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)

In an elevated plus-maze indole-3-pyruvic acid (IPA, 100-200 mg/kg), an endogenous metabolite of tryptophan, possesses in mice an activity typical of anxiolytics. IPA increased the ratio of the number of entries into open arms over the total number of entries into open and closed arms and the time spent in open arms. Similar effect was observed for diazepam, a standard anxiolytic. Pretreatment with IPA attenuated the anxiogenic effect of caffeine (50 mg/kg) and 3-hydroxykynurenine (1.2 micrograms, i.c.v.) but not that of pentylenetetrazole (10 mg/kg), or phenylethylamine (5 and 10 mg/kg). Pretreatment with IPA (50-200 mg/kg) did not attenuate pentylenetetrazole- or phenylethylamine-induced seizures in contrast to diazepam which prevents both types of seizures. The data suggest that IPA is an endogenous anxiolytic with novel profile.
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PMID:Anxiolytic effect of indole-3-pyruvic acid (IPA) in mice. 790 63

Kynurenate is an endogenous antagonist of the ionotropic glutamate receptors. It is synthesized from kynurenine, a tryptophan metabolite, and a significant increase in its brain concentration could be useful in pathological situations. We attempted to increase its neosynthesis by modifying kynurenine catabolism. Several kynurenine analogues were synthesized and tested as inhibitors of kynurenine hydroxylase (E.C.1.14.13.9) and of kynureninase (E.C.3.7.1.3), the two enzymes which catalyse the conversion of kynurenine to excitotoxin quinolinate. Among these analogues we observed that nicotinylalanine, a compound whose pharmacological properties have previously been reported, had an IC50 of 900 +/- 180 microM as inhibitor of kynurenine hydroxylase and of 800 +/- 120 microM as inhibitor of kynureninase. In the search for more potent molecules we noticed that meta-nitrobenzoylalanine had an IC50 of 0.9 +/- 0.1 microM as inhibitor of kynurenine hydroxylase and of 100 +/- 12 microM as inhibitor of kynureninase. When administered to rats meta-nitrobenzoylalanine (400 mg/kg) significantly increased the concentration of kynurenine (up to 10 times) and kynurenate (up to five times) in the brain. Similar results were obtained in the blood and in the liver. Furthermore meta-nitrobenzoylalanine increased in a dose dependent, long lasting (up to 13 times and up to 4 h) manner the concentration of kynurenate in the hippocampal extracellular fluid, as evaluated with a microdialysis technique. This increase was associated with a decrease in the locomotor activity and with protection from maximal electroshock-induced seizures in rats or from audiogenic seizures in DBA/2 mice. The conclusions drawn from the present study are: (i) meta-nitrobenzoylalanine is a potent inhibitor of kynurenine hydroxylase also affecting kynureninase; (ii) the inhibition of these enzymes causes a significant increase in the brain extracellular concentration of kynurenate; (iii) this increase is associated with sedative and anticonvulsant actions, suggesting a functional antagonism of the excitatory amino acid receptors.
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PMID:Inhibitors of kynurenine hydroxylase and kynureninase increase cerebral formation of kynurenate and have sedative and anticonvulsant activities. 796 5

The aim of our study was to analyse the possible implication of the serotoninergic system in the pathophysiology and the lethality of audiogenic seizures induced by magnesium deficiency, either by decreasing cerebral serotonin (5-HT) levels (p-chlorophenylalanine) or by increasing 5-HT levels in the brain (5-hydroxytryptophan, L-tryptophan, nialamide, fluoxetine). In magnesium-deficient mice, the percentages of audiogenic seizures and of fatal seizures were dependent on the time lapse between the p-chlorophenylalanine (PCPA) injection and the audiogenic test. The percentage was at least 24 h after the injection: in OF1 and C57BL/6 strains, PCPA fully protected the mice from seizure occurrence, whereas it only partially protected the animals of the other strains. 5-Hydroxytryptophan caused a decrease in the audiogenic seizures in magnesium-deficient OF1 mice as well as in control DBA/2 mice. In contrast L-tryptophan did not reduce the number of wild courses or of clonic and tonic seizures in either the magnesium-deficient OF1 strain or control DBA/2 mice. Nialamide and fluoxetine were only effective in decreasing the numbers of clonic and tonic convulsions of the audiogenic seizure without affecting the wild courses. The combination of nialamide and tryptophan caused a cessation of the audiogenic seizure phases in both magnesium-deficient OF1 and control DBA/2 mice. In contrast, the fluoxetine-tryptophan combination did not have the same effect on magnesium-deficient and non-magnesium-deficient mice. This work showed that the serotoninergic system plays a secondary role in the pathophysiology of audiogenic seizures in magnesium-deficient mice rather than in that of genetically audiosusceptible mice.
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PMID:Effect of various serotoninergically induced manipulations on audiogenic seizures in magnesium-deficient mice. 799 24

