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)

Mice with targeted deletion of the GABA catabolic enzyme succinic semialdehyde dehydrogenase (SSADH) manifest lethal tonic-clonic seizures, amenable to pharmacologic rescue, at 3-4 weeks of life. In the current report, we characterized amino acid profiles in SSADH(-/-) brain utilizing whole brain and regional extracts (frontal and parietal cortex, hippocampus, and cerebellum) to develop hypotheses concerning epileptogenesis. Of 35 amino acids quantified, we found significant dysregulation in SSADH(-/-) mice for 11 (GABA, glutamate, glutamine, alanine, aspartate, serine, taurine, cystathionine, methionine, homocarnosine, and arginine) as compared to age-matched littermates both before, and following, the period of generalized convulsive seizures and status epilepticus. Our results reveal imbalanced amino acid levels potentially involved in the transition from absence seizures to generalized convulsive seizures resulting in SSADH(-/-) mice. We conclude that the SSADH(-/-) mouse represents a unique epileptic model with the potential to reveal novel aspects of excitatory/inhibitory interactions in the genesis of seizures.
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PMID:Seizure evolution and amino acid imbalances in murine succinate semialdehyde dehydrogenase (SSADH) deficiency. 1526 67

The aim of the present study was to analyze biochemical effects of a neurosteroid, pregnenolone sulfate (PS), which accompany changes in the threshold of seizures, and to establish the contribution of local, hippocampal monoaminergic and amino acid systems, to the control of convulsive activity. Pretreatment of mice with PS (intracerebroventricularly) selectively enhanced the potency of peripherally (intraperitoneally) administered NMDA at the LD16 (88.0 mg/kg) to induce clonic-tonic convulsions (PS, LD84 = 184.7 nM; 95% CL = 181.4-188.1). The proconvulsive actions of picrotoxin and bicuculline, the GABA-A receptor antagonists, were not modified by pretreatment of mice with PS. Administration of PS alone (up to 240 nM icv) did not show any seizure-like activity. PS given at LD84, together with NMDA (at the LD16), increased the hippocampal concentration of alanine, and enhanced local metabolism of dopamine in a period immediately preceding the onset of seizures significantly stronger than did NMDA alone. These and other data indicate that the enhancement by PS of hippocampal levels of alanine may contribute to the seizures development as this amino acid is a precursor of glutamate, and a co-agonist of the NMDA receptors. On the other hand, simultaneously occurring stimulation of hippocampal dopaminergic system may be considered a compensatory phenomenon, limiting seizures propagation through the limbic forebrain. Summarizing, our results show that PS-induced potentiation of NMDA seizures is accompanied by selective changes in hippocampal dopamine turnover and alanine concentration.
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PMID:Pregnenolone sulfate potentiates the effects of NMDA on hippocampal alanine and dopamine. 1530 35

Glutamine synthesis in the astroglia reflects the sum of neurotransmitter cycling (glutamate and gamma-aminobutyric acid [GABA]) and de novo synthesis (anaplerosis), the latter catalyzed by pyruvate carboxylase. Previous studies have shown that the glutamate plus GABA cycling flux is correlated strongly with neuronal activity; however, the relationship between pyruvate carboxylase flux and neuronal activity is not known. In this study, pyruvate carboxylase flux was assessed during intravenous infusion of [2-(13)C]glucose using localized (1)H-[(13)C] NMR spectroscopy at 7 Tesla in vivo in halothane-anesthetized and ventilated adult Wistar rats during 85 min of bicuculline-induced seizures (1 mg/kg, intravenously) and in nontreated controls. During seizures, concentrations of lactate, alanine, glutamine, GABA, and succinate increased whereas glutamate and aspartate decreased such that the decrease in glutamate plus aspartate equaled the increase in glutamine plus GABA. Pyruvate carboxylase flux was assessed by the sum of [2-(13)C] and [3-(13)C] of glutamine and glutamate (Glx(2+3)) labeling during [2-(13)C]glucose infusion. During seizures the initial rate of Glx(2+3) synthesis (0.069 +/- 0.013 micromol/g/min) was not significantly different (P = 0.68) from that of the controls (0.059 +/- 0.010 micromol/g/min), indicating that anaplerotic flow through pyruvate carboxylase was unaltered. Intense neuronal activation of seizures did not seem to increase anaplerosis through pyruvate carboxylase, despite the substantial increase in neuronal activity and glutamate/glutamine cycling shown in a previous study (Patel et al., 2004b).
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PMID:Cerebral pyruvate carboxylase flux is unaltered during bicuculline-seizures. 1556 1

