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)

Long lasting alterations of synaptosomal amino acid neurotransmitters following a single or several audiogenic seizures and/or acoustic stimulations were investigated in six brain areas -olfactory bulbs (OB), amygdala (A), hippocampus (Hi), cerebellum (C), inferior colliculus (IC), pons-medulla (P)- of three sublines of Rb mice: audiogenic seizure-prone Rb1 and Rb2, seizure-resistant Rb3. Changes in the synaptosomal levels of aspartate (Asp), glutamate (Glu), taurine (Tau), 4-amino butyrate (GABA), glycine (Gly) and some closely related precursors, serine (Ser) and glutamine (Gln), were recorded 15-18 hours after a single or multiple acoustic stimulations. Changes were more frequent, or larger, after polystimulation. Some alterations appeared to be attributable to an effect of the acoustic stress. In both seizure-prone sublines, after a single or repeated seizures, an increase in synaptosomal Asp was observed in IC. Decreases in Asp and Tau in OB and Ser in A, an increase in Gln in IC were only observed after repeated seizures, in Rb1 and Rb2 mice.
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PMID:Long lasting effects of audiogenic seizures on synaptosomal neurotransmitter amino acids in Rb mice. 791 14

Extracellular levels of aspartate, glutamate and glutamine were monitored by microdialysis in the dorsal hippocampus of freely moving rats following the administration of a convulsant dose of pilocarpine (400 mg/kg, i.p.). Rats were either pretreated with the glutamate uptake inhibitor, 1-trans-pyrrolidine-2,4-dicarboxylic acid (PDC, 1 mM in the perfusion medium, -25 min), or received pilocarpine directly. All rats injected with pilocarpine (with or without PDC pretreatment) developed limbic seizures (latency 15.4 +/- 2.4 min). Without PDC pretreatment there were no significant changes in extracellular levels of aspartate, glutamate and glutamine following pilocarpine administration until the onset of limbic seizures when glutamine levels fell by 35%. Following PDC pretreatment there were large and sustained increases in extracellular hippocampal aspartate (250%) and glutamate (55%) levels, but no significant change in the glutamine level. When pilocarpine was administered to this group of rats, there were further selective, significant, transient increases in the extracellular levels of aspartate (31%) and glutamate (18%) which preceded the onset of seizures. Aspartate and glutamate levels were not significantly increased (relative to PDC controls) during seizures. The conditions for pilocarpine-induced increases in aspartate and glutamate release were established in parallel groups of anaesthetised rats where pilocarpine was administered via a microdialysis probe in the dorsal hippocampus. Following the infusion of 10 mM pilocarpine there were large and rapid increases in the levels of aspartate (143%) and glutamate (179%), which were completely abolished by the absence of calcium in the perfusion medium, or by the presence of atropine (20 mM) or tetrodotoxin (1 microM).
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PMID:Extracellular amino acid levels in hippocampus during pilocarpine-induced seizures. 809 93

Serum amino acid (AA) profiles are altered in epilepsy. It is not clear whether this is due to the disease process itself or to other variables such as seizure type, seizure frequency, duration of illness, medication, or altered liver function. We investigated serum AA profiles and liver enzymes in 73 epileptic patients and 90 healthy subjects and evaluated the data by analysis of variance to discriminate between age, sex, seizure type, duration of illness, seizure frequency, antiepileptic drug (AED) and increased serum liver enzyme levels, and their putative interaction with the serum AA profile. There was no correlation between the changes in the AA profile and age, duration of illness, seizure frequency, and seizure type. Seventy-two percent of the AED-treated patients and 33% of the unmedicated patients showed an increase in one or several serum liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or gamma-glutamyl transferase (gamma-GT)]; particularly gamma-GT. We observed a significant increase in serum concentrations of glutamine and glycine and decreased levels of taurine, threonine, serine, valine, methionine, isoleucine, leucine, phenylalanine, histidine, tryptophan, and arginine in AED-treated patients but not in unmedicated patients. These results show that the changes in the serum AA profiles of epileptic patients treated with AEDs occur in patients with alteration of serum liver enzymes; whether this implies a causal relation is still uncertain.
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PMID:Serum amino acids, liver status, and antiepileptic drug therapy in epilepsy. 809 92

