UMLS:C0036572 - FACTA Search

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Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term treatment leads to tolerance to and dependence on benzodiazepines. Abrupt termination of benzodiazepine administration triggers the expression of signs of dependence. Mice withdrawn from chronic treatment with diazepam showed a time-related evolution of anxiety, muscle rigidity, and seizures between days 4 and 21 after treatment discontinuation. A period between withdrawal days 1 and 3 was symptom-free. Surprisingly, during this "silent phase" the susceptibility of mice to alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate (ATPA) and kainate seizures and the magnitude of monosynaptic reflexes mediated by non-N-methyl-D-aspartate (NMDA) mechanisms were enhanced. In apparent contrast, the "active phase", between withdrawal days 4 and 21, was characterized by increased susceptibility to NMDA seizures and enhanced magnitude of polysynaptic reflexes, which are NMDA dependent. Treatment of mice with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) or 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline but not with the NMDA antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) during the silent phase prevented signs of dependence. In contrast, treatment with CPP but not with GYKI 52466 during the active phase prevented the symptoms. The development of tolerance to and dependence on diazepam was prevented by concurrent treatment of mice with CPP but was not prevented by GYKI 52466. These data indicate that NMDA-dependent mechanisms contribute to the development of tolerance to diazepam and to the expression of signs of dependence in mice after termination of long-term treatment with diazepam. Nevertheless, the non-NMDA-mediated silent phase is essential for triggering the symptoms. Therefore, AMPA antagonists may offer a therapeutic approach for preventing dependence on benzodiazepines that is an alternative to NMDA antagonism.
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PMID:Diazepam dependence prevented by glutamate antagonists. 834 15

Aniracetam (1-p-anisoyl-2-pyrrolidinone) selectively reverses the anticonvulsant activities of the non-NMDA receptor antagonists, GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3- benzodiazepine.HCl) and, to a lesser extent, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline), without affecting the anticonvulsant activity of the competitive NMDA receptor antagonist, D(-)-CPPene, in DBA/2 mice. Pretreatment with aniracetam (50 nmol i.c.v., 15 min before drugs) increases the ED50 values (mumol/kg i.p., 15 min) for GYKI 52466-induced protection against sound-induced clonic seizures in DBA/2 mice 7 fold, from 20.1 (11.9-33.9) to 142 (91.7-219), and for NBQX-induced protection 2 fold, from 39.7 (33.8-46.7) to 85.6 (63.9-115), respectively. Aniracetam on its own (12.5-100 nmol i.c.v.) has no convulsant activity, but reverses the anticonvulsant effect of GYKI 52466 (60 mumol/kg i.p., 15 min) in a dose-dependent manner.
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PMID:Aniracetam reverses the anticonvulsant action of NBQX and GYKI 52466 in DBA/2 mice. 845 82

alpha-Amino-3-hydroxy-5-methyl-isoxazole-4-propionate/kainate (AMPA/kainate) receptor antagonists (at subthreshold doses against electroconvulsions), 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466 at maximally 5 mg/kg) and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX at maximally 20 mg/kg) enhanced the protective effects of NMDA receptor antagonists, MK-801 (dizocilpine) or 2-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene), against electroconvulsions. Similarly, MK-801 or D-CPP-ene reduced the ED50 values of both NBQX and GYKI 52466 against maximal electroshock. The adverse effects of D-CPP-ene, evaluated in the chimney and rotorod tests, were potentiated by both GYKI 52466 (2.5 mg/kg) and NBQX (10 mg/kg). Also, D-CPP-ene (0.1 mg/kg) worsened the motor performance of mice pretreated with GYKI 52466 in the rotorod test. Neither MK-801 (0.025 mg/kg) nor D-CPP-ene (0.1 mg/kg) affected the NBQX-induced impairment of motor coordination. Similarly, GYKI 52466 (2.5 mg/kg) or NBQX (10 mg/kg) did not influence the performance of mice treated with MK-801 (0.2 mg/kg). It may be concluded that the blockade of more than one subtype of glutamate receptors leads to a more pronounced anticonvulsive effect when compared with the effect of blockade of an individual receptor subtype. In some cases more efficient seizure protection was not associated with increased adverse effects.
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PMID:Influence of combined treatment with NMDA and non-NMDA receptor antagonists on electroconvulsions in mice. 852 17

