Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Positron emission tomography (PET) is a relatively noninvasive neuroimaging method by means of which a large variety of human brain functions can be assessed. Localized neurochemical abnormalities detected by PET were found in patients with partial epilepsy and suggested the use of this modality for localizing epileptogenic regions of the brain. The clinical usefulness of PET is determined by its sensitivity and specificity for identifying epileptogenic areas as defined by ictal surface and intracranial EEG recordings. The findings obtained from comparative EEG and glucose PET data are reviewed with special emphasis on patients undergoing presurgical evaluation because of medically intractable temporal and extratemporal lobe epilepsy. The utility of glucose PET studies for identifying regions of seizure onset is presented, and the limited specificity of glucose metabolic abnormalities for the detection of various EEG patterns in clinical epilepsy is discussed. The authors review the available intracranial EEG and PET comparisons using [11C]flumazenil (FMZ) PET, a tracer for the assessment of tau-amino-butyric acid/benzodiazepine receptor function. They also summarize their experience with [11C]flumazenil PET in identifying cortical regions that show various ictal and interictal cortical EEG abnormalities in patients with extratemporal seizure origin. Finally, the authors demonstrate that further development of new PET tracers, such as alpha-[11C]methyl-L-tryptophan, is feasible and clinically useful and may increase the number of patients in whom PET studies can replace invasive EEG monitoring.
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PMID:Relationship between EEG and positron emission tomography abnormalities in clinical epilepsy. 1070 9

Topiramate is a novel antiepileptic drug, a fructopyranose derivative. In animal studies, topiramate suppresses maximal electroshock seizures, whereas it does not exert inhibitory effects on pentylenetetrazol-induced seizures. Since topiramate hardly affects the threshold of the seizure, topiramate has been believed to be a type of antiepileptic drug that blocks spread of seizures. Thus far, the mechanisms of its actions have been proven to include use-dependent inhibition of voltage-dependent Na+ channels in neurons, potentiation of GABA (gamma-amino-butyric acid)-induced Cl- influx, and inhibitory effects on inward currents by antagonizing kainate/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. In clinical studies conducted overseas, topiramate has been demonstrated to be effective in the treatment of partial seizures etc. In 55 countries including UK and USA, topiramate has been already approved for the clinical use as a drug for partial seizures, while a phase III study has been planned in Japan, using patients with symptomatic localization-related epilepsies.
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PMID:[Target pharmacology of topiramate, a new antiepileptic drug]. 1087 16

We investigated the involvement of striatal dopamine release in electrographic and motor seizure activity evoked by kainic acid in the guinea pig. The involvement of the dopamine receptor subtypes was studied by systemic administration of the dopamine D(1) receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390; 0.5 mg kg(-1)), or the dopamine D(2) antagonist, (5-aminosulphonyl)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride, 30 mg kg(-1)). Microdialysis and high performance liquid chromatography were used to monitor changes in extracellular levels of striatal dopamine and its metabolites, glutamate, aspartate and gamma-amino-butyric acid (GABA). These data were correlated with changes in the striatal and cortical electroencephalographs and clinical signs. We found that, although neither dopamine receptor antagonist inhibited behavioural seizure activity, blockade of the dopamine D(1)-like receptor with SCH 23390 significantly reduced both the 'power' of the electrical seizure activity and the associated change in extracellular striatal concentration of glutamate, whilst increasing the extracellular striatal concentration of GABA. In contrast, blockade of the dopamine D(2)-like receptor with sulpiride significantly increased the extracellular, striatal content of glutamate and the dopamine metabolites. These results confirm previous evidence in other models of chemically-evoked seizures that antagonism of the dopamine D(1) receptor tends to reduce motor and electrographic seizure activity as well as excitatory amino-acid transmitter activity, while antagonism of the dopamine D(2) receptor has relatively less apparent effect.
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PMID:Changes in striatal electroencephalography and neurochemistry induced by kainic acid seizures are modified by dopamine receptor antagonists. 1122 92