The current study measured extracellular fluid (ECF) levels of excitatory amino acids before and during the onset of thiamine deficiency-induced pathologic lesions. Male Sprague-Dawley rats were treated with daily pyrithiamine (0.25 mg/kg i.p.) and a thiamine-deficient diet (PTD). Microdialysates were simultaneously collected from probes inserted acutely via guide cannulae into right paracentral and ventrolateral nuclei of thalamus and left hippocampus of PTD and pair-fed controls. Hourly samples were collected from unanesthetized and freely moving animals. Basal levels obtained at a prelesion stage (day 12 of PTD treatment) were unchanged from levels in pair-fed controls. In samples collected 4-5 h after onset of seizures (day 14 of PTD), the levels of glutamate were elevated an average 640% of basal levels in medial thalamus and 200% in hippocampus. Glutamine levels declined, taurine and glycine were elevated, and aspartate, GABA, and alanine were unchanged during this period. Within 7 h after seizure onset glutamine was undetectable in both areas, whereas glutamate had declined to approximately 200% in thalamus and 70% in hippocampus. No significant change in glutamate, aspartate, or other amino acids was observed in dialysates collected from probes located in undamaged dorsal-lateral regions of thalamus. Number of neurons within ventrolateral nucleus of thalamus was significantly greater in PTD animals in which the probe was dialyzed compared with nondialyzed, suggesting that removal of excitatory amino acids was protective. No significant pathologic damage was evident in hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Extracellular glutamate is increased in thalamus during thiamine deficiency-induced lesions and is blocked by MK-801. 824 70

Intracellular pH and ammonium ion concentration are potent modulators of cerebral amino acid metabolism. Furthermore, intracellular acidosis and hyperammonemia accompany conditions such as ischemic encephalopathy and seizures and may contribute to the pathological sequelae observed. In vivo NMR spectroscopy permits multiple, non-destructive measurements of important cerebral metabolic intermediates in the same animal. We describe here the use of 1H, and 31P NMR spectroscopy to investigate the effects of acute changes in intracellular pH and ammonium ions on cerebral glutamate, glutamine, and lactate levels in vivo. We then show how 1H NMR can be used to indirectly follow the flow of 13C label from [1-13C] glucose into the cerebral glutamate pool, allowing us to measure cerebral TCA activity in normal and chronically hyperammonemic rats. Male Sprague-Dawley rats (160-210 gm), fasted 24-hours, were tracheotomized, paralyzed and ventilated on 30% O2/70% N2O. NMR spectroscopy was performed at a field strength of 8.4 Tesla using a Bruker AM-360 wide bore spectrometer. An elliptical surface-coil (8 x 12 mm) was double-tuned to either the 1H and 31P or 1H and 13C frequencies. After retraction of extracranial tissues, the coil was positioned over the skull 2 mm posterior to the bregma. Tail arteries and veins were cannulated allowing periodic measurements of PO2, pCO2, pH and glucose in arterial blood and intravenous infusions. Respiratory acidosis was induced in rats by the addition of CO2 to the ventilation gas mixture. Arterial pCO2 increased within 5 min from a pre-hypercarbic value of 36.4 +/- 6.1 mm Hg to 200-220 mm Hg and was maintained at this level for over 1 hour. Hypercarbia led to rapid cerebral acidification. Intracellular pH decreased from 7.18 +/- 0.08 (pre-hypercarbic period) to 6.68 +/- 0.06 (n = 4) at 10 min and remained stable throughout the NMR observation period. Glutamate decreased to 53 +/- 4% of control after 60 min of hypercarbia, while glutamine increased to 126 +/- 7% of control. Acute hyperammonemia was produced by a programmed intravenous infusion of 250 mM ammonium acetate, which rapidly raised and maintained the concentration of ammonium ions in the blood at approximately 500 microM. Shortly after the start of the infusion (10-20 min), the levels of glutamine and lactate rose continuously throughout the experiment, reaching levels of 170 +/- 25% and 260 +/- 60% of control, respectively (n = 12) after 50 min. Glutamate decreased during the same time interval to 80 +/- 4% of control (n = 12).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cerebral metabolic studies in vivo by combined 1H/31P and 1H/13C NMR spectroscopic methods. 842 59

