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

The potency of some competitive antagonists of N-methyl-D-aspartate (NMDA) to antagonize audiogenic seizures was evaluated in genetically epilepsy-prone rats following intraperitoneal or oral administration. The anticonvulsant effects were evaluated on seizures evoked by auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a perspex dome. Sixty and hundred-twenty minutes after intraperitoneal or 120 min after oral administration all compounds showed antiseizure activity with ED50 against clonus ranging from 11.6 to 384 mumol/kg after intraperitoneal and higher doses after oral administration. DL-(E)-2-Amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849) and its carboxyethylester (CGP 39551) and 3-((+/-)-2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (CPPene), were the most potent compounds when administered intraperitoneally and orally. 3-((+/-)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid ((-)-CPP) and (+)-CPP showed minor potency as anticonvulsants and 2-amino-7-phosphonoheptanoic acid (2AP7) was the least potent. Following oral treatment, the duration of action of CPPene was about 8 h, while CGP 39551 still protected against audiogenic seizures after 16 h. All compounds were anticonvulsant at doses below those at which overt behavioural side-effects were apparent. CPPene and (+/-)-CPP showed the best therapeutic index among the NMDA receptor antagonists studied. Since some of these compounds showed anticonvulsant properties after oral administration, potential use of these or other selective NMDA antagonists for antiepileptic therapy in man is suggested.
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PMID:Anticonvulsant activity of competitive antagonists of NMDA receptor in genetically epilepsy-prone rats. 139 87

Intravenous injection of N-methyl-D,L-aspartic acid (NMDLA) into mice produces characteristic convulsions followed by death. The present study was designed to determine the degree of blockade of these seizures/mortality by compounds acting at various subsites on the N-methyl-D-aspartic acid (NMDA) receptor complex (competitive and noncompetitive antagonists, as well as inhibitors of the strychnine-insensitive glycine subsite, and Zn++ subsite agonists), and also calcium channel blockers, clinically used anticonvulsants, plus selected compounds with activities or structures similar to specific agents chosen. Activity among compounds was correlated to in vitro potency regarding inhibition of binding of MK801 to the ionic channel subsite associated with the NMDA receptor. Furthermore, all compounds were examined for antiseizure properties with respect to tonic hindlimb extension elicited by maximal electroshock (MES) and clonus induced by pentylenetetrazol (PTZ). Drugs were subsequently classified according to their spectra of efficacy in these tests. The following characteristics emerged: 1) agents active at all 3 NMDA mechanisms (convulsions/mortality/MK801 binding) plus MES and PTZ, were MK801 and CPP [3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid]; 2) active at all the NMDA mechanisms and MES were ketamine and dextromethorphan; 3) active against NMDLA-induced convulsions/mortality, MES and PTZ, but not MK801 binding, were doxepin, desipramine and diazepam; 4) active against NMDLA-induced convulsions/mortality and MES were des-Me-doxepin, flunarizine and remacemide; 5) active against NMDLA-induced convulsions/mortality and PTZ was nisoldipine; 6) active against only NMDLA-induced convulsions/mortality were chlorpheniramine and iproniazid; 7) active in the MES and PTZ tests were phenobarbital, pentobarbital and valproate; 8) active in the MES test alone were phenytoin and carbamazepine; 9) active against PTZ only was ethosuximide; 10) active only in the in vitro MK801 binding assay were HA966, 7-Cl-kynurenate and AP7 (2-amino-7-phosphonoheptanoic acid); and 11) no demonstrable actions had AP4 (2-amino-4-phosphonobutyric acid) and mianserin. In conclusion, inhibition of NMDLA-induced convulsions/mortality in vivo is not necessarily correlated to a noncompetitive displacement of MK801 binding to NMDA receptor sites in vitro, nor is inhibition of NMDA-elicited convulsions/mortality correlated with a specific ability of a compound to inhibit either MES or PTZ seizures.
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PMID:Classification of compounds for prevention of NMDLA-induced seizures/mortality, or maximal electroshock and pentylenetetrazol seizures in mice and antagonism of MK801 binding in vitro. 145 42

Limbic seizures (forepaw clonus) were induced in Lewis rats by subcutaneous injections of lithium (3 mEq/kg) followed 24 h later by a muscarinic agent. Either 7 days before, 7 days after, or on the day of seizures, rats were inoculated with a spinal cord preparation. Other groups received these preparations but served as treatment (no seizure) controls. In three separate experiments, rats in which seizures had been induced at the time of inoculation displayed significant increases in the severity of clinical symptoms 14-20 days later relative to controls while rats in which seizures had been induced 7 days after inoculation displayed less severe symptoms; the latter effect was partially simulated by multiple injections of 1 mg/kg dexamethasone. The immunofacilitation effect was much stronger than the immunosuppression and explained 25-30% of the variance in the clinical severity scores.
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PMID:Severity of experimental allergic encephalomyelitis in rats depends upon the temporal contiguity between limbic seizures and inoculation. 147 92