There is a great body of evidence, that excitatory amino acid antagonists, apart from their anticonvulsive properties per se, potentiate the protective activity of conventional antiepileptics against maximal electroshock-induced seizures in mice. It is worth stressing, that combinations of valproate with either CGP 37849 (a competitive NMDA antagonist) or dizocilpine (MK-801, a non-competitive NMDA antagonist), providing a 50% protection against maximal electroshock, resulted in no adverse effects, as measured in the chimney test (motor coordination) or passive avoidance task (long-term memory). On the other hand, valproate administered alone at its ED50, to protect against maximal electroshock, produced profound adverse effects. However, some NMDA antagonists (D-CPP-ene, memantine, procyclidine or trihexyphenidyl) did enhance the protection offered by common antiepileptics but these combined treatments were associated with considerable side-effects on motor coordination and long-term memory. Interestingly, ifenprodil (an antagonist of the polyamine site within the NMDA receptor complex) possessed some anticonvulsive activity against electroconvulsions but failed to enhance the antielectroshock efficacy of conventional antiepileptics. AMPA/KA receptor antagonists (NBQX and GYKI 52466), similarly to NMDA antagonists, potentiated the protective action of antiepileptic drugs against maximal electroshock and these combinations were generally devoid of unwanted effects.
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PMID:Excitatory amino acid antagonists and the anticonvulsive activity of conventional antiepileptic drugs. 871 57

Aminophylline reversed the protective action of both, D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene-a competitive NMDA antagonist) and valproate (used as a conventional antiepileptic drug for comparative purposes) against maximal electroshock-induced seizures. The respective ED50 values of aminophylline were 55.7 and 98.4 mg/kg i.p. However, aminophylline (up to 100 mg/kg i.p.) did not influence the protective efficacy of 1-(4-aminophenyl)-4-methyl-7,8-methyl- enedioxy-5H-2,3-benzodiazepine (GYKI 52466-a non-NMDA antagonist). Strychnine affected the protection provided by D-CPP-ene, GYKI 52466, and valproate against maximal electroshock-the ED50 values of strychnine for the reversal of the anticonvulsive effects of D-CPP-ene, GYKI 52466 or valproate were 0.082, 0.35 and 0.28 mg/kg s.c., respectively. An involvement of strychnine sensitive glycinergic receptor-mediated events in the mechanism of the anticonvulsive activity of excitatory amino acid antagonists and valproate may be postulated. The ineffectiveness of aminophylline to reduce the anticonvulsive effects of GYKI 52466 may distinguish a new class of antiepileptic drugs offering an advantage over conventional antiepileptics in patients with epilepsy, requiring aminophylline for pulmonary reasons.
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PMID:Influence of aminophylline and strychnine on the protective activity of excitatory amino acid antagonists against maximal electroshock-induced convulsions in mice. 873 42

The behavioural and anticonvulsant effects of several 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones (2,3-BZs) and of 11b-aryl-7,11-dihydro-3-phenyl[1,2,4]oxadiazolo[5,4-a][2,3]benz odiazepin-6-ones (2,3-OBZs) were studied after intraperitoneal (i.p.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The seizures were evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a hemispheric Perspex dome. The 2,3-benzodiazepines studied after 30 min pretreatment were generally less potent than the related derivative 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) except 3,5-dihydro-7,8-dimethoxy-1-phenyl-4H-2,3-benzodiazepin-4-one (2,3-BZ-2) and 2,3-BZ-2M (3-methyl derivative of 2,3-BZ-2) which showed comparable activity. Thirty minutes after i.p. administration of 2,3-benzodiazepines, the rank order of potency for anticonvulsant activity against clonus was 2,3-BZ-2 > GYKI 52466 > 2,3-BZ-2M > 2,3-BZ-1 > 2,3-BZ-3, > 2,3-OBZ-1, > 2,3-OBZ-2 2,3-OBZ-3. The intracerebroventricular (i.c.v.) injection of aniracetam on it own (12.5 - 100 nmol/mouse) had no convulsant activity, but it reversed the anticonvulsant effects of some 2,3-benzodiazepines. In particular, the pharmacological actions of GYKI 52466, 2,3-BZ-2 and 2,3-BZ-2M, which proved to be the most potent 2,3-benzodiazepine derivatives as anticonvulsants, were significantly reduced by an i.c.v. pretreatment with aniracetam (50 nmol/mouse). Concomitant treatment with aniracetam (50 nmol/mouse) shifted to the right the dose-response curves and significantly increased the ED50 values for GYKI 52466, 2,3-BZ-2 and 2,3-BZ-2M. After 30 min pretreatment 2,3-BZ-2 showed a similar potency to GYKI 52466 in antagonizing seizures induced by i.c.v. administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), thus suggesting a clear involvement of AMPA receptors in the anticonvulsant activity of these compounds. In addition, 2,3-BZ-2 and 2,3-BZ-2M showed anticonvulsant properties longer lasting than GYKI 52466.
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PMID:GYKI 52466 and related 2,3-benzodiazepines as anticonvulsant agents in DBA/2 mice. 875 Jul 1