CNS oxygen (O2) toxicity is complex, and the etiology of its most severe manifestation, O2 convulsions, is yet to be determined. A role for depletion of the brain GABA pool has been proposed, although recent data have implicated production of reactive O2 species, e.g. H2O2, in this process. We hypothesized that the production of H2O2 and NH3 produced by monoamine oxidase (MAO) would lead to depletion of GABA and production of nitric oxide (NO.) respectively, and thereby enhance CNS O2 toxicity. In this study, rats treated with an MAO inhibitor (pargyline) or a nitric oxide synthase inhibitor (LNNA) were protected against O2-induced convulsions. Selected cerebral amino acids including arginine were measured in control and O2 treated rats (6 ATA, 20 min) with or without drug pretreatment. After O2 exposure, the cerebral pools of glutamate, aspartate, and GABA decreased significantly while glutamine content increased relative to control (P < 0.05). After treatment with either enzyme inhibitor, glutamine, glutamate and aspartate concentrations were maintained near control levels. Remarkably, GABA depletion by O2 was not prevented despite protection from seizures by both pargyline and LNNA. The NO. precursor, arginine, was increased significantly in the brain by toxic O2 exposure, but both pargyline and LNNA inhibited this effect. Simultaneous norepinephrine measurements indicated that its storage substantially decreased during hyperoxia (P < 0.05), but this effect too was blocked by either pargyline or LNNA. These data indicate that protection against O2 by these inhibitors is not related to preservation of the GABA pool. More importantly, O2 dependent norepinephrine metabolism and NO. synthesis appear to be interactive during CNS O2 toxicity.
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PMID:Cerebral amino acid, norepinephrine and nitric oxide metabolism in CNS oxygen toxicity. 846 4

The excitatory, glutamatergic granule cells of the hippocampal dentate gyrus are presumed to play central roles in normal learning and memory, and in the genesis of spontaneous seizure discharges that originate within the temporal lobe. In localizing the two GABA-producing forms of glutamate decarboxylase (GAD65 and GAD67) in the normal hippocampus as a prelude to experimental epilepsy studies, we unexpectedly discovered that, in addition to its presence in hippocampal nonprincipal cells, GAD67-like immunoreactivity (LI) was present in the excitatory axons (the mossy fibers) of normal dentate granule cells of rats, mice, and the monkey Macaca nemestrina. Using improved immunocytochemical methods, we were also able to detect GABA-LI in normal granule cell somata and processes. Conversely, GAD65-LI was undetectable in normal granule cells. Perforant pathway stimulation for 24 hours, which evoked population spikes and epileptiform discharges in both dentate granule cells and hippocampal pyramidal neurons, induced GAD65-, GAD67-, and GABA-LI only in granule cells. Despite prolonged excitation, normally GAD- and GABA-negative dentate hilar neurons and hippocampal pyramidal cells remained immunonegative. Induced granule cell GAD65-, GAD67-, and GABA-LI remained elevated above control immunoreactivity for at least 4 days after the end of stimulation. Pre-embedding immunocytochemical electron microscopy confirmed that GAD67- and GABA-LI were induced selectively within granule cells; granule cell layer glia and endothelial cells were GAD- and GABA-immunonegative. In situ hybridization after stimulation revealed a similarly selective induction of GAD65 and GAD67 mRNA in dentate granule cells. Neurochemical analysis of the microdissected dentate gyrus and area CA1 determined whether changes in GAD- and GABA-LI reflect changes in the concentrations of chemically identified GAD and GABA. Stimulation for 24 hours increased GAD67 and GABA concentrations sixfold in the dentate gyrus, and decreased the concentrations of the GABA precursors glutamate and glutamine. No significant change in GAD65 concentration was detected in the microdissected dentate gyrus despite the induction of GAD65-LI. The concentrations of GAD65, GAD67, GABA, glutamate and glutamine in area CA1 were not significantly different from control concentrations. These results indicate that dentate granule cells normally contain two "fast-acting" amino acid neurotransmitters, one excitatory and one inhibitory, and may therefore produce both excitatory and inhibitory effects. Although the physiological role of granule cell GABA is unknown, the discovery of both basal and activity-dependent GAD and GABA expression in glutamatergic dentate granule cells may have fundamental implications for physiological plasticity presumed to underlie normal learning and memory. Furthermore, the induction of granule cell GAD and GABA by afferent excitation may constitute a mechanism by which epileptic seizures trigger compensatory interictal network inhibition or GABA-mediated neurotrophic effects.
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PMID:Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus. 888 46