Febrile seizures (FS) may represent the most common seizure disorder in childhood and are known to be associated with putative genetic predispositions. Nevertheless, molecular genetic approaches toward understanding FS have been just initiated this decade. Recently, several genetic loci for FS have been mapped thereby assuring the genetic heterogeneity of FS. However, the exact molecular mechanisms of FS are yet to be elucidated. Genetic defects have been recently identified in autosomal dominant epilepsy with FS plus or generalized epilepsy with FS plus. The underlying mutations were found in genes encoding several Na+ channel subunits and the gamma2 subunit of gamma amino-butyric acid (GABA)A receptors in the brain. Furthermore, both channels are also associated with severe myoclonic epilepsy in infancy, where the seizure attacks often begin with prolonged FS and are precipitated by fever even afterwards. Na+ channels are associated with other temperature-sensitive disorders, and GABA(A) receptors are known to play an important role in the pathogenesis of FS. These lines of evidence suggest the involvement of various Na+ channels, GABA(A) receptors and additional auxiliary proteins in the pathogenesis of frequent FS and even in simple FS. This hypothesis may facilitate our understanding of the genetic background of FS.
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PMID:The genetics of febrile seizures and related epilepsy syndromes. 1285 May 8

Pyridoxine-dependent seizure is a rare autosomal recessive disorder that usually presents with neonatal intractable seizures. This syndrome results from an inborn abnormality of the enzyme glutamic acid decarboxylase, which results in reduced pyridazine-dependent synthesis of the inhibitory neurotransmitter gamma amino butyric acid. The full range of symptomatology is unknown; but can be associated with autism, breath holding and severe mental retardation, bilious vomiting, transient visual agnosia, severe articulatory apraxia motor dyspraxia, microcephaly and intrauterine seizures. Parenteral pyridine injection test is a highly effective and reproducible test in confirming the diagnosis. Pyridoxine should be administered as a diagnostic test in all cases of convulsive disorders of infancy in which no other diagnosis is evident. Epileptic seizure discharges subside within 2-6 minutes after the intravenous injection of 50-100 mg of pyridaoxine. Once the diagnosis is confirmed, maintenance therapy should be continued indefinitely and doses increased with age or intercurrent illnesses. The maintenance dose of Bg needed is still not clear. There is a relatively wide range for the daily B6 dose necessary to control the seizure i.e., 10-200 mg/day.
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PMID:Pyridoxine-dependent seizures: a review. 1288 19

The antiepileptic drugs sodium valproate (VPA) and lamotrigine (LTG) are increasingly used in combination in patients in whom monotherapy has failed to control seizures. Although these drugs are known to interact pharmacokinetically, several authors have proposed a pharmacodynamic interaction between the two. In order to investigate this we have studied the effects of combined treatment with LTG and VPA on basal and stimulated extracellular aspartate (ASP), glutamate (GLU), taurine (TAU), gamma amino butyric acid (GABA), 5-hydroxytryptamine (5-HT) and dopamine (DA) release in the hippocampus of freely moving rats using microdialysis. Additionally, we measured the possible effect of VPA on LTG in plasma, whole brain and dialysates. Neither LTG (10 mg/kg) nor VPA (300 mg/kg) given alone significantly altered basal levels of ASP, GLU or TAU. When given together, however, the two drugs significantly reduced extracellular ASP and GLU while increasing TAU levels. In the case of GABA, LTG was without effect on basal levels of the transmitter, but these increased following VPA and this persisted with both drugs. When transmitter release was stimulated by 50 muM veratridine, marked increases in the release of all amino acids occurred and this was decreased by LTG in all cases. VPA alone only altered GABA release, increasing it by approximately the same extent as basal GABA. For all of the amino acids studied, however, VPA reversed the decreases in release seen after LTG. VPA and LTG increased and decreased respectively basal 5-HT and DA. When given together the increase in extracellular 5-HT was greatly prolonged, but no effect on DA release was seen. When 5-HT release was evoked by veratridine this was increased by VPA and no other treatment. With DA, however, neither drug alone altered evoked release, but the two combined led to a marked increase. Co-administration of VPA with LTG showed no significant effect of this combination on LTG in any of the three compartments studied indicating that in this case a significant pharmacokinetic contribution to our findings is unlikely, which suggests that there is a probable pharmacodynamic interaction of the two drugs.
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PMID:Effects of combined lamotrigine and valproate on basal and stimulated extracellular amino acids and monoamines in the hippocampus of freely moving rats. 1566 Feb 42