The behavioural and neuropathological effects of both systemic and intrahippocampal injections of paraquat dichloride (1,1'-dimethyl 4,4'-bipyridinium dichloride) were studied in rats. Paraquat (0.1-1.0 mumol) injected into the dorsal hippocampus, produced limbic motor seizures within a few minutes of injection followed by neuronal damage in the CA1 and CA3 pyramidal cell layers, pyriform cortex, dentate granule cell layer and in the hilus fascia dentata at 24 hr (n = 9 rats). A smaller dose of paraquat (10 nmol) was ineffective. The effects of intrahippocampal injections of paraquat (1 mumol) were prevented by administering it together with atropine (50 nmol; n = 6 rats) or by giving it 60 min. after MK 801 (0.3 mg.kg-1 intraperitoneally). Systemic injections of paraquat (20-100 mg.kg-1) also produced forelimb clonus and rearing in 10 out of 15 animals. Neuronal cell death was found 24 hr later in 9 of these rats and was restricted to the pyriform cortex, the brain region with the highest concentrations of paraquat. Atropine (150 mg.kg-1 intraperitoneally given 60 min. previously) completely prevented the motor seizures but cell death still occurred in 2 of the 6 animals tested. In conclusion, both systemic and intrahippocampal injections of paraquat produced behavioural excitation accompanied 24 hr later by brain damage and antagonist studies suggested involvement of muscarinic and NMDA receptors in the neurotoxic mechanism.
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PMID:Production of limbic motor seizures and brain damage by systemic and intracerebral injections of paraquat in rats. 148 May 53

Repetition of seizures appears to increase severity in a number of seizure models, but the nature of these severity increases has not been elucidated in naturally occurring genetic epilepsy models. The genetically epilepsy-prone rat (GEPR) is highly susceptible to many seizure provoking stimuli, and high intensity acoustic stimuli induce audiogenic seizures (AGS). The role of forebrain structures in AGS in the GEPR has not been clear, and the presence of cortical epileptiform EEG activity in the GEPR is controversial. The present study examined the effects of 21 daily AGS repetitions on behavior and EEG activity recorded from the cortex of two GEPR substrains that exhibit moderate (GEPR-3) or severe AGS (GEPR-9). The results indicated that AGS repetition induced seizure severity increases in both GEPR substrains and resulted in prominent cortical epileptiform EEG activity. The AGS behavioral patterns remained distinctly different in the two substrains throughout seizure repetition. In each substrain a different additional behavioral phase was expressed; the GEPR-9 exhibited post-tonic clonus, and the GEPR-3 exhibited facial and forelimb clonus. These findings indicate that seizure repetition results in expansion of the neuronal network subserving AGS to involve forebrain structures. The medial geniculate body and amygdala appear to be part of this expanded network, and long-term potentiation, which was reported in the pathway between the latter brain structures, may be involved. These data suggest that recruitment of forebrain structures into the AGS neuronal network appears to be essential for production of the additional ictal behaviors evoked by AGS repetition.
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PMID:Repetition of audiogenic seizures in genetically epilepsy-prone rats induces cortical epileptiform activity and additional seizure behaviors. 153 91

Previous studies suggest that organic solvents show anticonvulsant and convulsant effects, respectively at low and high doses. In the present study the first experiment was designed to determine low and high doses of injected acute n-hexane, ethyl acetate and toluene in mice through LD50 estimations. In the second experiment, high doses (around LD50) were employed to evaluate the convulsant effects. Finally, the third experiment evaluated the ability of low doses to prevent electroshock- and PTZ-induced convulsions. Results showed that n-hexane increased the severity of the electroshock-induced seizures only at low doses and had no anticonvulsant effects. Ethyl acetate produced generalized clonic seizures and deaths at high doses and was ineffective to prevent electroshock- and PTZ-induced seizures at low doses. Toluene induced forelimb clonus at high doses and protected against electroshock-induced seizures at low doses. Therefore, the biphasic property on convulsant activity seems to be a feature not shared among organic solvents.
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PMID:Anticonvulsant and convulsant effects of organic solvents. 153 82

