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)

Numerous studies suggest that modifications in concentrations of both excitatory and inhibitory amino acids are implicated in the pathophysiology of portal-systemic encephalopathy (PSE), a neuropsychiatric disorder associated with chronic liver disease in humans. In this study, amino acid levels were measured by High Performance Liquid Chromatography (HPLC) in Cerebrospinal Fluid (CSF) of 10 dogs (age range: 3 mo.- 3 yr 4 mo.) exhibiting a congenital portal-systemic shunt, either intra or extra-hepatic, and 8 age-matched control dogs who showed no signs of hepatic or neurologic disorders. Dogs with congenital shunts manifested signs of encephalopathy such as disorientation, head pressing, vocalization, depression, seizures and coma. CSF from dogs with congenital shunts contained significantly increased amounts of glutamate (2 to 3-fold increase, p<0.01), glutamine (6-fold increase, p<0.05) and aromatic amino acids (phenylalanine, tyrosine and tryptophan) compared to CSF of control dogs. Concentrations of GABA and branched chain amino acids (valine, leucine, isoleucine) were within normal limits. Modifications of brain glutamate (an excitatory amino acid) as well as tryptophan (the precursor of serotonin) could contribute to the neurological syndrome characteristic of congenital PSE in dogs.
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PMID:Selective alterations of cerebrospinal fluid amino acids in dogs with congenital portosystemic shunts. 947 3

A seizure-protecting effect of the delta-sleep-inducing peptide (DSIP) and its analogues was revealed. An intensive sorption of H3 tryptophan occurred under the effect of the DSIP and its analogues. The data obtained suggests that the serotoninergic system plays no important part in the seizure-protecting effect.
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PMID:[The delta sleep-inducing peptide, its analogs and the serotoninergic system in the development of anticonvulsant action]. 948 48

A major route of tryptophan metabolism is via the hepatic and cerebral synthesis of kynurenine, a substance subsequently used by astrocytes in the brain for the production of the neuroactive substances kynurenic acid and quinolinic acid. Both kynurenic and quinolinic acids have been implicated in modulating the activity of excitatory amino acid pathways in the brain, the former as a neuroprotectant because of its antagonist properties, and the latter as an excitotoxin because of its agonist actions, at NMDA receptors. We therefore determined the concentrations of tryptophan and kynurenine in maternal venous and umbilical cord blood, and in amniotic fluid, of infants after labor and vaginal delivery, and after delivery by cesarean section. Concentrations of tryptophan and kynurenine were significantly higher in umbilical vein plasma compared with maternal venous plasma. Tryptophan and kynurenine concentrations in umbilical vein plasma and amniotic fluid were significantly higher after labor, compared with samples obtained from infants of the same gestational age delivered by cesarean section. There was no umbilical vein-to-artery concentration difference for kynurenine in samples obtained after either labor or cesarean section, but there was a significant gradient for tryptophan in samples obtained after vaginal delivery, indicating increased transfer of this amino acid during labor. There was a significant correlation between umbilical vein tryptophan and kynurenine concentrations for both the labor and cesarean section groups, and plasma kynurenine concentrations were also significantly correlated with both umbilical vein cortisol concentrations and the duration of the second stage of labor in the vaginally delivered infants. These results suggest that the placental transfer of tryptophan and the fetal synthesis of kynurenine are increased during labor. These findings have implications for understanding the vulnerability of the infant brain to ischemic/hypoxic damage in the perinatal period. By analogy with the adult brain, the molar ratio of these substances is likely to determine the susceptibility of the brain to seizure and excitotoxic damage.
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PMID:Maternal, umbilical, and amniotic fluid concentrations of tryptophan and kynurenine after labor or cesarean section. 972 15

Several reports have indicated that cortical resection is effective in alleviating intractable epilepsy in children with tuberous sclerosis complex (TSC). Because of the multitude of cortical lesions, however, identifying the epileptogenic tuber(s) is difficult and often requires invasive intracranial electroencephalographic (EEG) monitoring. As increased concentrations of serotonin and serotonin-immunoreactive processes have been reported in resected human epileptic cortex, we used alpha-[11C]methyl-L-tryptophan ([11C]AMT) positron emission tomography (PET) to test the hypothesis that serotonin synthesis is increased interictally in epileptogenic tubers in patients with TSC. Nine children with TSC and epilepsy, aged 1 to 9 years (mean, 4 years 1 month), were studied. All children underwent scalp video-EEG monitoring, PET scans of glucose metabolism and serotonin synthesis, and EEG monitoring during both PET studies. [11C]AMT scans were coregistered with magnetic resonance imaging and with glucose metabolism scans. Whereas glucose metabolism PET showed multifocal cortical hypometabolism corresponding to the locations of tubers in all 9 children, [11C]AMT uptake was increased in one tuber (n=3), two tubers (n=3), three tubers (n=1), and four tubers (n=1) in 8 of the 9 children. All other tubers showed decreased [11C]AMT uptake. Ictal EEG data available in 8 children showed seizure onset corresponding to foci of increased [11C]AMT uptake in 4 children (including 2 with intracranial EEG recordings). In 2 children, ictal EEG was nonlocalizing, and in 1 child there was discordance between the region of increased [11C]AMT uptake and the region of ictal onset on EEG. The only child whose [11C]AMT scan showed no regions of increased uptake had a left frontal seizure focus on EEG; however, at the time of his [11C]AMT PET scan, his seizures had come under control. [11C]AMT PET may be a powerful tool in differentiating between epileptogenic and nonepileptogenic tubers in patients with TSC.
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PMID:Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography. 985 29

