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)

We examined the effects of convulsive seizures on in vitro RNA synthesis by cerebral cortex nuclei in El mice. The rate of incorporation of [3H]uridine-5'-triphosphate by intact nuclei during seizures was decreased to 47.4% compared with the rate during the interictal period, but gradually recovered. During the 30-min period after onset of seizures, the rate of RNA synthesis was significantly lower in El mice than in identically stimulated ddY mice. Seizures in El mice had no effect on liver RNA synthesis, suggesting that the alteration of RNA polymerase activity is specific to the brain. Analysis of gel electrophoresis of polyadenylated RNA synthesized in the presence of ammonium sulphate revealed a marked decrease in high-molecular weight RNA species 15 min after seizures in El mice compared with the pattern in nonstimulated ddY mice. This shift from high- to low-molecular weight RNA species was not attributable to RNase activity, but it appeared to be related RNA polymerase.
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PMID:Alteration of RNA synthesis in vitro in intact cerebral cortex nuclei induced by convulsions in seizure-susceptible El mice. 243 22

The effect of seizures on synthesis of the polyadenylic acid (poly(A]-containing messenger RNA (mRNA) isolated from brain polysomes in a genetically seizure-susceptible E1 mouse was studied in vivo. The seizure in the E1 mice was induced by tossed-up stimulation. Immediately after the seizure ceased, the labeled orotic acid was injected into the brain. The incorporation rates of labeled orotic acid into poly(A)-containing mRNA isolated from polysomes are represented as the specific radioactivity (SR) (dpm/mg RNA) and the relative specific radioactivity (RSR) (dpm/mg RNA/dpm/mumoles of acid soluble uridine-5'-monophosphate (UMP]. Both the rates were reduced to 70% in SR and 65% in RSR at 1 h after the seizures. This reduction was gradually recovered to the level of interictal E1 mice at 6 h. The seizure-induced alterations are not attributable to the difference in the uridine nucleotide pool because the SR of UMP was not significantly affected by the seizure. The peak of labeled poly(A)-containing mRNA by analysis of gel electrophoresis displaced towards a lower molecular weight at 1 h after the seizures. The RNA showed a higher ratio of AMP and UMP per GMP and CMP in nucleotide composition, implying that this RNA is identical with DNA. These results suggest that the temporary decrease found in cytoplasmic mRNA synthesis induced by the seizures of E1 mice appears to be a result of impaired transcriptional processes in heterogeneous nuclear RNA synthesis and that the smaller mRNA coding for protein associated with seizures is newly synthesized during the postictal period.
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PMID:Alterations in polyadenylic acid-containing messenger RNA synthesis of brain polysomes after seizures of seizure-susceptible E1 mice. 281 90

Na+-independent [3H]gamma-aminobutyric acid (GABA) binding to membrane preparations from frontal cortex, hippocampus, and thalamus is competitively inhibited by the in vitro addition of a naturally occurring pyrimidinic compound, uridine. Moreover, the intraperitoneal injection of uridine produces a dose-related decrease in the cerebellar content of cyclic GMP and antagonizes its increase elicited by bicuculline. The pyrimidinic compound also shows an antagonism toward bicuculline-induced seizures. The relationship between the anti-convulsant actions of uridine and GABA-mediated inhibitory neurotransmission is discussed in terms of an activation of GABA receptor function by the naturally occurring pyrimidinic compound.
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PMID:Interaction between uridine and GABA-mediated inhibitory transmission: studies in vivo and in vitro. 286 53

PALA (N-phosphonoacetyl-L-aspartate) impairs de novo pyrimidine biosynthesis by inhibiting the enzyme aspartate transcarbamylase. During cancer chemotherapy trials the drug was given by weekly intravenous infusion. Seizures developed in 9 (11%) of the first 80 patients to receive a total dose of 9 gm/m2 or more. Seven of the affected patients had structural brain lesions; they developed seizures at a lower total dose (median of 16.4 gm/m2) than the 2 patients without clinically detectable brain lesions (115 to 130 gm/m2). Reversible encephalopathy was observed in 6 (7.5%) additional patients without clinically detectable cause other than PALA. Both seizures and encephalopathy began after the second dose of PALA or later. Experiments in rats demonstrated similar delayed-onset seizures after two or three combined systemic and intracerebral doses of PALA at 4-day intervals. Concurrent administration of uridine or carbamyl aspartate prevented the development of seizures in rats, indicating that pyrimidine starvation of the central nervous system was responsible for PALA neurotoxicity.
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PMID:Neurotoxicity of the pyrimidine synthesis inhibitor N-phosphonoacetyl-L-aspartate. 712 6

