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)

Previous investigations in seizure-prone mice have suggested that an abnormally elevated production of the astrocyte-derived neuroexcitant, quinolinic acid (QUIN), plays a role in seizure susceptibility. In order to evaluate further the role of QUIN metabolism in genetic murine seizure models, the activities of its biosynthetic enzyme 3-hydroxyanthranilic acid oxygenase (3HAO), and of two other astrocytic enzymes, kynurenine aminotransferase (KAT) and glutamine synthetase (GS), were measured in the brains of seizure-prone EL and DBA/2 mice and two non-epileptic strains (BALB/c and Swiss-Webster). 3HAO activity was found to be markedly higher in both EL and DBA/2 mice than in the non-epileptic strains in all brain regions examined. The activity of 3HAO was not modified by the tossing procedure employed to promote seizures in EL mice. While some strain differences were noted in the activities of KAT and GS, these enzymes did not distinguish seizure-prone from the non-epileptic mice. In order to delineate better the relationship between glial activation and 3HAO, KAT and GS, further studies were performed in the ibotenate-lesioned hippocampus. In mice (but not in rats), the activity of 3HAO was selectively increased in gliotic tissue. These data demonstrate substantial species and strain differences in astroglial enzymes and in their response to brain injury. The observation of widespread abnormally high 3HAO activity in two distinct seizure-prone mouse strains strengthens the hypothesis that enhanced production of QUIN contributes to seizure susceptibility in mice.
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PMID:Differential expression of the astrocytic enzymes 3-hydroxyanthranilic acid oxygenase, kynurenine aminotransferase and glutamine synthetase in seizure-prone and non-epileptic mice. 780 40

The kynurenine pathway metabolites quinolinic acid and kynurenic acid have been hypothetically linked to the occurrence of seizure phenomena. The present immunohistochemical study reports the activation of astrocytes containing three enzymes responsible for the metabolism of quinolinic acid and kynurenic acid in a rat model of chronic epilepsy. Rats received 90 min of patterned electrical stimulation through a bipolar electrode stereotaxically positioned in one hippocampus. This treatment induces non-convulsive limbic status epilepticus that leads to chronic, spontaneous, recurrent seizures. One month after the status epilepticus, the rats showed neuronal loss and gliosis in the piriform cortex, thalamus, and hippocampus, particularly on the side contralateral to the stimulation. Astrocytes containing the kynurenic acid biosynthetic enzyme (kynurenine aminotransferase) and the enzymes for the biosynthesis and degradation of quinolinic acid (3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase, respectively) became highly hypertrophied in brain areas where neurodegeneration occurred. Detailed qualitative and quantitative analyses were performed in the hippocampus. In CA1 and CA3 regions, the immunostained surface area of reactive astrocytes increased up to five-fold as compared to controls. Enlarged cells containing the three enzymes were mainly observed in the stratum radiatum, whereas the stratum pyramidale, in which neuronal somata degenerated, showed relatively fewer reactive glial cells. Hypertrophied kynurenine aminotransferase- and 3-hydroxyanthranilic acid oxygenase-immunoreactive cells were comparable in their morphology and distribution pattern. In contrast, reactive quinolinic acid phosphoribosyl transferase-positive glial cells displayed diversified sizes and shapes. Some very large quinolinic acid phosphoribosyl transferase-immunoreactive cells were noticed in the molecular layer of the dentate gyrus. In the hippocampus, the number of immunoreactive glial cells increased in parallel to the hypertrophic responses. In addition, pronounced increases in immunoreactivities, associated with hypertrophied astrocytes, occurred around lesioned sites in the thalamus and piriform cortex. These findings indicate that kynurenine metabolites derived from glial cells may play a role in chronic epileptogenesis.
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PMID:Kynurenine pathway enzymes in a rat model of chronic epilepsy: immunohistochemical study of activated glial cells. 823 7

L-alpha-Aminoadipic acid is a lysine metabolite with neuroexcitatory properties, and has previously been shown to inhibit the production of the broad spectrum excitatory amino acid receptor antagonist kynurenic acid in brain tissue slices. The effects of L-alpha-aminoadipic acid on the levels of extracellular kynurenic acid were now studied by microdialysis in the dorsal hippocampus of freely moving rats. Application of L-alpha-aminoadipic acid through the microdialysis probe dose dependently decreased both the concentration of endogenous kynurenic acid and of kynurenic acid which was produced de novo from its bioprecursor L-kynurenine (500 microM applied through the probe). 500 microM L-alpha-aminoadipic acid lowered the kynurenic acid concentration in the dialysate by 47% and 28% with and without precursor loading, respectively, whereas D-alpha-aminoadipic acid was without effect. Co-administration of 500 microM L-alpha-aminoadipic acid with 50 microM veratridine, which by itself produces a substantial decrease in the levels of extracellular kynurenic acid, did not result in a further reduction in kynurenic acid concentrations. Extensive neuronal degeneration caused by an intrahippocampal injection of quinolinic acid (120 nmol) did not interfere with the effect of L-alpha-aminoadipic acid. Taken together, these data suggest that the effect of L-alpha-aminoadipic acid on extracellular kynurenic acid levels is likely due to its direct action on astrocytes, which are known to harbor kynurenic acid's biosynthetic enzyme, kynurenine aminotransferase. L-alpha-Aminoadipic acid may modulate kynurenic acid function in the brain and thus play a role in the pathogenesis of neurodegenerative and seizure disorders.
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PMID:L-alpha-aminoadipic acid as a regulator of kynurenic acid production in the hippocampus: a microdialysis study in freely moving rats. 856 17