We examined energy metabolism and amino acid content in the hippocampus of amygdaloid-kindled rats using (1)H NMR spectroscopy. Three weeks after the last stage 5 seizure, kindled rats were killed by microwave irradiation. The hippocampus was dissected out and subjected to MeOH/CHCl(3) extraction. All (1)H spectra were analyzed to quantify absolute concentrations using a non-linear least squares method, combined with a prior knowledge of chemical shifts. Saturation effects were compensated for by the T1 measurement of each component. Levels of energy metabolism-related compounds, phosphocreatine, creatine, glucose and succinate were the same in both kindled rats and sham controls. Lactate concentration had a tendency to increase, although this was not statistically significant. When compared with sham controls, levels of aspartate, glutamate, glycine and glutamine, as well as GABA and inositol, were increased in the ipsilateral but not the contralateral hippocampus. In contrast, levels of taurine, alanine and threonine were unchanged. Finally, N-acetylaspartylglutamate content was elevated, whereas N-acetyl-l-aspartate content was unaltered in the ipsilateral hippocampus of kindled animals. Our results suggest that amygdala kindling may affects amino acid metabolism, but not energy metabolism.
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PMID:In vitro 1H NMR spectroscopy shows an increase in N-acetylaspartylglutamate and glutamine content in the hippocampus of amygdaloid-kindled rats. 1574 51

Childhood absence epilepsy is an idiopathic, generalized, nonconvulsive epilepsy with a multifactorial genetic etiology. The KCNK9 gene coding for the TASK3 (Twik-like acid-sensitive K</U)+) channel is present on chromosome 8 at position 8q24, a locus that has shown positive linkage to the human absence epilepsy phenotype. Sequencing of the KCNK9 gene in the genetic absence epilepsy rats from Strasbourg (GAERS), a well established genetic model of this disease, reveals an additional alanine residue in a polyalanine tract within the C-terminal intracellular domain. This additional alanine is absent in the inbred nonepileptic control (NEC) strain, Wistar, and Wistar albino Glaxo strain bred in Rijswijk, another inbred rat model of absence epilepsy. Expression of the mutant channel in CHO cells produces a K+ current that is blocked by acidic pH and millimolar concentrations of barium or ruthenium red and is not different from the wild-type channel. In brain slices, thalamic neurons display a prominent pH-sensitive tonic K+ current, but no difference was observed between GAERS and NEC or Wistar rats. Ruthenium red had no effect in cortical, reticular thalamic, or sensory thalamic neurons in either GAERS or NEC, indicating that the TASK3 homodimer is not present in these structures. Twik-like acid-sensitive K+(TASK3) channels, therefore, are probably associated with TASK1 to form ruthenium red-insensitive heterodimers in these neurons. Finally, no difference was found between GAERS and NEC rats in the modulation of the leak K+ current following activation of muscarinic receptors. These studies describe the first mutation found in a genetic model of absence epilepsy. Although our experiments showed no difference in the leak K+ current between GAERS and NEC rats, further work is needed to ascertain whether this mutation contributes to the generation of absence seizures, possibly by mechanisms related to the expansion of the polyalanine run.
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PMID:A TASK3 channel (KCNK9) mutation in a genetic model of absence epilepsy. 1578 65

The ketogenic diet (KD) is an established treatment for medically refractory pediatric epilepsy. Its anticonvulsant mechanism is still unclear. We examined the influence of the KD on the CSF levels of excitatory and inhibitory amino acids in 26 children (mean age 6.1 years) with refractory epilepsy. Seventeen amino acids were determined before and at a mean of 4 months after the start of the KD. Seizures were quantified. Highly significant changes were found in eight amino acids: increases in GABA, taurine, serine, and glycine and decreases in asparagine, alanine, tyrosine and phenylalanine. However, aspartate, glutamate, arginine, threonine, citrulline, leucine, isoleucine and valine/methionine remained unchanged. A significant correlation with seizure response was found for threonine (P=0.016). The GABA levels were higher in responders (>50% seizure reduction) than in nonresponders during the diet (P=0.041). In the very good responders (>90% seizure reduction), the GABA levels were significantly higher at baseline as well as during the diet. Age differences were found with significantly larger decreases in glutamate and increases in GABA in connection with the diet in younger children. Our results indicate that the KD significantly alters the levels of several CSF amino acids that may be involved in its mechanism of action and the increase in GABA is of particular interest.
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PMID:The ketogenic diet influences the levels of excitatory and inhibitory amino acids in the CSF in children with refractory epilepsy. 1596 Dec 83

The Na(+)-independent alanine-serine-cysteine transporter 1 (Asc-1) is exclusively expressed in neuronal structures throughout the central nervous system (CNS). Asc-1 transports small neutral amino acids with high affinity especially for D-serine and glycine (K(i): 8-12 microM), two endogenous glutamate co-agonists that activate N-methyl-D-aspartate (NMDA) receptors through interacting with the strychnine-insensitive glycine binding-site. By regulating D-serine (and possibly glycine) levels in the synaptic cleft, Asc-1 may play an important role in controlling neuronal excitability. We generated asc-1 gene knockout (asc-1(-/-)) mice to test this hypothesis. Behavioral phenotyping combined with electroencephalogram (EEG) recordings revealed that asc-1(-/-) mice developed tremors, ataxia, and seizures that resulted in early postnatal death. Both tremors and seizures were reduced by the NMDA receptor antagonist MK-801. Extracellular recordings from asc-1(-/-) brain slices indicated that the spontaneous seizure activity did not originate in the hippocampus, although, in this region, a relative increase in evoked synaptic responses was observed under nominal Mg(2+)-free conditions. Taken together with the known neurochemistry and neuronal distribution of the Asc-1 transporter, these results indicate that the mechanism underlying the behavioral hyperexcitability in mutant mice is likely due to overactivation of NMDA receptors, presumably resulting from elevated extracellular D-serine. Our study provides the first evidence to support the notion that Asc-1 transporter plays a critical role in regulating neuronal excitability, and indicate that the transporter is vital for normal CNS function and essential to postnatal survival of mice.
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PMID:Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice. 1602 68