Kainic acid (KA) neurotoxicity was examined in transgenic (Tg) mice overexpressing human CuZn-superoxide dismutase (SOD-1). The doses of KA required to produce seizures, the severity of the seizures, and the regions damaged were similar in SOD-1 Tg and non-transgenic wild-type mice. Intraperitoneal KA injection induced seizure-related neuronal damage in the CA3 and CA1 regions of the hippocampus and in other regions of the brain in both SOD-1 Tg and wild-type mice. These damaged neurons were labeled with the terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL) technique up to 72 h, although no significant difference in the number of TUNEL-positive neurons was observed between SOD-1 Tg and wild-type mice. In situ hybridization showed that c-fos, c-jun, and hsp70 genes were expressed in the hippocampus, cortex, and other regions of the brain after KA treatment. The expression of these genes was maximal 1 to 4 h following KA treatment but persisted longer in the hippocampus and other regions in SOD-1 Tg compared with wild-type mice; however, cell death in the hippocampus, assessed using cresyl violet staining, was similar in SOD-1 Tg and wild-type mice. The data show that superoxide radicals modulate both immediate early gene and heat shock gene expression after KA-induced seizures. The prolonged expression of c-fos, c-jun, and hsp70 in SOD-1 Tg compared with wild-type mice may indicate that hippocampal neurons survive longer in SOD-1 Tg than in wild-type animals; however, cell death as well as the seizure threshold, seizure severity and the pattern of regional vulnerability were not affected substantially by increased levels of SOD in the brain.
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PMID:DNA fragmentation and Prolonged expression of c-fos, c-jun, and hsp70 in kainic acid-induced neuronal cell death in transgenic mice overexpressing human CuZn-superoxide dismutase. 911 97

Four unrelated patients are described with a syndrome that included developmental delay, seizures, ataxia, recurrent infections, severe language deficit, and an unusual behavioral phenotype characterized by hyperactivity, short attention span, and poor social interaction. These manifestations appeared within the first few years of life. Each patient displayed abnormalities on EEG. No unusual metabolites were found in plasma or urine, and metabolic testing was normal except for persistent hypouricosuria. Investigation of purine and pyrimidine metabolism in cultured fibroblasts derived from these patients showed normal incorporation of purine bases into nucleotides but decreased incorporation of uridine. De novo synthesis of purines and cellular phosphoribosyl pyrophosphate content also were moderately decreased. The distribution of incorporated purines and pyrimidines did not reveal a pattern suggestive of a deficient enzyme activity. Assay of individual enzymes in fibroblast lysates showed no deficiencies. However, the activity of cytosolic 5'-nucleotidase was elevated 6- to 10-fold. Based on the possibility that the observed increased catabolic activity and decreased pyrimidine salvage might be causing a deficiency of pyrimidine nucleotides, the patients were treated with oral pyrimidine nucleoside or nucleotide compounds. All patients showed remarkable improvement in speech and behavior as well as decreased seizure activity and frequency of infections. A double-blind placebo trial was undertaken to ascertain the efficacy of this supplementation regimen. Upon replacement of the supplements with placebo, all patients showed rapid regression to their pretreatment states. These observations suggest that increased nucleotide catabolism is related to the symptoms of these patients, and that the effects of this increased catabolism are reversed by administration of uridine.
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PMID:Developmental disorder associated with increased cellular nucleotidase activity. 932 56

Pharmacokinetic differences may play a part in the age-related differences in the incidence of adverse effects. The most common idiosyncratic reaction to lamotrigine (LTG) is rash, affecting 10-20% of patients. Risk factors are young age, concurrent valproate (VPA), high starting dose, and rapid escalation. In children, cytochrome P450 (CYP)-catalyzed metabolism is increased, and uridine diphosphate (UDP)-glucuronosyltransferase (UGT)-catalyzed metabolism is not significantly different from that in adults. A CYP-catalyzed arene oxide intermediate of LTG has been identified. The increase CYP metabolism of LTG in children could result in increased formation of the reactive metabolite and a higher incident of rash. Children often received higher milligram per kilogram doses compared with adults. The higher dose would cause an increased amount of LTG metabolized to the reactive arene oxide intermediate. VPA therapy is associated with a transient elevation in liver-function tests in 15-30% of patients and a rare, fatal hepatotoxicity. Most cases of VPA hepatotoxicity occurred in children younger than 2 years who had preexisting neurologic or other physical defects. Hypotheses regarding the pathogenesis of the hepatotoxicity include preexisting mitochondrial disease or inborn errors of metabolism, VPA inhibition of beta-oxidation, and toxicity from VPA metabolites VPA, 4-ene-VPA, and 2,4-diene-VPA. Infants and children have higher concentration ratios of 4-ene-VPA to VPA. Polytherapy with enzyme inducers increases the formation of the hepatotoxic metabolites. The role of underlying metabolic disorders associated with hepatodegeneration and intractable seizures without VPA is a major confounder in identifying risk factors and demonstrates the difficulty in separating underlying disease factors in rare idiosyncratic reactions.
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PMID:Children versus adults: pharmacokinetic and adverse-effect differences. 1206 6