Endogenous kynurenic acid (KYNA), an excitatory amino acid receptor antagonist with antineurotoxic and anticonvulsant activity, was assessed by microdialysis in the hippocampus of kindled rats. One week after the completion of amygdala or hippocampal kindling (stage 5), the dialysate concentration of KYNA in the hippocampus of both hemispheres was 1.7 +/- 0.1-fold higher than in shams (P < 0.01). Veratridine (50 microM), applied through the probe, reduced extracellular KYNA by 28% within 1 h in controls (P < 0.05), but was ineffective in stage 5 kindled rats. At the preconvulsive stage 2, dialysate KYNA concentration and the effect of veratridine were similar to controls. The activity of KYNA's biosynthetic enzyme, kynurenine aminotransferase, did not change in the hippocampus 1 week after stage 5 seizures. These data indicate an enhanced liberation of KYNA in teh hippocampus of fully kindled animals due to an impairment of normal regulatory mechanisms. This may be of relevance for the control of hippocampal excitability during epileptogenesis.
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PMID:Electrical kindling is associated with a lasting increase in the extracellular levels of kynurenic acid in the rat hippocampus. 859 49

Intracerebral administration of L-alpha-aminoadipic acid (L-AAA) at 500 mg/kg body weight to rats caused a complex behavioral change with sporadic wet-dog shakes. Animals developed severe limbic seizures between 1 and 6 h after L-AAA injection, characterized by generalized convulsions. Twenty days after L-AAA injection kynurenine aminotransferase (KAT) activity measured in hippocampal brain tissue slices prepared with a McIlwain chopper at 30 microns showed a significant 43% decrease. Subcutaneous injection of kynurenine at 500 mg/kg showed a 63% increase in KAT activity twenty days later. This increase was offset by a concomitant administration of 500 mg/kg L-AAA stereotaxically on day one. In astrocyte culture kynurenic acid synthesis is inhibited by L-AAA and L-pipecolic acid. The possible involvement of kynurenic acid in the modulation of neuronal degeneration is discussed.
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PMID:L-alpha-aminoadipate inhibits kynurenate synthesis in rat brain hippocampus and tissue culture. 923 35

The role of impaired mitochondrial function in processes leading to the generation of seizures was studied in mice. An inhibitor of mitochondrial complex III, 3-nitropropionic acid, which is known to evoke convulsions per se, and was used here in subthreshold dose, enhanced seizures generated by electric current and application of 4-aminopyridine. In contrast, 3-nitropropionic acid did not affect convulsions induced by gamma-aminobutyric acid (GABA) receptor antagonists - bicuculline, pentylenetetrazol and picrotoxin, glycine antagonist - strychnine, cholinomimetic drug-pilocarpine, and kynurenine aminotransferase inhibitor - aminooxyacetic acid. It is hypothesised that deranged mitochondrial metabolism renders the central nervous system more susceptible to factors inducing seizures via direct depolarization.
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PMID:Proconvulsive effects of the mitochondrial respiratory chain inhibitor--3-nitropropionic acid. 1097 24

The effect of nitric oxide synthase (NOS) inhibitors on the brain production of endogenous glutamate receptor antagonist, kynurenic acid, was estimated in vitro. Under standard incubation conditions N(G)-nitro-L-arginine, but not N(G)-nitro-L-arginine methyl ester, up to 5 mM, or 7-nitroindazole, up to 100 microM, inhibited de novo synthesis of kynurenic acid in cortical slices. However, during prolonged incubation, N(G)-nitro-L-arginine methyl ester also reduced the production of kynurenic acid. The substrate for NOS, L-arginine (up to 5 mM), did not influence kynurenic acid synthesis and did not reverse the N(G)-nitro-L-arginine-evoked changes, suggesting that the observed effects are not related to disturbed generation of NO. Enzymatic studies revealed that N(G)-nitro-L-arginine and its methyl ester blocked the activity of brain kynurenine aminotransferase (KAT) I. The activity of KAT II was diminished only by N(G)-nitro-L-arginine. Kinetic analyses have shown that N(G)-nitro-L-arginine and its methyl ester reduce Vmax and increase Km of KAT I, whereas N(G)-nitro-L-arginine diminishes Vmax of KAT II. In conclusion, we report that N(G)-nitro-L-arginine and its methyl ester impair brain synthesis of kynurenic acid, probably via NO-independent mechanism, what could contribute, at least partially, to the enhancement of neurotoxicity or seizures observed in some experimental designs based on their use.
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PMID:N(G)-nitro-L-arginine and its methyl ester inhibit brain synthesis of kynurenic acid possibly via nitric oxide-independent mechanism. 1198 33

Disturbed formation of kynurenic acid, an endogenous antagonist of glutamate ionotropic receptors, might contribute to the pathogenesis of seizures. Here, the effect of anticonvulsant drug, carbamazepine on the production of kynurenic acid was studied. Carbamazepine (0.5-3 mM) enhanced kynurenic acid synthesis in rat cortical slices and also increased the activity of kynurenine aminotransferase (KAT) I at 0.1-3.0 mM concentration. Thus, anticonvulsant drugs, such as carbamazepine, might act partially via stimulation of kynurenic acid production.
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PMID:Carbamazepine enhances brain production of kynurenic acid in vitro. 1536 12