Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014547 (focal epilepsy)
 1,627 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors review some of their experimental data on the contribution of Na(+)- and K(+)-dependent adenosine triphosphatase (Na+,K(+)-ATPase) to focal epilepsy. It has been previously demonstrated that high extracellular K+ concentration increases glial Na+,K(+)-ATPase specific activities in normal conditions while this was not observed in neuronal preparations. At this time, it was hypothesized that this molecular mechanism could play a role in removing K+ released in the extracellular space during neuronal firing. These results have therefore been investigated in acute and chronic epileptogenic lesions of cats with freeze lesion. It was demonstrated that within the primary (F) and the secondary or 'mirror' (M) focus the K+ activation of the glial Na+,K(+)-ATPase dramatically decreased compared to both control animals (C) and the perifocal (PF) non epileptogenic area. Similar results were observed in man when using specimens of anterolateral temporal neocortex obtained during temporal lobectomies in patients with intractable temporal lobe epilepsy, compared with postmortem human specimens or control brain tissues. The modifications of the level of phosphorylation of partially purified Na+,K(+)-ATPase was also investigated in the epileptic cortex in these two experimental conditions. The catalytic subunits were resolved by sodium dodecylsulfate (SDS) gel electrophoresis and their phosphorylation levels were measured in the presence of various concentrations of K+ ions which dephosphorylate the catalytic subunit. K(+)-induced dephosphorylation was decreased in primary and secondary foci of acutely lesioned cats. Those alterations, due to a decreased affinity for K+, were limited to the alpha (-) subunit. In cats with chronic lesions, the dephosphorylating step of the Na+,K+-ATPase catalytic subunit recovered to normal affinity for K+.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Contribution of Na+,K(+)-ATPase to focal epilepsy: a brief review. 132 44

We investigated the influence of milacemide, a glycinamide derivative with putative antiepileptic activity, on the K(+)-activation of Na+,K(+)-ATPase in bulk isolated glial cells and synaptosomes of control and epileptogenic cortex of cats with a chronic freeze lesion. In the primary and secondary epileptic foci of non-treated animals, glial Na+,K(+)-ATPase lost its physiological K(+)-activation, while the synaptosomal enzyme was unchanged. These data reproduced previous work done on the kinetic measurement of the enzymic activities. In treated animals (500 mg/kg milacemide given orally for 2 weeks after the freeze lesion), the glial enzyme showed a normal K(+)-activation in the epileptic foci. These results confirm the existence of an abnormal glial Na+,K(+)-ATPase in cold-induced focal epilepsy and suggest that the antiepileptic activity of milacemide might be secondary to an activation of glial Na+,K(+)-ATPase, contributing to antagonize ictal transformation and seizure spread.
 ...
PMID:Milacemide stimulates deficient glial Na+, K(+)-ATPase in freezing-induced epileptogenic cortex of cats. 216 31

The generation of focal cortical epilepsy as observed in human partial complex seizures is presumably due to enhanced physiologic responses or paroxysmal depolarization shifts (PDSs). However, the molecular mechanism that underlies these phenomena remains unknown. It could be due to a genetically determined error in a structural or regulatory protein or to posttranslational events that modulate membrane excitability. Since neither neuronal PDSs or interictal EEG spikes are sufficient to produce clinical epilepsy, the clinical expression of epilepsy may need the breakdown of neuronal or glial mechanisms that limit the spread of seizures. Hence, biochemical membrane studies of neurons and glia are necessary to understand the expression of human and experimental epilepsy. This chapter will review the role of glia in controlling neuronal excitability and neuron-glia relationships in experimental and human epilepsy. Data exploring the hypothesis that glial control of extracellular K+ or (K+)o is deficient in focal epilepsy induced by cold lesions will be reviewed. The role of glial carbonic anhydrase (CA) and glial control of putative amino acid transmitters in audiogenic epilepsy will be discussed. In the cold lesion, (K+)o activation constants of synaptosomal (Na+,K+)-ATPase are significantly decreased in the actively firing chronic focus, suggesting that the apparent affinity of the synaptosomal enzyme for K+ was increased within epileptic tissue that was actively firing. Interestingly, while sustained focal paroxysms could raise synaptosomal (Na+,K+)-ATPase, glial (Na+,K+)-ATPase and its activation by (K+)o remained decreased during sustained paroxysms in both acute and chronic lesions. Moreover, while the decrease of the absolute level of glial enzyme activity was less evident 45 days after lesion production, the poor response of glial enzyme to (K+)o never reversed to "normal" values. Hence, these experiments provided new information that glial (Na+,K+)-ATPase responds to K+ in a different manner when compared to synaptic enzyme. Glial ATPase and its activation by (K+)o remain decreased in either actively discharging acute lesions or in the indolent chronic foci. This could mean a reduction in the ability of glial membranes to maintain (K+)o homeostasis. As already suggested by Dichter, the impairment in glial control of elevated (K+)o could be mainly responsible for the transition of interictal discharges to ictal episodes, within the primary and the secondary foci.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Neuron-glia relationships in human and experimental epilepsy: a biochemical point of view. 287 19