The epileptogenic and neurodegenerative effects of dendrotoxin K, from Dendroaspis polylepis, a specific blocker of a non-inactivating, voltage-sensitive K+ channel, were studied after focal injection into one dorsal hippocampus in rats. Administration of 35 pmol dendrotoxin K elicited motor seizures and bilateral electrocortical discharges after a latent period (5.3 +/- 2.1 min), in all of the treated animals (n = 6). At 24 h, histological examination of brain (n = 5) coronal sections (10 microns; n = 6 per brain) detected bilateral damage to the hippocampal formation which extended 300 microns rostral and caudal to the injection tract. Quantitation of the damage revealed significant bilateral neuronal cell loss in the CA1 and CA4 pyramidal cell layer relative to the corresponding brain regions of rats (n = 3) injected with bovine serum albumin (105 pmol), which per se was ineffective in all respects. Dendrotoxin K (35 pmol) also caused a significant loss of CA3 pyramidal neurons and dentate gyrus granule cells ipsilateral to the site of toxin injection. In one out of six rats, a lower dose (3.5 pmol) of dendrotoxin K produced convulsive behaviour and electrocortical seizures but after a longer latency and these were accompanied by significant neuronal loss in the CA1, CA3 and CA4 pyramidal cell layer ipsilateral to the injected side. The lowest dose (0.35 pmol; n = 6 rats) of dendrotoxin K used failed to induce seizures and did not cause hippocampal damage (n = 6 rats). Systemic (i.p.) treatment with dizocilpine maleate (3 mg/kg) or LY 274614 (5 mg/kg i.p.), two N-methyl-D-aspartate receptor antagonists (given 15 min beforehand), prevented dendrotoxin K (35 pmol)-induced motor seizures and electrocortical epileptogenic discharges in 100% of the animals (n = 6 per group) treated. Similarly, these antagonists minimized the damage typically produced in the rat hippocampus, with no significant neuronal loss being observed. By contrast, NBQX (30 mg/kg, i.p. given 15 min previously), a non-N-methyl-D-aspartate antagonist, failed to prevent seizures normally evoked by dendrotoxin K (35 pmol; n = 6 rats); also, this treatment was unable to abolish CA1 pyramidal cell loss but minimized the loss in hippocampal sectors distant to the site of dendrotoxin K injection. However, complete protection against motor and electrocortical seizures and hippocampal damage was afforded by GYKI 52466 (10 mg/kg i.p.; n = 6 rats), a more effective non-N-methyl-D-aspartate receptor antagonist. These findings differ from the reported lack of protection by N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor antagonists to rats receiving intra-hippocampal injection of alpha-dendrotoxin; this difference may stem from the ability of alpha-dendrotoxin to block predominantly a slowly inactivating K+ current whereas dendrotoxin K inhibits a non inactivating variant. In conclusion, the present data on dendrotoxin K, together with the previously described pattern of neurotoxicity for alpha-dendrotoxin, show that these homologues act via different mechanisms and, thus, can be used effectively as complementary tools to study seizures and neuronal cell death.
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PMID:N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors mediate seizures and CA1 hippocampal damage induced by dendrotoxin-K in rats. 886 35

