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

Bilateral inferior olive lesions, produced by systemic administration of the neurotoxin 3-acetylpyridine (3AP) produce a proconvulsant state specific for strychnine-induced seizures and myoclonus. We have proposed that these phenomena are mediated through increased excitation of cerebellar Purkinje cells, through activation of glutamate receptors, in response to climbing fiber deafferentation. An increase in quisqualic acid (QA)-displaceable [3H]AMPA [(RS)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid] binding in cerebella from inferior olive-lesioned rats was observed, but no difference in [3H]AMPA binding displaced by glutamate, kainic acid (KA) or glutamate diethylester (GDEE) was seen. The excitatory amino acid antagonists GDEE and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10 imine] were tested as anticonvulsants for strychnine-induced seizures in 3AP inferior olive-lesioned and control rats. Neither drug effected seizures in control rats, however, both GDEE and MK-801 produced a leftward shift in the strychnine-seizure dose-response curve in 3AP inferior olive-lesioned rats. GDEE also inhibited strychnine-induced myoclonus in the lesioned group, while MK-801 had no effect on myoclonus. The decreased threshold for strychnine-induced seizures and myoclonus in the 3AP-inferior olive-lesioned rats may be due to an increase in glutamate receptors as suggested by the [3H]AMPA binding data.
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PMID:The effects of inferior olive lesion on strychnine seizure. 212 20

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

Male Sprague-Dawley rats developed posthypoxic myoclonus following 10-min cardiac arrest and resuscitation. In current studies, roles of N-methyl-D-aspartate (NMDA), non-NMDA (a-amino-3-hydroxy-5-methylisoxazole-4-propionate, AMPA, and kainate), and metabotropic glutamate receptors in the pathophysiology of posthypoxic myoclonus were investigated. Treatments with the competitive or noncompetitive NMDA receptor antagonist, D(-)-2-amino-5-phosphonopentanoic acid (D[-]-AP-5) (ED50: 12.5 mg/kg, i.p.) or MK-801 maleate (ED50: 0.034 mg/kg, i.p.), and competitive or noncompetitive non-NMDA (AMPA/kainate) receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) (ED50: 9.25 nM/5 microliters, i.c.v.) or 1-(4-ami -nophenyl)-4-methyl-7,8-methylenedioxy -5H-2,3-benzodiazepine hydrochloride (GYKI 52466) (ED50: 0.67 mg/kg, IP), significantly decreased myoclonus episodes in rats. On the other hand, treatment with the metabotropic glutamate receptor antagonist, L(+)-2-amino-3-phosphonopropionic acid (L[+]-AP-3) (50 or 500 nM/5 microliters, i.c.v., exerted no significant effect on myoclonus scores in posthypoxic rats. These results indicate that activation of NMDA and non-NMDA receptors receptors may mediate posthypoxic myoclonus in rats, whereas, involvement of metabotropic glutamate receptors needs to be studied further.
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PMID:Effects of glutamate receptor antagonists on posthypoxic myoclonus in rats. 873 76

In previous investigations we found an increase of D2 dopamine receptors in the striatum of patients with nocturnal myoclonus syndrome (NMS) after treatment with dopamimetics. Under the hypothesis, that, according to animal experiments, the glutamatergic system could be involved in this atypical dopaminergic up-regulation in NMS. The glutamate release inhibitor lamotrigine was tested in up to now two NMS patients. The results and the success of this approach and its implications are discussed.
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PMID:Lamotrigine in the treatment of nocturnal myoclonus syndrome (NMS): two case reports. 873 47

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

The molecular mechanisms of myoclonus are unknown. Drugs used in the symptomatic treatment of myoclonus were developed for other indications, such as epilepsy. Antimyoclonic drugs are not a single family of compounds but rather constitute a heterogeneous group of agents that act at various sites along the metabolic pathway of neurotransmitters or as receptor agonists or antagonists. For some drugs, the mechanism of antimyoclonic action is obscure despite many known actions. Myoclonus is affected by manipulation of more than one neurotransmitter system, and the neurotransmitters most linked to myoclonus are gamma-aminobutyric acid (GABA), glutamate, glycine, and serotonin. This is a review of the pharmacology of drugs acting on those neurotransmitters that are known or potential antimyoclonic drugs. A time of continuing advances in molecular biology and drug development is propitious for the pharmacotherapy of disorders that historically have been so refractory to conventional drug treatment.
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PMID:The pharmacology of antimyoclonic drugs. 889 98