Germline mutations in the presenilin 1 (PS1) gene apparently account for the majority of early-onset, familial Alzheimer's disease (AD). Using a mutation-screening strategy (denaturing gradient gel electrophoresis; DGGE), we analyzed a large family with early onset AD and seizures. The patients in this family showed a novel missense mutation in exon 5 of the PS1 gene (A to T change in codon 120, altering glutamine to aspartic acid). This novel mutation is located within the second hydrophilic domain of the molecule, a region not particularly involved in previously described germline mutations, and is of unknown biological significance. These results also demonstrate that DGGE can be used effectively to screen for mutations within this gene.
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PMID:A novel mutation of presenilin 1 in familial Alzheimer's disease in Israel detected by denaturing gradient gel electrophoresis. 893 4

The purpose of this study was to determine the time of onset, duration, and the efficacy of in vivo gene transfer in protecting the ornithine transcarbamylase deficient spf/Y mouse from an acute ammonium challenge. The animals were challenged with ammonia (10 mmol/kg NH4Cl) 1, 2, 7, 14, or 28 d after the administration of a recombinant adenoviral construct deleted in E1 and with a temperature sensitive mutation in E2. Although there was no protection with the control LacZ virus, the ornithine transcarbamylase (OTC)-containing vector provided partial protection from both behavioral symptoms (ataxia, seizures, and abnormal response to sound) and biochemical abnormalities (ammonium, aspartate, alanine, and glutamine) within 24 h and complete protection by 48 h. Mortality was also decreased. Animals receiving the vector 7 and 14 d before the ammonium load were also protected, whereas those treated 28 d before the challenge were not. OTC enzyme activity in liver of untreated spf/Y mice was 5% of control C3H mice. After gene transfer, activity was increased to near control levels through 14 d but had returned to baseline by 28 d. These studies indicate that adenovirus-mediated gene transfer confers a metabolic benefit within 24 h of administration and provides protection against an acute metabolic insult for at least 2 wk.
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PMID:Adenovirus-mediated in vivo gene transfer rapidly protects ornithine transcarbamylase-deficient mice from an ammonium challenge. 909 55

The effects of valproate on CNS concentrations of gamma-aminobutyric acid (GABA), glulamate (GLU), glutamine (GLN); dopamine (DA), serotonin (5-HT), and metabolites were examined in tissue extracts of caudate nucleus of genetic substrains of Balb/c mice susceptible (EP) or resistant (ER) to audiogenic seizures. Generalized tonic-clonic seizures observed in EP mice were inhibited by valproate, administered 1 h prior to testing, in a dose-response fashion. Concentrations of GABA, GLU, and GLN, which were lower in EP mice than in ER mice, were significantly increased by valproate at doses of 180 and 360 mg/kg. Concentrations of homovanillic acid (HVA) and hydroxyindoleacetic acid (5-HIAA), metabolites of DA and 5-HT, were substantially increased by valproate at these doses. The in situ activity of tyrosine hydroxylase (TH) was not significantly influenced by valproate, whereas a valproate-induced increase in tryptophan hydroxylase (TPH) activity was observed in both striatum and in midbrain tegmentum. The data are consistent with the interpretation that anti-convulsive doses of valproate influences the intraneuronal metabolism of monoamines, GABA, and glutamate concurrently. Valproate's influence on the metabolism of both major inhibitory (GABA) and excitatory (GLY amino acids in striatum could contribute to its anti-convulsive effects in genetically seizure prone mice, as well as to the accumulation of DA and 5-HT metabolites.
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PMID:Effects of valproate on amino acid and monoamine concentrations in striatum of audiogenic seizure-prone Balb/c mice. 914 15


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