The gamma-amino-butyric acid type A receptors (GABAAR) are a heteropentameric receptor complex, composed of 16 possible subunits in various combinations, forming a ligand-gated ion channel. Subunit composition is the primary determinant of GABAAR physiology and pharmacology. Here we have measured mRNA levels for 16 GABAAR subunits in isolated dentate granule neurons (DGN) from eight pediatric patients undergoing resective surgery for intractable epilepsy. We found tightly correlated expression of a subset of GABAAR subunit mRNAs within a single DGN (alpha1, gamma1, and gamma2; alpha4, alpha5, and beta2; alpha4 and beta3). Analysis of inter-patient variability (ANOVA) of eleven highly expressed GABAAR subunit mRNAs found seven of the subunits varied between patients, as did whole cell GABAAR currents. Due to inter-patient differences, there is heterogeneity in DGN GABAAR subunit mRNA and physiology within pediatric epilepsy patients. Patient-specific GABAAR expression might contribute to variability in anti-epileptic drug efficacy, side-effect profiles, and seizure susceptibility.
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PMID:Heterogeneous GABAA receptor subunit expression in pediatric epilepsy patients. 1575 75

Multiple intracellular and extracellular regulatory factors affect transcription of the tyrosine hydroxylase (TH) gene encoding the rate-limiting enzyme in the biosynthesis of the neurotransmitters dopamine, norepinephrine and epinephrine. Short chain fatty acids like butyrate are known to alter TH gene expression, but the mechanism of action is unknown. In this report, transient transfection assays identified the proximal TH promoter to contain sufficient genetic information to confer butyrate responsiveness to a reporter gene. Deletion studies and gel shift analyses revealed that the promoter region spanning the cAMP response element is an absolute requirement for transcriptional activation by butyrate. The branched short chain fatty acid valproate is used for seizure control in humans. Significantly, it has a similar aliphatic structure to butyrate, and it was found to have similar effects on TH in PC12 cells. Site-directed mutagenesis indicated that the effects of both fatty acids were mediated through the canonical CRE. Butyrate treatment also resulted in CREB phosphorylation without changing CREB protein levels. The increased phosphorylation of CREB correlated with accumulation of TH mRNA. The adenylate cyclase inhibitor dideoxyadenosine blocked both CREB phosphorylation and accumulation of TH mRNA. The data are consistent with the conclusion that butyrate induces post-translational modifications of pre-existing CREB molecules in a cAMP/PKA-dependent manner to alter TH transcription. These results support the role of butyrate as a novel exogenous regulatory factor in TH gene expression. Our data delineate a molecular mechanism through which diet-derived environmental signals (e.g. butyrate) can modulate catecholaminergic systems by affecting TH gene transcription.
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PMID:Short chain fatty acids regulate tyrosine hydroxylase gene expression through a cAMP-dependent signaling pathway. 1621 87

A 34-year-old man with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) showed chronic intestinal pseudo-obstruction (CIPO), which was improved by the administration of distigmine bromide. He exhibited generalized tonic clonic seizures at the age of 21, and mitochondrial DNA analysis showed the MELAS mutation. At the age of 34, he became akinetic mutism after nonconvulsive status epilepticus and needed enteral nutrition through a nasogasrtic tube. However, he developed abdominal distention and vomiting, and was diagnosed as CIPO, therefore tube feeding was stopped. Although the administration of domperidone, mosapride citrate, butyric acid bacteria, sodium picosulfate, prostaglandin F2 alpha, pantothenic acid, dioctyl sodium sulfosuccinate, and so on, was ineffective, the administration of distigmine bromide improved his bowel motion disturbance and abnormal distention. The present case is the first MELAS patient with CIPO to be ameliorated by distigmine bromide, which might work acetylcholine receptor on the interstitial cells of Cajal.
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PMID:[Distigmine bromide improves chronic intestinal pseudo-obstruction in a case of MELAS]. 1751 Dec 91

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial inherited epileptic syndrome characterized by phenotypic heterogeneity from the milder febrile seizures to the severest epileptic encephalopathy such as severe myoclonic epilepsy in infancy (SMEI). GEFS+ is a disorder with a genetic heterogeneity. Molecular genetics have revealed that four genes are associated with the pathogenesis of GEFS+. These include mutations in genes encoding subunits of neuronal voltage-gated sodium channels (SCN1A, SCN1B, SCN2A) and gamma(2) subunit of the gamma amino-butyric acid (GABA)(A) receptor (GABRG2). These genes have been confirmed as having a role in autosomal dominant GEFS+ families. In addition, the phenotypes of the affected members may depend on the types and locations of these gene mutations. This review states the molecular genetic progress of GEFS+ in brief.
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PMID:[Progress in molecular genetics of generalized epilepsy with febrile seizures plus]. 1845 5


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