Our previous publication (Eur. J. Pharmacol. 1995, 294, 411-422) reported preliminary chemical and biological studies of some 2,3-benzodiazepines, analogues of 1-(4-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466), which have been shown to possess significant anticonvulsant activity. This paper describes the synthesis of new 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones and the evaluation of their anticonvulsant effects. The observed findings extend the structure-activity relationships previously suggested for this class of anticonvulsants. The seizures were evoked both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. 1-(4'-Aminophenyl)- (38) and 1-(3'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin- 4-one (39), the most active compounds of the series, proved to be more potent than 1 in all tests employed. In particular, the ED50 values against tonus evoked by auditory stimulation were 12.6 micromol/kg for derivative 38, 18.3 micromol/kg for 39, and 25.3 micromol/kg for 1. Higher doses were necessary to block tonic extension induced both by maximal electroshock and by pentylenetetrazole. In addition these compounds exhibited anticonvulsant properties that were longer lasting than those of compound 1 and were less toxic. The novel 2,3-benzodiazepines were also investigated for a possible correlation between their anticonvulsant activities against convulsions induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and their affinities for benzodiazepine receptors (BZR). The 2,3-benzodiazepines did not affect the binding of [3H]flumazenil to BZR, and conversely, their anticonvulsant effects were not reversed by flumazenil. On the other hand the 2,3-benzodiazepines antagonized seizures induced by AMPA and aniracetam in agreement with an involvement of the AMPA receptor. In addition, both the derivative 38 and the compound 1 markedly reduced the AMPA receptor-mediated membrane currents in guinea-pig olfactory cortical neurons in vitro in a noncompetitive manner. The derivatives 25 and 38-40 failed to displace specific ligands from N-methyl-D-aspartate (NMDA), AMPA/kainate, or metabotropic glutamate receptors.
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PMID:1-Aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones: novel AMPA receptor antagonists. 911

Evans blue dye, given i.c.v. in rats in a dose of 208 nmol, causes electrical and behavioural seizures which resemble those induced by the glutamate analogue, kainate, or by electrical kindling of the amygdala. Chicago sky blue, 201 nmol i.c.v., produces similar seizures. The principal elements of the seizures are wet-rat-shakes, facial and forelimb clonus, rearing and spike-and-waves in the EEG. A non-NMDA receptor antagonist, GYKI 52466 and a benzodiazepine, diazepam, significantly delay the onset to the occurrence of the first forelimb clonus. The cholinergic antagonist, scopolamine, significantly reduces the delay to onset of first facial clonus. The competitive NMDA receptor antagonist, D-CPPene, the non-specific dopamine antagonist, haloperidol, and the purinergic agonist, 2-chloroadenosine, have no effect on the measured parameters. During the induction of seizures by Evans blue, the average extracellular glutamate concentration in hippocampus or cortex does not increase statistically significantly in comparison to pre-seizure values. Histological examination of limbic areas indicates that the moderate to severe Evans blue-induced cell damage is similar to that seen after limbic seizures induced by pilocarpine and in the hippocampus is partially preventable by D-CPPene but not by diazepam or GYKI 52466. It is proposed that Evans blue-induced seizures may be useful as a new model for studying the mechanisms of intractable epilepsy of the complex partial seizure type.
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PMID:The vital dye Evans blue mimics limbic seizures induced by kainate or pilocarpine. 912 13

Excitatory amino acids participate in the generation of seizure activity. Consequently, the effects of GYKI 52466 [1-(4-aminophenyl)-4-methoxy-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride], an antagonist of glutamate-mediated events, on the protective activity of conventional antiepileptic drugs against pentetrazol were studied. GYKI 52466 (up to 10 mg/kg, i.p.) did not affect the clonic phase of pentetrazol (injected s.c. at its CD97 of 90 mg/kg) convulsions. Only the antipentetrazol activity of valproate (100 mg/kg) was enhanced by GYKI 52466 (10 mg/kg)--the percentage of mice protected was significantly increased from 20 to 90%. The anticonvulsive activity of clonazepam (at 0.01), ethosuximide (at 50), and phenobarbital (at 2.5 mg/kg) was not modified by GYKI 52466 (up to 10 mg/kg). The combination of valproate (100 mg/kg) with GYKI 52466 (10 mg/kg) did not affect the performance of mice evaluated in the chimney test. However, this combination resulted in significant memory deficits, measured in the passive avoidance task. In no case did GYKI 52466 (10 mg/kg) affect either total or free plasma levels of antiepileptic drugs (as measured by immunofluorescence), so a pharmacokinetic interaction is not probable. Finally, the interaction of the non-NMDA receptor antagonist with antiepileptic drugs does not seem promising in the pentetrazol test, recognized as a model of human myoclonic epilepsy.
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PMID:GYKI 52466 [1-(4-aminophenyl)-4-methoxy-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] and the anticonvulsive activity of conventional antiepileptics against pentetrazol in mice. 964 69

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