Two half-brothers and their mother had symptomatic pyruvate dehydrogenase complex deficiency. The infants had severe congenital lactic acidosis, seizures, and apneic spells and died at the ages 3 and 4 months. The mother was less symptomatic with mental retardation, truncal ataxia, and dysarthria. The residual pyruvate dehydrogenase activities in cultured skin fibroblasts from the 2 infants and their mother were 7, 15, and 10% of control values. Immunoblot analysis showed negligible amounts of E1 alpha and E1 beta subunits of the complex. Northern blot analysis for the E1 alpha subunit showed normal results. In the 2 sons, complementary DNA sequence analysis revealed a cytosine to thymine mutation in exon 4, resulting in a change of arginine 127 to tryptophan in the E1 alpha subunit. Restriction enzyme analysis of the polymerase chain reaction product representing exon 4 of the E1 alpha gene revealed that the mother was a heterozygotes. Complementary DNA restriction analysis and methylation analysis of the X chromosome DXS255 loci revealed skewed activation of the mutant allele, consistent with the deficient pyruvate dehydrogenase activity in the mother's fibroblasts. The milder maternal phenotype is consistent with variable X-inactivation patterns in different organs of female heterozygotes.
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PMID:Pyruvate dehydrogenase deficiency: molecular basis for intrafamilial heterogeneity. 802 67

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

This overview summarizes the major and minor side effects and drug interactions of fluoxetine. The adverse reactions include the "serotonin syndrome", cardiovascular complications, extrapyramidal side effects such as akathisia, dyskinesias, and parkinsonian-like syndromes and an apparently increased risk of suicidality. Fluoxetine-induced mania and hypomania, seizures and sexual disorders are evaluated along with minor symptoms of allergic reactions, stuttering, hematological changes, psoriasis, and inappropriate secretion of the antidiuretic hormone. The major fluoxetine-drug interactions involve the amino acids L-dopa and L-tryptophan, anorexiants, anticonvulsants, antidepressants, anxiolytics, calcium channel blockers, cyproheptadine, lithium salts, and drugs of abuse. The underlying mechanism and the paradoxical effects of fluoxetine are addressed.
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PMID:Fluoxetine: adverse effects and drug-drug interactions. 825 2

Amino acid levels in plasma were measured by amino acid autoanalyser in 130 convulsive children. The levels of taurine, serine and tryptophan were significantly lower in convulsive children as compared to normal control; in contrast, isoleucine, homocystine, GABA, histidine, arginine and ammonia were higher. The children with paroxysmal disorders (headache, dizziness and abdominal epilepsy) had the highest levels of isoleucine, histidine and arginine and the lowest levels of glutamate and cystein. Clinical seizure activity within 6 months prior to the test seemed to have no obvious effect on the plasma amino acid pattern, except for the levels of glycine and arginine tended to return to normal, and the level of GABA was significantly increased in patients with the seizure being controlled. The patients treated with carbamazepin as a single anticonvulsant had the highest GABA level compared to those with other anticonvulsants. Hyperglycinemia and hyperammonaemia were also noted in patients who took valproic acid. The levels of serine, isoleucine and phenylalanine in the CSF within 6 hours after convulsion were significantly lower than the normal control; while asparagine, tyrosine, lysine and arginine were significantly higher. The concentration of ammonia in the CSF was also elevated after convulsion as compared to the normal control. Amino acids play an important role in the generation of epilepsy and recently there has been an increasing number of studies to help determine their effects during an epileptic attack. However, there still is much debate and controversy on this topic. Therefore, further studies are needed and researchers should carefully consider factors that might affect the accurate assessment of the results.
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PMID:Alteration of amino acid in plasma and cerebrospinal fluid of children with seizure disorders. 851 Jan 96