In these experiments we have tested the effect of bis(acetato)tetrakis (imidazole) copper(II) on the release and uptake of 14C-GABA and 3H-glutamate from brain slices and brain cortical synaptosomes. Cu(OAc)2(Im)4 in concentrations ranging from 1 to 100 microM has increased the release of GABA and glutamate from brain slices and synaptosomal preparations in a dose-related manner when the effect on GABA release is two-fold greater than glutamate and 10-fold greater than alanine. Pretreatment with a GABA uptake inhibitor such as 1-2 mM nipecotic acid has no effect on 14C-GABA release, whereas hydroxy aspartate, the glutamate uptake inhibitor, has elevated the stimulated release of glutamate. Copper(II) chloride, the inorganic form of copper, had no significant effect either on GABA release or on glutamate release. The stimulated release of exogenous GABA and glutamate was Ca2+-dependent, because it was inhibited by EGTA, and neuronal, because it was blocked by tetrodotoxin. The recent results can explain the anticonvulsant activity of Cu(OAc)2(Im)4 against strychnine-induced seizures by increasing the net release of GABA from cortical neurons.
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PMID:Stimulated release of exogenous GABA and glutamate from cerebral cortical synaptosomes and brain slices by bis(acetato)tetrakis(imidazole) copper(II) complex. 1632 73

A leucine to alanine substitution (L9'A) was introduced in the M2 region of the mouse alpha4 neuronal nicotinic acetylcholine receptor (nAChR) subunit. Expressed in Xenopus oocytes, alpha4(L9'A)beta2 nAChRs were > or =30-fold more sensitive than wild type (WT) to both ACh and nicotine. We generated knock-in mice with the L9'A mutation and studied their cellular responses, seizure phenotype, and sleep-wake cycle. Seizure studies on alpha4-mutated animals are relevant to epilepsy research because all known mutations linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) occur in the M2 region of alpha4or beta2 subunits. Thalamic cultures and synaptosomes from L9'A mice were hypersensitive to nicotine-induced ion flux. L9'A mice were approximately 15-fold more sensitive to seizures elicited by nicotine injection than their WT littermates. Seizures in L9'A mice differed qualitatively from those in WT: L9'A seizures started earlier, were prevented by nicotine pretreatment, lacked EEG spike-wave discharges, and consisted of fast repetitive movements. Nicotine-induced seizures in L9'A mice were partial, whereas WT seizures were generalized. When L9'A homozygous mice received a 10 mg/kg nicotine injection, there was temporal and phenomenological separation of mutant and WT-like seizures: an initial seizure approximately 20 s after injection was clonic and showed no EEG changes. A second seizure began 3-4 min after injection, was tonic-clonic, and had EEG spike-wave activity. No spontaneous seizures were detected in L9'A mice during chronic video/EEG recordings, but their sleep-wake cycle was altered. Our findings show that hypersensitive alpha4* nicotinic receptors in mice mediate changes in the sleep-wake cycle and nicotine-induced seizures resembling ADNFLE.
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PMID:Novel seizure phenotype and sleep disruptions in knock-in mice with hypersensitive alpha 4* nicotinic receptors. 1633 34

The aim of this study was to evaluate the role of the GRIK3 functional polymorphism (Ser310Ala) in the pathogenesis of alcoholism. This polymorphism was investigated in two types of studies: (1) the association study in a whole group of alcoholics (116 patients fulfilling ICD-10 alcohol dependence (AD) criteria and 255 controls, Polish descent) and homogenous overlapping subgroups of patients with: a history of delirium tremens and/or alcohol seizures, early age of onset of alcoholism (AOO<26 years), a co-occurrence of dissocial personality disorder, a history of familial alcoholism; (2) the family-based study (using Transmission Disequilibrium Test (TDT) in 100 Polish families with alcohol dependence). The history of alcoholism was obtained using SSAGA (Polish version). GRIK3 functional polymorphism was determined using PCR. TDT revealed an adequate transmission of both alleles to the affected offspring in the whole group of alcohol families (29 x Ser, 24 x Ala; chi2=0.472; d.f.=1; p=0.492) and in the homogenous subgroups of families. No significant associations between any of the above mentioned alcohol phenotypes and Ser310 allele were observed (the whole AD group: p=0.66 AD with delirium and/or seizures: p=0.521; early onset AD: p=0.868; AD with familial history of alcoholism: p=0.798 and AD with dissocial personality disorder: p=0.618). These findings do not seem to support the hypothesis of the role of this polymorphism in the pathogenesis of alcoholism.
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PMID:Family-based and case-control association studies of glutamate receptor GRIK3 Ser310Ala polymorphism in Polish patients and families with alcohol dependence. 1635 44


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