A double blind cross over trial of Sodium Valproate (Na VPA) vs Magnesium Valproate (Mg VPA) was performed in 122 patients affected by focal or generalized epilepsies. Only modest differences resulted from the comparison between the two drugs: retention was 8% superior in patients treated with Mg VPA, the number of critic episodes and the quantification of interictal events was significantly lower in patients affected by focal epilepsy treated with Mg VPA. The incidence of side effects was the same for the two drugs.
 ...
PMID:[Comparative study of preparations of sodium and magnesium valproate (VPA) in treatment of patients with epileptic seizures]. 315 Jan 26

Hemispheric language dominance, as determined by intracarotid amobarbital sodium injections, and handedness, as reflected by writing and drawing preference, were evaluated in a select group of patients with intractable seizures who had documented focal epilepsy originating from one temporal lobe. Of the patients with left temporal lobe seizure focus, an unusually high percentage of right-handed patients (4/26 [15%]) had right hemisphere language dominance. Pathologic findings of the resected temporal lobe in these patients revealed microscopic damage (hippocampal sclerosis) of the hippocampus in three of three cases; one patient also had a small hamartoma in the midtemporal gyrus. We hypothesize that crossed dominance resulted from disruption by epileptiform activity during early development of selective areas of the left hemisphere.
 ...
PMID:Right-hemisphere language dominance in right-handed epileptic patients. 647 15

Glutamate is the principal excitatory neurotransmitter in the brain and, as such, it inevitably plays a role in the initiation and spread of seizure activity. It also plays a critical role in epileptogenesis. The process of "kindling" limbic seizures in rodents by repeated electrical stimulation is dependent on activation of N-methyl-D-aspartate (NMDA) receptors. The function of these receptors is enhanced in the hippocampus of kindled rats and in the cerebral cortex of patients with focal epilepsy. Microdialysis studies show an increase in the extracellular concentration of glutamate and aspartate before or during seizure onset, suggesting that either enhanced amino acid release or impaired uptake contributes to seizure initiation. Glutamate antagonists selective for NMDA or non-NMDA receptors are potent anticonvulsants when given systemically in a wide variety of animal models of epilepsy. They are of limited efficacy against kindled seizures in rats and (on the basis of preliminary evidence) in patients with drug-refractory complex partial seizures. Cognitive side effects appear to be a significant problem with competitive, as well as noncompetitive, NMDA antagonists. Glutamate receptor antagonists provide significant protection against brain damage following global or focal cerebral ischemia or acute traumatic injury in rodent models. Anticonvulsant compounds of the lamotrigine type, which act on sodium channels and reduce ischemia-induced glutamate release, are cerebroprotective in rodent ischemia models and are free from the cognitive side effects of NMDA-receptor antagonists.
 ...
PMID:The role of glutamate in epilepsy and other CNS disorders. 797 2

Studies of neurons from human epilepsy tissue and comparable animal models of focal epilepsy have consistently reported a marked decrease in dendritic spine density on hippocampal and neocortical pyramidal cells. Spine loss is often accompanied by focal varicose swellings or beading of dendritic segments. An ongoing excitotoxic injury of dendrites (dendrotoxicity), produced by excessive release of glutamate during seizures, is often assumed to produce these abnormalities. Indeed, application of glutamate receptor agonists to dendrites can produce both spine loss and beading. However, the cellular mechanisms underlying the two processes appear to be different. One recent study suggests NMDA-induced spine loss is produced by Ca2+-mediated alterations of the spine cytoskeleton. In contrast, dendritic beading is not dependent on extracellular Ca2+; instead, it appears to be produced by the movement of Na+ and Cl- intracellularly and an obligate movement of water to maintain osmolarity. A decrease in dendritic spine density was recently reported in a model of recurrent focal seizures in early life. Unlike results from other models, dendritic beading was not observed, and other signs of neuronal injury and death were absent. Thus, additional mechanisms to those of excitotoxicity may produce dendritic spine loss in epileptic tissue. A hypothesis is presented that spine loss can be a product of a partial deafferentation of pyramidal cells, resulting from an activity-dependent pruning of neuronal connectivity induced by recurring seizures. The dendritic abnormalities observed in epilepsy are commonly suggested to be a product and not a cause of epilepsy. However, anatomical remodeling may be accompanied by alterations in molecular expression and targeting of both voltage- and ligand-gated channels in dendrites. It is conceivable that such changes could contribute to the neuronal hyperexcitability of epilepsy.
 ...
PMID:Spine loss and other dendritic abnormalities in epilepsy. 1107 33