Epilepsy with myoclonus is thought to be linked to the motor system. At birth, development of the central nervous system in humans is far from being achieved. Post-natal changes take place at different levels in this neuronal system. These modifications suggest that the motor cortex is a highly dynamic structure during post-natal development. They may account for the age-dependence of various epileptic syndromes. (1) The number of synapses increases during the early post-natal years and then decreases to reach the adult level around puberty. (2) Neurons differentiate and synthesize various neurotransmitters. (3) Dendrites grow actively and participate in the formation of local cortical circuits. (4) Electrophysiological properties of cortical neurons change during the first months of rodent development. This could reflect modifications of the ion channels present in the cell membrane. (5) The pyramidal tract myelinate and exuberant collaterals are selectively removed. These two processes are dependent on neuronal electrical activity. It has been demonstrated that selective collateral stabilization is promoted by glutamate release and stimulation of the N-methyl-D-aspartate (NMDA) receptor. So, seizures occurring during the neonatal period may interact with these normal developmental features. Furthermore, neuronal electrical activity and seizures stimulate the transcription of specific messenger RNAs coding for neurotrophic factors like nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF). The overproduction of neurotrophic factors leads to maldevelopment of the cortex.
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PMID:Epilepsy with myoclonus and post-natal development of the motor system in humans: a hypothesis. 941 55

Posthypoxic myoclonus and seizures precipitate as secondary neurological consequences in ischemic/hypoxic insults of the central nervous system. Neuronal hyperexcitation may be due to excessive activation of glutamatergic neurotransmission, an effect that has been shown to follow ischemic/hypoxic events. Therefore, riluzole, an anticonvulsant that inhibits the release of glutamate by stabilizing the inactivated state of activated voltage-sensitive sodium channels, was tested for its antimyoclonic and neuroprotective properties in the cardiac arrest-induced animal model of posthypoxic myoclonus. Riluzole (4-12 mg/kg i.p.) dose-dependently attenuated the audiogenic seizures and action myoclonus seen in this animal model. Histological examination using Nissl staining and the novel Fluoro-Jade histochemistry in cardiac-arrested animals showed an extensive neuronal degeneration in the hippocampus and cerebellum. Riluzole treatment almost completely prevented the neuronal degeneration in these brain areas. The neuroprotective effect was more pronounced in hippocampal pyramidal neurons and cerebellar Purkinje cells. These effects were seen at therapeutically relevant doses of riluzole, and the animals tolerated the treatment well. These findings indicate that the pathogenesis of posthypoxic myoclonus and seizure may involve excessive activation of glutamate neurotransmission, and that riluzole may serve as an effective pharmacological agent with neuroprotective potential for the treatment of neurological conditions associated with cardiac arrest in humans.
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PMID:Effect of riluzole on the neurological and neuropathological changes in an animal model of cardiac arrest-induced movement disorder. 1002 76

