivity as a major factor in the expression of kindled seizures.
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PMID:The effects of AMPA receptor antagonists on kindled seizures and on reflex epilepsy in rodents and primates. 133 44

The effect of i.p. or i.v. administration of the non-N-methyl-D-aspartate antagonists, GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylendioxy-5H-2,3-benzodiazepin e.HCl, molecular weight 330) and NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline, molecular weight 342) on sound-induced seizures in rats and photically induced myoclonus in baboons was studied. In both species an anticonvulsant effect occurred 15-60 min after administration of GYKI 52466 or NBQX. The ED50 value for clonic seizure suppression for GYKI 52466 at 30 min was 39 (rats, i.p.) and at 15 min was 13 (Papio papio, i.v.) mumol kg-1 and for NBQX at 30 min was 40 (rats, i.p.) and at 15 min approximately 10 (Papio papio, i.v.) mumol kg-1. Side effects were not observed in rats; apparent side effects in baboons probably arose from drug formulation. The anticonvulsant actions of GYKI 52466 and NBQX suggest a possible role for non-NMDA antagonists in the therapy of epilepsy.
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PMID:The non-N-methyl-D-aspartate receptor antagonists, GYKI 52466 and NBQX are anticonvulsant in two animal models of reflex epilepsy. 168 56

We report the effect of focal injections of N-methyl-D-aspartate (NMDA, 5 nmol) and 2-amino-7-phosphonoheptanoate (APH, 5 and 10 nmol) into the ventrolateral thalamic nucleus on behavioural symptoms of the high pressure neurological syndrome in rats. The injection of NMDA significantly lowers the threshold pressure for tremor and increases its intensity. The injection of APH significantly increases the threshold pressure for tremor and decreases its intensity. APH, 10 nmol, significantly increases the threshold pressure for myoclonus and convulsions. These protective effects are, however, less pronounced than those produced by either systemic injection of APH or its focal infusion into the basal ganglia output system.
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PMID:Effect of NMDA and 2-amino-7-phosphonoheptanoate focal injection into the ventrolateral thalamic nucleus on the high pressure neurological syndrome in the rat. 215 22

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

Studies of pathogenetic mechanisms of myoclonus and spinal spasticity have established a strong association between deficient inhibitory glycinergic transmission and pathologic rigidity and tremor. Consistent with known cases in the clinical literature, electrophysiologic data from animal models of myoclonus implicate dysfunction of segmental spinal cord circuitry. The present study sought to further explore pathogenetic mechanisms at the circuit level. In vitro preparations of isolated spinal cord from neonatal rodents allowed for stable recordings of individual cells as well as populations of motoneurons. Blockade of glycine receptors enhanced 5- to 15-Hz sinusoidal oscillations that were synchronous in entire populations of motoneurons as well as along multiple segments of the spinal cord. Oscillations at motoneurons were mediated largely by non-NMDA excitatory synaptic inputs. Blockade of GABAA receptors, and not GABAB receptors, abolished sinusoidal oscillations, suggesting a critical role for GABAA receptors in the premotoneuronal circuitry responsible for generation or transmission of the sinusoidal oscillations. These data offer new insights into possible pathogenetic mechanisms of spinal myoclonus and may help guide future research leading to specific therapies for hyperkinetic movement disorders of spinal origin.
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PMID:Involvement of glycine and GABAA receptors in the pathogenesis of spinal myoclonus: in vitro studies in the isolated neonatal rodent spinal cord. 747 87

Eleven of 40 decerebrated cats were found to exhibit periods of spontaneous or sensory myoclonus and locomotion beginning 24 h after decerebration. Histological analysis showed that the cats generating myoclonus hemorrhagic lesions in the retrorubral nucleus (RRN) and ventral mesopontine junction (vMPJ). However, with intact RRN and vMPJ never showed myoclonus. To verify that the lesions were responsible for myoclonus, 6 additional cats received N-methyl-D-aspartate (NMDA, 0.5 M/0.5 microliter) injections in the areas of RRN and vMPJ to produce bilateral lesions. Coordinated rhythmic leg movement (locomotion) or myoclonic twitches developed in all of these cats beginning 3 hours after NMDA injection. These NMDA lesion-induced movements appeared either spontaneously (5 out of 6 cats) or after sensory stimulation (1 cat). Four cats received saline control injections in the RRN and vMPJ and did not have spontaneous, or sensory stimulation-induced, myoclonic twitches during the 48 h observation period. These results indicate that the RRN and vMPJ have a suppressive effect on myoclonic twitches and rhythmic leg movement. Dysfunction of these regions could release motor activity into sleep and waking states.
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PMID:Brainstem-mediated locomotion and myoclonic jerks. I. Neural substrates. 903 17

Morphine administration can lead to a variety of side-effects, including myoclonus. In an animal model, high morphine doses given intrathecally elicit hindlimb myoclonic seizures which are not influenced by traditional opioid receptor antagonists, such as naloxone. Ketamine prevents this seizure-like activity in a dose-dependent manner. The response is stereoselective, with S-ketamine far more potent than R-ketamine. A competitive NMDA antagonist, NPC17742, also prevents the seizures, although less potently than ketamine. Dextromethorphan has limited activity in this model, while haloperidol and pentothal are without any effect.
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PMID:Blockade of morphine-induced hindlimb myoclonic seizures in mice by ketamine. 907 78

Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem of vertebrates. Glycine is accumulated into synaptic vesicles by a proton-coupled transport system and released to the synaptic cleft after depolarization of the presynaptic terminal. The inhibitory action of glycine is mediated by pentameric glycine receptors (GlyR) that belong to the ligand-gated ion channel superfamily. The synaptic action of glycine is terminated by two sodium- and chloride-coupled transporters, GLYT1 and GLYT2, located in the glial plasma membrane and in the presynaptic terminals, respectively. Dysfunction of inhibitory glycinergic neurotransmission is associated with several forms of inherited mammalian myoclonus. In addition, glycine could participate in excitatory neurotransmission by modulating the activity of the NMDA subtype of glutamate receptor. In this article, we discuss recent progress in our understanding of the molecular mechanisms that underlie the physiology and pathology of glycinergic neurotransmission.
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PMID:Molecular biology of glycinergic neurotransmission. 929 60

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

Generalized 1Hz, burst-and-slow-wave complexes were observed in a comatosed patient with acute disseminated encephalomyelitis (ADEM) when she showed extremely intractable, generalized convulsions and fragmented myoclonus in the whole body. Two types of short-latency SEPs were obtained separately during the burst and slow phase of the EEG (SEP-burst and SEP-slow, respectively), which showed a two fold greater amplitude of N20 in the former than in the latter. This suggests enhanced responsiveness to the peripheral stimuli during the burst phase as compared with the slow phase. CSF and serum were positive for autoantibodies to NMDA receptors. The "burst and slow complexes" reported here are considered to be an atypical EEG pattern of a generalized epileptic phenomenon.
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PMID:"Burst and slow complexes" in nonconvulsive epileptic status. 1656 28


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