1. The aim of the study was to determine if a more rational therapeutic approach could be devised for neuroleptic resistant psychotic patients treated for months and years with clozapine. Clozapine is an atypical antipsychotic medication, but its therapeutic benefit has been limited by a high incidence of agranulocytosis and seizures. 2. The study has been performed in an open setting and included 12 patients. Some of them developed a secondary depression and were treated with fluoxetine. 3. Pharmacokinetic analysis were conducted at the same time as clinical evaluations, grading using the BPRS, the PDS, and QLS, and determinations of plasma and red blood cell clozapine and desmethylclozapine, plasma and RBC fluoxetine and norfluoxetine, whole blood serotonin and tryptophan. 4. A positive linear correlation was found only between RBC concentration and the evolution of the QLS. 5. Clozapine is efficacious both on positive and negative symptoms but its mechanism of action remains unclear. Positive symptoms disappear more quickly, sometimes followed by a post psychotic depression. Negative symptoms improve more slowly but regularly. They seem to be correlated with serotoninergic mechanisms. For whole blood 5HT, an important increase was seen about 4 weeks after Cloza administration, and then a decrease. 6. Therapeutic drug monitoring (on the same sample drawn for haematological monitoring providing) could play a useful role in the management of patients treated by clozapine: compliance, lowest dose, possible toxicity, drug interaction, lack of efficacy, relapse predictivity.
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PMID:Pharmacoclinical strategy in neuroleptic resistant schizophrenic patients treated by clozapine: clinical evolution, concentration of plasma and red blood cell clozapine and desmethylclozapine, whole blood serotonin and tryptophan. 1036 54

Hepatic encephalopathy (HE) and portal-systemic encephalopathy (PSE) are the terms used interchangeably to describe a complex neuropsychiatric syndrome associated with acute or chronic hepatocellular failure, increased portal systemic shunting of blood, or both. Hepatic encephalopathy complicating acute liver failure is referred to as fulminant hepatic failure (FHF). The clinical manifestations of HE or PSE range from minimal changes in personality and motor activity, to overt deterioration of intellectual function, decreased consciousness and coma, and appear to reflect primarily a variable imbalance between excitatory and inhibitory neurotransmission. Pathogenic mechanisms that may be responsible for HE have been extensively investigated using animal models of HE, or cultures of CNS cells treated with neuroactive substances that have been implicated in HE. Of the many compounds that accumulate in the circulation as a consequence of impaired liver function, ammonia is considered to play an important role in the onset of HE. Acute ammonia neurotoxicity, which may be a cause of seizures in FHF, is excitotoxic in nature, being associated with increased synaptic release of glutamate (Glu), the major excitatory neurotransmitter of the brain, and subsequent overactivation of the ionotropic Glu receptors, mainly the N-methyl-D-aspartate (NMDA) receptors. Hepatic encephalopathy complicating chronic liver failure appears to be associated with a shift in the balance between inhibitory and excitatory neurotransmission towards a net increase of inhibitory neurotransmission, as a consequence of at least two factors. The first is down-regulation of Glu receptors resulting in decreased glutamatergic tone. The down-regulation follows excessive extrasynaptic accumulation of Glu resulting from its impaired re-uptake into nerve endings and astrocytes. Liver failure inactivates the Glu transporter GLT-1 in astrocytes. The second factor is an increase in inhibitory neurotransmission by gamma-aminobutyric acid (GABA) due to (a) increased brain levels of natural benzodiazepines; (b) increased availability of GABA at GABA-A receptors, due to enhanced synaptic release of the amino acid; (c) direct interaction of modestly increased levels of ammonia with the GABA-A-benzodiazepine receptor complex; and (d) ammonia-induced up-regulation of astrocytic peripheral benzodiazepine receptors (PBZR). Brain ammonia is metabolised in astrocytes to glutamine (Gln), an osmolyte, and increased Gln accumulation in these cells may contribute to cytotoxic brain edema, which often complicates FHF. Glutamine efflux from the brain is an event that facilitates plasma-to-brain transport of aromatic amino acids. Tryptophan and tyrosine are direct precursors of the aminergic inhibitory neurotransmitters, serotonin and dopamine, respectively. Changes in serotonin and dopamine and their receptors may contribute to some of the motor manifestations of HE. Finally, oxindole, a recently discovered tryptophan metabolite with strong sedative and hypotensive properties, has been shown to accumulate in cirrhotic patients and animal models of HE.
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PMID:Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. 1061 92