The experiments strongly suggested that the reason why Purkinje cells die so easily after global brain ischemia relates to deficiencies in aldolase C and EAAT4 that allow them to survive pathologically intense synaptic input from the inferior olive after the restoration of blood flow. This conclusion is based on: (a) the remarkably tight correspondence between the regional absence of aldolase C and EAAT4 in Purkinje cells and the patterned loss of Purkinje cells after a bout of global brain ischemia; (b) the necessity of the olivocerebellar pathway for the ischemic death of Purkinje cells; and (c) the build-up of pathologically synchronous and high-frequency burst activity within the inferior olive during recovery from ischemia. Indeed, the correspondence between the absence of aldolase C and EAAT4 to sensitivity to ischemia could be demonstrated for zones of Purkinje cells as small as two neurons. A second finding was that Purkinje cells are not uniformly sensitive to transient ischemia, since they die most frequently in zones where aldolase C and EAAT4 are absent. One implication of the experiment is that factors beyond the unique synaptic and membrane properties of Purkinje cells play an important role in determining this neuron's high sensitivity to ischemia. The data strongly imply that two properties of Purkinje cells that make them susceptible to ischemic death are their reduced capability to sequester glutamate and reduced ability to generate energy during anoxia. The patterned death of Purkinje cells is sufficient to induce a form of audiogenic myoclonus, as determined with a neurotoxic dose of ibogaine. Ibogaine-induced myoclonus is recognized behaviorally as a reduced ability to habituate to a startle stimulus and resembles the myoclonic jerk of rats during recovery from a prolonged bout of global brain ischemia. Commonalities of ischemia and ibogaine-induced neurodegeneration are the intricately striped Purkinje cell loss in the posterior lobe and a nearly complete deafferentation of the lateral aspect of the fastigial nucleus from the cerebellar cortex, in particular the dorsolateral protuberance. Thus, the data point strongly to a cerebellar contribution to audiogenic myoclonus. Single-neuron electrophysiology experiments in monkeys have demonstrated that the evoked activity in the deep cerebellar nuclei occurs too late to initiate the startle response (60) and electromyography of the postischemic myoclonus of rats corroborates this view (see Chapter 31) (20). However, the nearly complete loss of GABAergic terminals in the dorsolateral protuberance after Purkinje cell death would be expected to dramatically increase its tonic firing and the background excitation of the brain-stem structures that it innervates. The fastigial nucleus innervates a large number of autonomic and motor structures in the brainstem and diencephalon, including the ventrolateral nucleus of the thalamus and the gigantocellular reticular nucleus in the medulla--structures that have been implicated in human posthypoxic myoclonus (6, 7). We propose that the posthypoxic myoclonic jerk of rats is, at least in part, due to disinhibition of the fastigial nucleus produced by patterned Purkinje cell death in the vermis. The argument is as follows: the loss of GABAergic inhibition in the fastigial nucleus after ischemia leads to diaschisis of the motor thalamus and reticular formation which, in turn, is responsible for enhanced motor excitability and myoclonus. That the audiogenic myoclonus after global brain ischemia in the rat gradually resolves over a period of 2 to 3 weeks is consistent with this view, as restoration of background excitability after CNS damage in rats has been documented to occur within this time-frame (61). Our view brings together the physiologic finding that posthypoxic myoclonus appears to originate in the sensory-motor cortices and/or reticular formation with the consistent anatomical finding of Purkinje cell loss after ischemia, and explains the puzzle of Marsden's unique cases of myoclonus associated with coeliac disease (1). Moreover, our argument is consistent with findings both in rats (62, 63) and humans (64) that damage to the vermis impairs the long-term habituation of the startle reflex. It remains to be determined whether the pathologically enhanced startle responses after vermal damage resemble brain-stem reticular or cortical myoclonus at the electrophysiologic level of analysis. What is the purpose of the regional expression of aldolase C and EAAT4 in Purkinje cells? The close correspondence between the spatial distribution of aldolase C and the parasagittal anatomy of the cerebellum (48) has led to the view that aldolase C may help specify connectivity during development. While the present experiments do not address this issue, they underscore the fact that aldolase plays a fundamental role in metabolism. Because Purkinje cells have a repressed expression of aldolase A (31), whatever role the absence of aldolase C may play during development comes at the price of metabolic frailty later in adulthood. From another point of view, aldolase C and EAAT4 appear to confer upon Purkinje cells the ability to survive their own climbing fiber. Indeed, climbing fibers form a distributed synapse that synchronously releases glutamate (or aspartate) at all levels of the dendritic tree simultaneously (65, 66). Such synchronous activation triggers calcium influx throughout the Purkinje cell dendrites at a magnitude that is unparalleled in the nervous system (12), and, thus, places an extraordinarily high metabolic demand on the Purkinje cell. The apparently reduced level of aldolase in a subpopulation of Purkinje cells provides the condition for energy failure and death during anoxia so long as the climbing fibers are intact or when climbing fiber activation is pharmacologically enhanced under normoxic conditions, such as after ibogaine (53-56). Lastly, the argument that diaschisis produced by patterned cerebellar degeneration leads to thalamo-cortical and reticular hyperexcitability agrees with C. David Marsden and his colleagues' bold demonstration of an inhibitory influence of cerebellar cortex on motor cortex in humans (67). Our anatomic data indicate that the spatially distinct zones of Purkinje cells, which are killed by global brain ischemia, may be the origin of such inhibition.
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PMID:Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. 1196 59


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