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)

Tolerance to the anticonvulsant effects of clobazam has been studied in three murine models of epilepsy: pentylenetetrazole- and N-methyl-D,L-aspartic acid-induced seizures and audiogenic-induced seizures in the DBA/2 strain. Tolerance occurred most rapidly in the pentylenetetrazole model but the development of tolerance could be reduced by increasing the dose interval. Tolerance to the protective effects of clobazam occurred more readily to the first tonic seizure than to the full tonic clonic seizure. The development of tolerance could not be attributed to smaller concentrations of clobazam in brain or to increasing concentrations of the metabolite. Although slower to develop, tolerance to clobazam did occur in the N-methyl-D,L-aspartate model. However, tolerance to the protection from the full tonic clonic seizure in DBA/2 mice could not be detected, even when the dose of clobazam was reduced to the smallest dose that acutely protected most of the mice. In contrast, the protection given by clobazam to the induction of the wild-run in DBA/2 mice, did exhibit tolerance. Studies on the mechanism of tolerance to the anticonvulsant activity of benzodiazepines must take account of the seizure model used and the dose and interval between doses.
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PMID:Tolerance to the anticonvulsant effects of clobazam in mice. 155 26

Partially purified (Na+,K+)-ATPase (E.C. 3.6.1.3.) was investigated in the epileptic cortex of audiogenic DBA/2 mice and in the primary and secondary foci of cats with acute or chronic freeze lesions. No differences in specific activities measured at 3 mM K+ were observed between epileptic and control cortex, except an increase of enzymic activities in the primary focus of acutely lesioned cats. The (Na+,K+)-ATPase catalytic subunits were resolved by SDS-gel electrophoresis and their phosphorylation levels were measured in presence of K+ ions and phenytoin. K+ was more effective in inducing maximal dephosphorylation of (Na+,K+)-ATPase in C57/BL, with identical affinity in the two strains. Phenytoin decreased the net phosphorylation level of (Na+,K+)-ATPase by about 50% in C57/BL mice, but only by 20% in DBA/2 mice. Both K+ and phenytoin dephosphorylating influences were decreased in primary and secondary foci of acutely lesioned cats. Those changes were limited to the alpha(-) subunit. In chronic cats, the dephosphorylating step of the (Na+,K+)-ATPase catalytic subunit recovered a normal affinity to K+, but its sensitivity to phenytoin remained decreased. Those differences in K+ and phenytoin influences on brain (Na+,K+)-ATPases between control and epileptic cortex might be responsible for the ictal transformation and seizure spread. In cats, the alteration of the alpha(-) isoform could mainly affect the glial cells.
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PMID:Phosphorylation of brain (Na+,K+)-ATPase alpha catalytic subunits in normal and epileptic cerebral cortex: I. The audiogenic mice and the cat with a freeze lesion. 165 58

Two novel N-methyl-D-aspartate (NMDA) antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid CPG 37849 and the corresponding 1-ethyl ester CGP 39551, were tested as anticonvulsants in DBA/2 mice and photosensitive Senegalese baboons, Papio papio. In DBA/2 mice, CGP 37849 is more potent than CGP 39551 when administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) (ED50 for suppression of clonic seizures at 60 min: i.c.v. 0.038 and 0.21 nmol; i.p. 3.40 and 19.1 mumol/kg, respectively). When administered orally in mice, the two compounds are approximately equipotent (ED50 CGP 37849, 35.2 mumol/kg; ED50 CGP 39551, 28.1 mumol/kg). The time course of action of CGP 39551 is exceptionally prolonged: 42 mumol/kg i.p. protects against clonic seizures for 48 h. Protection provided by other NMDA antagonists in mice is of much shorter duration: 2-amino-5-phosphono-pentanoic acid (AP5) 1 h, 2-amino-7-phosphono-heptanoic acid (AP7) 4 h, 2-amino-7-phosphono-heptanoic acid 1-ethyl ester 3 h, 4-(3-phosphonopropyl)-2-piperazine carboxylic acid (CPP) 2 h, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) 4 h, and CGP 37849 4 h. After oral administration of the drugs, the therapeutic index (TI = ratio of the ED50 values for rotorod performance and anticonvulsant protection) remains relatively constant at 5.9-7.2 for 3 h (CGP 37849) and 4.0-6.1 for 24 h (CGP 39551). After i.p. administration, the TI values are CGP 37849 at 1 h 2.4, and at 3 h 20.0, CGP 39551 at 1 h 2.3, at 3 h 7.1, and at 24 h 3.6. In baboons, acute administration of CGP 37849 at doses of 48-191 mumol/kg intravenously (i.v.) suppresses photically induced myoclonus for at least 285 min, with severe side effects at the highest dose tested. CGP 39551 at doses of 169-675 mumol/kg i.v. shows weak anticonvulsant activity only at the highest dose tested (accompanied by severe side effects). CGP 37849 at 48-96 mumol/kg orally (p.o.) fails to protect against photically induced myoclonus up to 4 h after administration, but 191 mumol/kg (40 mg/kg) p.o. produces complete suppression of seizures after 24 h. On the other hand, CGP 39551 at 169 mumol/kg (40 mg/kg) p.o. produces total suppression of seizure activity at 4 h with a longer duration of anticonvulsant action (2-3 days).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Anticonvulsant activity of two orally active competitive N-methyl-D-aspartate antagonists, CGP 37849 and CGP 39551, against sound-induced seizures in DBA/2 mice and photically induced myoclonus in Papio papio. 167 45