In animal models of epilepsy the anticonvulsant profile of loreclezole resembles that of barbiturates and benzodiazepines. We examined whether the increase in seizure threshold to pentylenetetrazole infusion produced by 10 mg/kg of loreclezole, pentobarbital or diazepam could be reversed by a spectrum of benzodiazepine partial inverse to full inverse agonists (FG-7142 beta-carboline carboxylate, CGS-8216, Ro-15-4513 and DMCM) or by a benzodiazepine neutral antagonist (Ro-15-1788). The doses of the benzodiazepine inverse agonists were chosen to produce a 20-40% decrease in seizure threshold. The seizure threshold increase produced by loreclezole and pentobarbital was reduced by all the benzodiazepine inverse agonists and potentiated by Ro-15-1788. Diazepam was antagonized by the benzodiazepine inverse agonists and by the neutral antagonist. The generality of this finding was examined in amygdala-kindled rats. The decrease in the duration of forepaw clonus and the reduction in behavioural stage34 produced by loreclezole, pentobarbital and diazepam was reversed by CGS-8216. Ro-15-1788, which itself showed anticonvulsant effects in this model, antagonized the effects of diazepam, but not loreclezole or pentobarbital. Thus loreclezole behaves more like a barbiturate than a benzodiazepine in these two in vivo models. This suggests a possible mechanism of action of loreclezole at a neuromodulatory site within the GABAA receptor complex, which is unlikely to be a benzodiazepine receptor.
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PMID:In vivo studies on the mechanism of action of the broad spectrum anticonvulsant loreclezole. 156 36

The dose-related time course and occurrence of different seizure subtypes was examined in mice after i.c.v. administration of N-methyl-D-aspartate (NMDA), kainate (KA) or quisqualate (QA). At doses of 0.2 to 1 nmol, NMDA dose-dependently induced a single clonic-tonic seizure. Low doses (0.1 to 0.3 nmol) of KA induced only mild myoclonus and whole body clonus, which were dose-dependently replaced by short-delay clonic-tonic seizures at higher doses (0.4 to 1.2 nmol). In contrast, mice treated with 13 to 32 nmol of QA exhibited either mild myoclonus or whole body clonus as well as clonic-tonic seizures. Clonic-tonic seizures induced by NMDA or KA appeared at shorter latencies than those induced by QA, whereas whole body clonus induced by KA or QA appeared with long onset latencies. These results clearly show that i.c.v. administration of NMDA, KA and QA produces different patterns of seizures in mice. This study confirms that NMDA, KA and QA induce convulsions through different underlying mechanisms and suggests that different anatomical pathways are involved in these models.
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PMID:Comparative analysis of seizures induced by intracerebroventricular administration of NMDA, kainate and quisqualate in mice. 157 1

Felbamate (2-phenyl-1,3-propanediol dicarbamate, FBM) was subjected to a series of carefully selected in vivo and in vitro tests to provide additional insight into mechanism of action, margin of safety, and clinical potential. FBM was effective against intracerebroventricular (i.c.v.) N-methyl-D-aspartate (NMDA)-induced clonus and i.c.v. NMDA- and quisqualic acid (quis)-induced forelimb tonic extension in mice and ineffective against i.c.v. quis-induced clonus in mice. FBM was also effective in preventing the expression of Stage 5 kindled seizures in corneal-kindled rats. The calculated protective indices (rotorod median toxic dose divided by anticonvulsant median effective dose) ranged from 28 to 146 for those tests in which FBM displayed activity. With the in vitro tests, FBM did not significantly displace [3H]MK-801 from its binding site. In contrast, FBM was effective in blocking sustained repetitive firing in mouse spinal cord neurons grown in tissue culture (median inhibitory concentration 67 micrograms/ml). This effect on repetitive firing suggests indirectly that FBM modulates sodium channel conductance. The results, when compared to similar data for phenytoin, carbamazepine, valproate, and ethosuximide, support the concept that FBM is a relatively nontoxic agent with a unique profile of anticonvulsant action, a broad margin of safety, and a clinical potential that includes at least generalized tonic-clonic and complex partial seizures.
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PMID:A neuropharmacological evaluation of felbamate as a novel anticonvulsant. 159 38

The proconvulsant properties of the chlorinated hydrocarbon insecticide, endosulfan, were investigated using electrical kindling of the amygdala. Male rats were implanted with electrodes in the amygdala and stimulated once daily with a standard kindling stimulus 60-90 min following endosulfan (0, 2.5, 5.0 mg/kg, PO). No alterations were observed in either the threshold to induce an afterdischarge (AD) or the duration of clonus upon seizure generalization. Endosulfan significantly reduced the number of stimulations required to produce Stage 5 generalized seizures. Seizures prior to stimulation were evident in a subset of animals from both dosage groups and were never observed in controls. The presence of kindled seizures was maintained in the absence of further dosing, as amygdala stimulation 2-4 weeks after the last endosulfan treatment resulted in generalized seizures in all animals. These results suggest that faster kindling rates induced by endosulfan are not readily attributable to transient toxicant-related increases in excitability of the nervous system. It was concluded that endosulfan has proconvulsant properties that may be related to an action on GABA within the central nervous system.
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PMID:Proconvulsant activity of endosulfan in amygdala kindling. 159 88


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