Uridine, like adenosine, is released under sustained depolarization and it can inhibit hippocampal neuronal activity, suggesting that uridine may be released during seizures and can be involved in epileptic mechanisms. In an in vivo microdialysis study, we measured the extracellular changes of nucleoside and amino acid levels and recorded cortical EEG during 3-aminopyridine-induced epilepsy. Applying silver impregnation and immunohistochemistry, we examined the degree of hippocampal cell loss. We found that extracellular concentration of uridine, adenosine, inosine, and glutamate increased significantly, while glutamine level decreased during seizures. The release of uridine correlated with seizure activity. Systemic and local uridine application was ineffective. The number of parvalbumin- and calretinin-containing interneurons of dorsal hippocampi decreased. We conclude that uridine is released during epileptic activity, and suggest that as a neuromodulator, uridine may contribute to epilepsy-related neuronal activity changes, but uridine analogues having slower turnover would be needed for further investigation of physiological role of uridine.
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PMID:Uridine release during aminopyridine-induced epilepsy. 1526 60

The Ministry of Health and Welfare, Japan banned coadministration of carbapenems, such as panipenem/betamipron (PAPM), meropenem (MEPM), and valproic acid (VPA) because clinical reports have indicated that the coadministration caused seizures in epileptic patients due to lowered plasma levels of VPA. In this study, we have clarified the mechanism of the drug-drug interaction using PAPM, MEPM, and doripenem [S-4661; (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-caboxylic acid monohydrate], a newly synthesized carbapenem. In vitro experiments using monkey liver slices suggested that the apparent synthetic rate of VPA glucuronide (VPA-G) increased in the presence of carbapenems. However, no such increase was observed in the experiment using monkey liver microsomes. Although no increase of uridine 5'-diphosphate D-glucuronic acid was found in monkey liver slices in the presence of carbapenems, potent inhibitory activity of carbapenems for the hydrolysis of VPA-G was found in monkey and rat liver homogenate. In vivo hydrolysis of VPA-G was clearly shown by the existence of VPA in plasma after dosing of VPA-G to rats, and its inhibition by carbapenems was also clearly shown by the negligible levels of VPA in rat plasma after coadministration of carbapenems and VPA-G. These results clearly indicate one of the important causes of drug interaction as follows: carbapenems would inhibit the hydrolytic enzyme, which is involved in the hydrolysis of VPA-G to VPA, resulting in a decrease of plasma concentration of VPA.
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PMID:Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats. 1534 60

The neuropeptide galanin exhibits anticonvulsant effects in experimental epilepsy. Two galanin receptor subtypes, GalR1 and GalR2, are present in the brain. We examined the role of GalR1 in seizures by studying the susceptibility of GalR1 knockout (KO) mice to status epilepticus (SE) and accompanying neuronal injury. SE was induced in GalR1 KO and wild type (WT) mice by Li-pilocarpine, 60 min electrical perforant path stimulation (PPS), or systemic kainic acid (KA). Seizures were analyzed using Harmonie software. Cell injury was examined by FluoroJade B- and terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling; neurogenesis was studied using bromodeoxyuridine labeling. Compared with WT littermates, GalR1 KO showed more severe seizures, more profound injury to the CA1 pyramidal cell layer, as well as injury to hilar interneurons and dentate granule cells upon Li-pilocarpine administration. PPS led to more severe seizures in KO, as compared with WT mice. No difference in the extent of neuronal degeneration was observed between the mice of two genotypes in CA1 pyramidal cell layer; however, in contrast to WT, GalR1 KO developed mild injury to hilar interneurons on the side of PPS. KA-induced seizures did not differ between GalR1 KO and WT animals, and led to no injury to the hippocampus in either of experimental group. No differences were found between KO and WT mice in both basal and seizure-induced neuronal progenitor proliferation in all seizure types. Li-pilocarpine led to more extensive glia proliferation in GalR1 KO than in WT, and in both mouse types in two other SE models. In conclusion, GalR1 mediate galanin protection from seizures and seizure-induced hippocampal injury in Li-pilocarpine and PPS models of limbic SE, but not under conditions of KA-induced seizures. The results justify the development and use of GalR1 agonists in the treatment of certain forms of epilepsy.
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PMID:Patterns of seizures, hippocampal injury and neurogenesis in three models of status epilepticus in galanin receptor type 1 (GalR1) knockout mice. 1535 Jun 53


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