This study evaluated whether valproic acid, a branched-chain fatty acid which has been used in the treatment of seizures, would influence the binding Of L-tryptophan to rat hepatic nuclei. Previous studies have indicated that binding of L-tryptophan to hepatic nuclear envelope protein was saturable, stereospecific, and of high affinity. In this study, we investigated whether valproic acid, which under certain conditions is heptatoxic, would influence L-tryptophan binding to rat hepatic nuclei as assayed by in vitro L-(5-3H)tryptophan binding. Our results indicate that the addition of valproic acid to hepatic nuclei or nuclear envelopes in vitro has little influence on their L-(5-3H)tryptophan binding. On the other hand, when valproic acid (80 mg/100 g body weight) is tube-fed 2 h before killing, the isolated nuclei show decreased specific L-tryptophan binding (total binding minus non-specific binding using unlabeled L-tryptophan (10(-4)M), at 2000-fold excess) compared with controls. Other fatty acids (oleic, palmitic or linoleic acid at 10(-4)M) when added with excess, unlabeled L-tryptophan (10(-4)M) in vitro to hepatic nuclei revealed some (but less than with valproic acid) decreased specific binding compared with controls. At high doses, valproic acid (80 mg/100 g body weight) appears to decrease tryptophan-induced stimulation of hepatic protein synthesis, probably in a hepatotoxic manner.
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PMID:Toxic effect of valproic acid on tryptophan binding to rat hepatic nuclei. 861 51

An investigation of the effects of chronic administration of ethanol by the liquid diet procedure and its subsequent withdrawal on tryptophan (Trp) metabolism and disposition was performed in rats. Treatment with the control liquid diet caused an enhancement of liver Trp pyrrolase activity and mRNA abundance. These effects are not due to the starvation associated with this feeding procedure, because they occur in rats maintained on the liquid diet ad libitum. Chronic ethanol administration in the liquid diet did not further influence the above increased expression of Trp pyrrolase mRNA but caused inhibition of pyrrolase activity in competition with the effects of the diet. The control liquid diet decreased liver Trp concentration, but exerted no significant effects on other aspects of Trp disposition. The most striking and robust finding was a highly significant elevation in both Trp pyrrolase activity and mRNA expression at 7 h following discontinuation of ethanol availability, at which time there were demonstrable behavioural signs of ethanol withdrawal. The increase in Trp pyrrolase mRNA during alcohol withdrawal may be caused by corticosterone, whose circulating concentration was also increased. The changes in Trp pyrrolase activity during ethanol withdrawal were associated with significant alterations in Trp disposition including decreased brain Trp concentration and 5-hydroxytryptamine synthesis and turnover. These alterations may play a pivotal role in the behavioural manifestations of ethanol withdrawal including the hyperexcitement underlying audiogenic seizures. We suggest that rat Trp pyrrolase gene regulation may be an important biological determinant of the ethanol withdrawal syndrome and requires further study, and that the use of the liquid diet procedure in Trp metabolic studies requires inclusion of adequate controls and special attention to the effects of the liquid diet itself.
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PMID:Effects of chronic administration and subsequent withdrawal of ethanol-containing liquid diet on rat liver tryptophan pyrrolase and tryptophan metabolism. 873 17

Cycloheximide (20 mg/kg body wt, given intraperitoneally at-1 and 3 h after withdrawal of an ethanol-containing liquid diet) prevents the activation of liver tryptophan pyrrolase, the consequent inhibition of synthesis of brain 5-hydroxytryptamine, and the audiogenic seizures observed at 7 h after alcohol withdrawal. We suggest that a rapidly-turning-over protein mediates the alcohol withdrawal syndrome and discuss the possible role of liver tryptophan pyrrolase.
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PMID:Prevention by cycloheximide of the audiogenic seizures and tryptophan metabolic disturbances of ethanol withdrawal in rats. 884 29


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