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)

Intrahippocampal infusion of nanogram amounts of the neurotoxin kainic acid were used to investigate possible relationships between the convulsive and the local neurodegenerative properties of the amino acid. Bilateral hippocampal depth electrodes and cortical leads were employed to provide simultaneous and continuous electroencephalographic records following kainate injection in unanesthetized freely-behaving rats. In every animal, morphological analysis was performed 3-5 days after administration of kainic acid and attempts were made to correlate neuronal destruction with electroencephalographic patterns. Doses as low as 500 pg kainate led to behavioral sequelae consisting of grooming, scratching and enhanced locomotor activity. In a roughly dose-dependent fashion (range 500 gp-250 ng), these behaviors increased in frequency and at the highest doses the rats also displayed wet-dog shakes, stereotype mouth movements and occasional facial myoclonus. Apart from these automatisms, generalized motor seizures were never seen. Following kainic acid, a spectrum of electroencephalographic changes could occur consisting of one or more of the following: high voltage fast activity, slow and fast high voltage spiking, paroxysmal bursts, spindle bursts or postictal depression periods. The combination of any two of these changes were defined as an ictal episode if they occurred in all four leads simultaneously. Upon morphological examination, only the highest dose used (250 ng) resulted reliably in the degeneration of CA3, CA4 and, partly, CA1 pyramidal cells on the injected side. While the duration of electroencephalographic changes at this dose was significantly higher than at any of the lower doses, the number of seizures or the total time spent in seizures was not different at 250 ng from that at 50 ng. At the latter dose, however, only marginal cell damage could be found. Our data indicate that very low doses of kainic acid directly applied to hippocampal CA3 neurons, can elicit bilateral changes in the electroencephalogram indicative of repetitive limbic seizures which are not necessarily accompanied by neuronal degeneration. At higher doses (250 ng), kainic acid treatment results in both seizure activity and nerve cell death but the two effects appear mechanistically unrelated. While there is no clear-cut dose-response relationship between neuronal damage and seizures, extended electroencephalographic changes of a 15-30 Hz fast activity or simple spiking phenomena may be instrumental for the degenerative process. This dissociation between convulsive and neurodegenerative properties of kainic acid, however, does not argue against a role of an endogenous substance related to kainic acid in the etiology of temporal lobe seizure disorders.
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PMID:Intrahippocampal kainic acid, seizures and local neuronal degeneration: relationships assessed in unanesthetized rats. 717 85

We review the neurochemical and behavioral profile of the selective gamma-aminobutyric acid (GABA) uptake inhibitor, (R)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride [tiagabine (TGB), previously termed NNC 05-0328, NO 05-0328, and NO-328], which is currently in phase III clinical trials for epilepsy. TGB is a potent, and specific GABA uptake inhibitor. TGB lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites. In electrophysiological experiments in hippocampal slices in culture, TGB prolonged the inhibitory postsynaptic potentials (IPSP) and inhibitory postsynaptic currents (IPSC) in the CA1 and CA3 produced by the addition of exogenous GABA. In vivo microdialysis shows that TGB also increases extracellular GABA overflow in a dose-dependent manner. Together these biochemical data suggest that the in vitro and in vivo mechanism of action of TGB is to inhibit GABA uptake specifically, resulting in an increase in GABAergic mediated inhibition in the brain. TGB is a potent anticonvulsant agent against methyl-6,7-dimethyoxy-4-ethyl-B-carboline-3-carboxylate (DMCM)-induced clonic convulsions (mice), subcutaneous pentylenetetrazol (PTZ)-induced tonic convulsions (mice and rats), sound-induced convulsions in DBA/2 mice and genetically epilepsy-prone rats (GEPR), and electrically induced convulsions in kindled rats. TGB is partially efficacious, against subcutaneous PTZ-induced clonic convulsions, and photically induced myoclonus in Papio papio. TGB is weakly efficacious in the intravenous PTZ seizure threshold test and the maximal electroshock seizure (MES) test and produces only partial protection against bicuculline (BIC)-induced convulsions in rats. The overall biochemical and anticonvulsant profile of TGB suggests potential utility in the treatment of chronic seizure disorders such as generalized clonic-tonic epilepsy (GTCS), photomyoclonic seizures, myoclonic petit mal epilepsy, and complex partial epilepsy.
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PMID:A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. 755 76

Although glycogen is the only carbohydrate reserve of the brain, its overall contribution to brain functions remains unclear. It has been proposed that glycogen participates in the preservation of such functions during hypoxia. Several reports also describe a relationship between brain glycogen and susceptibility to epilepsy. To address these issues, we used our brain-specific Glycogen Synthase knockout (GYS1(Nestin-KO)) mouse to study the functional consequences of glycogen depletion in the brain under hypoxic conditions and susceptibility to epilepsy. GYS1(Nestin-KO) mice presented significantly different power spectra of hippocampal local field potentials (LFPs) than controls under hypoxic conditions. In addition, they showed greater excitability than controls for paired-pulse facilitation evoked at the hippocampal CA3-CA1 synapse during experimentally induced hypoxia, thereby suggesting a compensatory switch to presynaptic mechanisms. Furthermore, GYS1(Nestin-KO) mice showed greater susceptibility to hippocampal seizures and myoclonus following the administration of kainate and/or a brief train stimulation of Schaffer collaterals. We conclude that brain glycogen could play a protective role both in hypoxic situations and in the prevention of brain seizures.
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PMID:Role of brain glycogen in the response to hypoxia and in susceptibility to epilepsy. 2657 89

Since brain glycogen is stored mainly in astrocytes, the role of this polysaccharide in neurons has been largely overlooked. To study the existence and relevance of an active neuronal glycogen metabolism in vivo, we generated a mouse model lacking glycogen synthase specifically in the Camk2a-expressing postnatal forebrain pyramidal neurons (GYS1Camk2a-KO), which include the prefrontal cortex and the CA3 and CA1 cell layers of the hippocampus. The latter are involved in memory and learning processes and participate in the hippocampal CA3-CA1 synapse, the function of which can be analyzed electrophysiologically. Long-term potentiation evoked in the hippocampal CA3-CA1 synapse was decreased in alert behaving GYS1Camk2a-KO mice. They also showed a significant deficiency in the acquisition of an instrumental learning task - a type of associative learning involving prefrontal and hippocampal circuits. Interestingly, GYS1Camk2a-KO animals did not show the greater susceptibility to hippocampal seizures and myoclonus observed in animals completely depleted of glycogen in the whole CNS. These results unequivocally demonstrate the presence of an active glycogen metabolism in neurons in vivo and reveal a key role of neuronal glycogen in the proper acquisition of new motor and cognitive abilities, and in the changes in synaptic strength underlying such acquisition.
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PMID:Lack of Neuronal Glycogen Impairs Memory Formation and Learning-Dependent Synaptic Plasticity in Mice. 3145 67