1. In order to determine whether the strychnine-insensitive glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex is fully activated in vivo, the ability of the selective glycine receptor agonist, D-serine, to modulate seizure susceptibility in the mouse has been examined. 2. D-Serine (10-200 micrograms per mouse, i.c.v.) dose-dependently increased the potency of NMDLA in inducing seizures in Swiss Webster mice by approximately 3 fold. L-Serine was without significant effect. 3. The potency of pentylenetetrazol in inducing seizures was also enhanced by D-, but not L-serine, although the magnitude of the shift (1.6 fold) was considerably less than for NMDLA. 4. Similar doses of D-serine were also able to block the anticonvulsant effect of the non-selective glycine receptor antagonist, kynurenic acid, against seizures induced by NMDLA, but were without effect on the anticonvulsant effect of the competitive NMDA receptor antagonist, 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). 5. D-Serine completely antagonized the protective effect of the selective glycine receptor antagonist, 7-chlorokynurenic acid, against sound-induced seizures in DBA/2 mice, but was less effective in this model against the less selective antagonist, kynurenic acid. 6 The results indicate that in vivo, NMDA receptors are not maximally potentiated by endogenous glycine and suggest an important involvement of the glycine modulatory site on the NMDA receptor/ion channel complex in the pathophysiology of epilepsy.
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PMID:Modulation of seizure susceptibility in the mouse by the strychnine-insensitive glycine recognition site of the NMDA receptor/ion channel complex. 169 74

The rate of occurrence of audiogenic seizures and seizures induced by the benzodiazepine receptor inverse agonist methyl-beta-carboline-3-carboxylate (beta-CCM) were analyzed in several recombinant congenic strains of mice bred from B10.D2 and DBA/2J. Although both types of seizures have similar behavioral patterns and might involve GABAergic mechanisms, no correlation was observed between the occurrence of the two types of seizures across the strains, suggesting that these two types of seizures depend on different genetic mechanisms.
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PMID:Analysis of B10.D2 recombinant congenic mouse strains shows that audiogenic and beta-CCM-induced seizures depend on different genetic mechanisms. 173 42

Repeated administration of subconvulsant doses of lidocaine or cocaine results in the development of an increased susceptibility to seizures induced by the two drugs (pharmacological kindling). It has been hypothesized that the local anesthetic properties of cocaine are responsible for its convulsant and epileptogenic actions. As genetic factors appear to mediate acute sensitivity to the convulsant properties of cocaine and the development of cocaine-kindled seizures, the present studies used a pharmacogenetic approach to address this question further. The convulsant effects of lidocaine were evaluated in BALB, C57, DBA and SJL mice and compared with previous studies evaluating cocaine-induced seizures. We have also evaluated the development of lidocaine- versus cocaine-kindled seizures and the effects of repeated treatment with cocaine or lidocaine on subsequent lidocaine seizure susceptibility in three of these inbred mouse strains. As observed for cocaine, genetic factors influence the convulsant properties of lidocaine; however, the differences between the strains of mice in susceptibility to lidocaine-induced seizures (SJL greater than DBA = BALB = C57) did not parallel those seen for cocaine-induced seizures (C57 greater than DBA = BALB greater than SJL). Similarly, the time course for the expression of kindled seizures and the differences between the various inbred strains were not the same for lidocaine kindling and cocaine kindling. However, depending on the genetic background of the subject, the repeated administration of lidocaine, or cocaine, resulted in the development of sensitization or tolerance to the convulsant effects of lidocaine in an identical manner.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A pharmacogenetic evaluation of the role of local anesthetic actions in the cocaine kindling process. 177 40