Oxcarbazepine (OXC) has been licensed for monotherapy and add-on therapy of focal epilepsy in Germany since February 2000. It is chemically related to carbamazepine, and its anticonvulsant effect has been proven in placebo-controlled double blind studies to be comparable to standard antiepileptic drugs such as carbamazepine, valproate, and phenytoin. Patients whose epilepsy is not well controlled with carbamazepine or in whom side effects occur with carbamazepine can be switched to oxcarbazepine overnight, i.e., without a titration phase. In a retrospective analysis on 51 patients with focal epilepsy, the exchange of carbamazepine with oxcarbazepine was investigated. An exchange in a dosage ratio of 1:1-1:1.5 led to a reduction in seizure frequency by more than 50% in 51% of patients. Oxcarbazepine was better tolerated than carbamazepine. During exchange, CNS toxicity occurred more often with high initial dosages and with an exchange ratio of 1:1.5. In patients pretreated with high dosages of carbamazepine, an exchange ratio of 1:1 and rapid subsequent titration to the maximally tolerated dosage may thus be preferable. In 35% (18/51) of patients treated with oxcarbazepine, hyponatremia developed, which was symptomatic in three patients. Sodium levels should be controlled after exchange and if side effects occur. In conclusion, the overnight switch to oxcarbazepine is an attractive option in patients insufficiently controlled by carbamazepine.
 ...
PMID:[Ad hoc change from carbamazepine to oxcarbazepine--effectiveness and tolerance. A retrospective analysis]. 1178 35

Epilepsy is a common neurological disorder with an incidence of approximately 0.5%. In order to develop better strategies for treatment of epilepsy, more insight on the etiology and pathogenesis of epilepsy is required. In 2001, based on the diagnostic scheme of the International League Against Epilepsy, three new forms of familial epilepsy were identified. These include familial temporal lobe epilepsy, familial focal epilepsy with variable foci, and generalized epilepsy with febrile seizure plus. Mutation of a distinct set of genes has been reported in several forms of epilepsy. Mutation of LGI1 gene has been identified in familial lateral temporal lobe epilepsy while mutations of genes which encode sodium channels and GABAA receptors have been reported in generalized epilepsy with febrile seizure plus. However, no disease-causing gene has yet been found in families with familial mesial temporal lobe epilepsy or those with familial focal epilepsy with variable foci. Here, we review the genetic background of these three familial epilepsy syndromes, and provide a better insight on their genetic etiology.
 ...
PMID:Genetic etiology of new forms of familial epilepsy. 1798 85

We conducted a Japanese Expert Consensus (EC) study for the treatment of childhood epilepsies following the method reported from the USA and EU (Wheless JW, et al., 2005, 2007), and compared the results to reveal differences in the choice of antiepileptic drugs (AEDs). The subjects were 41 pediatric board-certified epileptologists who responded to the 23 questionnaires. A 9-point scale was used to grade each AED, in which 9 was the best whereas 1 was the worst for appropriateness of choice for each epileptic syndrome. Lamotrigine (LTG) is frequently used for idiopathic generalized epilepsy except for valproate sodium (VPA) in both the USA and EU, while VPA and clonazepam were the main AEDs in Japan. For cryptogenic complex partial epilepsy and benign focal epilepsy, carbamazepine was a first-line AED among the USA, EU, and Japan, although other first-line AEDs were oxcarbamazepine (OCBZ), LTG, and levetiracetam (LEV) in both the USA and EU, while it was zonisamide in Japan. Regarding the treatment for symptomatic generalized epilepsy, West syndrome and Lennox-Gastaut syndrome, VPA and ACTH were first-line AEDs commonly used in the USA, EU, and Japan, while the other first-line AEDs were topiramate (TPM) and LTG in the USA and EU, and CZP and clobazam in Japan. This Japanese EC study demonstrated the difference in the selection of AEDs for epileptic syndromes between the USA and EU, which use more newly-introduced AEDs including TPM, LTG, OCBZ and LEV as first-and second-line AEDs, and Japan.
 ...
PMID:[Treatment of childhood epilepsies: Japanese Expert Consensus study and a comparison of the results with those of the USA and EU]. 2066 30


1 2 3 Next >>