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

In this review, recent studies on the electrophysiological effects of de novo synthesized ("endogenous") kynurenic acid (KYNA) are discussed. Endogenous KYNA is normally formed as a byproduct of tryptophan metabolism. Evidence for a physiological role in neuronal excitability has not been strong, in part because brain levels are much lower than the KD of KYNA at the glycine site of the NMDA receptor, where KYNA is thought to exert its most potent effect. The results suggest that, unexpectedly, even low concentrations of endogenous KYNA have physiological consequences. These levels of KYNA reduced the number of hippocampal slices with spontaneous epileptiform discharges after exposure to buffer lacking magnesium. However, effects on evoked responses to single afferent stimuli were not detected. Taken together, the data argue for a potentially important role of endogenous KYNA in suppression of seizure-like activity, and suggest a novel approach to anticonvulsant drug development that could have few side effects.
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PMID:Electrophysiological effects of exogenous and endogenous kynurenic acid in the rat brain: studies in vivo and in vitro. 1102

Metabolism of tryptophan (TRP) through the kynurenine (KYN) pathway in brain, liver, and kidney produces intermediates including the neuroactive agonist quinolinic acid (QA) and the antagonists kynurenic acid (KA) and anthranilic acid (AA) for N-methyl D-aspartate (NMDA) receptors in the central nervous system. We hypothesized that elevated concentrations of QA, KA, or AA can moderate the convulsions that are observed during exposure of rats to hyperbaric oxygen (HBO). We found that i.p. administration of TRP or KYN (both of which cross the blood-brain barrier) had no effect on HBO-induced seizures. However, AA (administered i.p.) or gavage administration of the KYN pathway blocking drug Ro 61-8048, both of which enter the brain from the circulatory system, affect the time to first convulsion and/or coma during HBO in a manner consistent with a modulatory role for seizure activity.
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PMID:Evidence that kynurenine pathway metabolites mediate hyperbaric oxygen-induced convulsions. 1103 31

The discovery of focal or multifocal cortical lesions using magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning in the majority of infants with West syndrome has led to a surgical approach in the treatment of some patients with intractable infantile spasms. The locations of these lesions should be concordant with localization of focal ictal and/or interictal electroencephalographic (EEG) abnormalities prior to proceeding with cortical resection. When a single lesion is present on the MRI or PET, and there is good correlation with EEG localization, surgical treatment is generally quite favorable in terms of both seizure control and cognitive development. Interictal glucose metabolism PET scans in children with intractable cryptogenic infantile spasms show unifocal cortical hypometabolism in about 20% of cases. In the majority, however, multifocal asymmetric hypometabolism is suggestive of multifocal underlying lesions, possibly multifocal cortical dysplasia. When the pattern of glucose hypometabolism is symmetric, a lesional etiology is less likely, thus neurometabolic or neurogenetic disorders should be considered. Therefore, the pattern of glucose hypometabolism on PET in infants with intractable cryptogenic spasms is a useful guide to decide whether a medical or surgical approach should be undertaken. In order to achieve the best cognitive outcome with surgery, it is important to resect the entire 'nociferous' area rather than just the seizure focus. Our research with new PET imaging probes has attempted to provide a comprehensive evaluation of the epileptogenic zone including the 'nociferous' cortex. We have used [(11)C]flumazenil (FMZ), which labels gamma aminobutyric acid(A) (GABA(A)) receptors, and have found this to be particularly useful in showing: (i) decreased receptor binding with medial temporal involvement thus indicating resection of medial temporal structures, (ii) the peri-lesional epileptogenic zone surrounding MRI lesions, (iii) the seizure onset zone in MRI-negative cases, and (iv) potential secondary epileptic foci. Another recently developed PET probe, alpha[(11)C]methyl-L-tryptophan (AMT) which is a precursor for the serotonin and the kynurenine metabolism pathways, is capable of differentiating between epileptogenic and non-epileptogenic tubers in patients with tuberous sclerosis complex and intractable epilepsy (including infantile spasms). Subsequently, we have applied AMT PET in patients with multifocal cortical dysplasia to determine the predominant seizure focus, and the results have been promising with regard to seizure control but not cognitive development. Thus, the introduction of newer more specific PET probes for epilepsy has led to improved and more accurate localization of seizure foci that should ultimately improve outcome of epilepsy surgery in West syndrome.
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PMID:Surgical treatment of West syndrome. 1170 Dec 75


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