A series of 2-substituted 3-(1,3,4-thiadiazol-2-yl)thiazolidin-4-ones were synthesized and evaluated for anticonvulsant activity in a genetic model of reflex epilepsy (sound-induced seizures in DBA/2 mice). The combination of preferred substituents in the 2-position coupled with the introduction of a mercapto group on the thiadiazole moiety led to a number of active compounds. The anticonvulsant activity of most derivatives is better than that of the clinically useful anticonvulsant sodium valproate and some of them appear to possess potencies in the same range as phenytoin and clobazam.
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PMID:Synthesis and anticonvulsant properties of 3-(1,3,4-thiadiazol-2-yl) thiazolidin-4-ones. 179 76

The excitatory amino acid antagonists, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline) and GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine) that act on non-NMDA receptors, provide potent anticonvulsant protection against AMPA [RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in Swiss mice and against sound-induced seizures in seizure-susceptible DBA/2 mice. Maximal anticonvulsant protection is observed 5-30 min after the i.p. administration of NBQX and 5-15 min after the i.p. administration of GYKI 52466 in DBA/2 mice. The ED50 values for the protection against AMPA-induced seizures by NBQX (30 min, i.p.) and GYKI 52466 (15 min, i.p.) are 23.6 (11.6-48.0) and 18.5 (11.5-29.5) mumol/kg, respectively. The ED50 values at 15 min for the protection against sound-induced seizures in DBA/2 mice are 31.3 (24.9-39.4) mumol/kg (NBQX, i.p.), 37.8 (21.2-67.4) mumol/kg (NBQX, i.v.) and 13.7 (11.5-16.5) mumol/kg (GYKI 52466, i.p.). In DBA/2 mice the therapeutic index (ratio of ED50 values for impaired rotarod performance and anticonvulsant action) is 6.6 for NBQX (15 and 30 min, i.p.) and 2.0 for GYKI 52466 (15 min, i.p.).
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PMID:The anticonvulsant effect of the non-NMDA antagonists, NBQX and GYKI 52466, in mice. 179 56

Milacemide (MLM, CP 1552 S, 2-N-pentylaminoacetamide), a glycinamide derivative, is currently being evaluated clinically for antiepileptic activity. Anticonvulsant properties have been shown in various animal models, but the mechanism of action of MLM is unclear. We studied its activity in audiogenic seizures of DBA/2J mice. MLM was effective in inhibiting the convulsions induced by sound with a biphasic dose-effect relation. The ED50 was 109 mg/kg orally against tonic extension. Higher doses were necessary to abolish clonic convulsion and running response. Because impaired cerebral (Na+, K+)-ATPase activity is supposed to play a role in epileptogenesis, we tested MLM on in vitro cortical enzymatic activity of DBA/2J mice. Basal (Na+, K+)-ATPase activity was unchanged by several concentrations of MLM in normal C57BL/6J and audiogenic DBA/2J mice. K+ activation (from 3 to 18 mM) of (Na+, K+)-ATPase is abolished in DBA/2J mice as compared with C57BL/6J mice, suggesting impaired glial (Na+, K+)-ATPase. In the presence of MLM (from 30 to 1000 mg/L), cortical (Na+, K+)-ATPase of DBA/2J mice is activated by high concentrations of K+, as in C57BL/6J mice. Results suggest that the antiepileptic activity of MLM in audiogenic mice may be secondary to an activation of a deficient glial (Na+, K+)-ATPase.
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PMID:Effect of milacemide on audiogenic seizures and cortical (Na+, K+)-ATPase of DBA/2J mice. 184 59

The neurological mutant mouse strain E1 is a model for complex partial seizures in humans. The inheritance of epileptic seizures with seven conventional chromosomal markers and over 60 endogenous proviral markers was studied by means of back-crosses of E1 with two seizure-resistant strains, DBA/2J and ABP/LeJ. The major gene responsible for this epileptic phenotype (El-1) was localized to a region distal with respect to the centromere on chromosome 9. At least one other gene, El-2, linked to proviral markers on chromosome 2, also influences the seizure phenotype. In addition, a potential modifier of seizures was detected in the DBA/2J background. The location of El-1 on distal chromosome 9 may allow identification of an epilepsy candidate gene in humans on the basis of conserved synteny with human chromosome 3.
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PMID:Genes for epilepsy mapped in the mouse. 187 1


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