Maximal Electroshock-induced Seizures Research Articles

Sedative and anticonvulsant effects of an alcoholic extract of Capparis decidua

Capparis decidua (frock) Edgew (family Capparidaceae) is a xerophytic shrub, commonly known as karrel or ker, whose bark and shoot are used as analgesic, anti-inflammatory, hypolipidemic, and antidiabetic agents. The plant contains generous quantities of alkaloids. An alcoholic extract of aerial parts of C. decidua, including flowers and fruits, was screened for central nervous system (CNS) activity using conventional behavioral animal models. In the open field test all doses of C. decidua extract tested decreased the number of rearings, grooming, and fecal bolus (P < 0.001) when compared with control. In the barbiturate-induced sleeping test a significant (P < 0.001) a decrease in latency of sleeping and increase in sleeping time were observed at all doses (100, 200, and 300 mg/kg). C. decidua extract increased the percentage of animals exhibiting motor deficit in the rotarod test. In the pentylenetetrazole-induced seizures test the C. decidua extract dose-dependently decreased (P < 0.05) the number of animals with convulsions and increased convulsion latency (P < 0.001); none of the animals treated with extract died in the test. C. decidua extract decreased the duration of tonic hind leg extension in maximal electroshock-induced seizures (P < 0.001) when compared with control. The findings of the present animal study suggested that C. decidua has CNS depressant and anticonvulsant activities.

Interactions between sildenafil and antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Interactions between sildenafil and antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Anticonvulsant and sedative-hypnotic activity of some novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2-styrylquinazoline-4(3H)-ones

A few novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones were synthesized and evaluated for anticonvulsant, neurotoxicity, sedative-hypnotic, and phenobarbitone-induced hypnosis potentiation test. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight derivatives were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models in mice. Spectroscopic data were consistence with the newly synthesized compounds. The neurotoxicity was assessed using the Rotorod method. Out of 15 compounds only 7e and 7o showed anticonvulsant activity at various doses in one or more test models. All except 7d, 7m, and 7n exhibited significant sedative-hypnotic activity via actophotometer screen. Central nervous system (CNS)-depressant activity screened with the help of the forced swim method resulted into some potent compounds. No percentage increase in the sleeping time was observed in any of the synthesized compounds evaluated by the phenobarbitone-induced hypnosis potentiation test. On the basis of experimental data, it can be concluded that synthesized compounds possessed relatively better sedative-hypnotic and CNS-depressant activities.

N-(anilinomethyl)-p-isopropoxyphenylsuccinimide potentiates the anticonvulsant action of phenobarbital and valproate in the mouse maximal electroshock-induced seizure model

The aim of this study was to determine the influence of N-(anilinomethyl)-p-isopropoxyphenylsuccinimide (AMIPPS) on the protective action of carbamazepine, phenobarbital, phenytoin, and valproate in the mouse maximal electroshock seizure model. Results indicate that AMIPPS administered separately (i.p., at doses of 75 and 150 mg/kg), significantly elevated the threshold for electroconvulsions in mice. Moreover, AMIPPS (37.5 mg/kg) significantly enhanced the anticonvulsant activity of phenobarbital and valproate, but not that of carbamazepine or phenytoin in the maximal electroshock seizure test in mice. AMIPPS (18.75 mg/kg) had no impact on the antiseizure action of phenobarbital and valproate against maximal electroshock seizure-induced seizures in mice. Pharmacokinetic experiments revealed that AMIPPS significantly increased total brain valproate concentrations and it had no impact on total brain concentrations of phenobarbital in mice. In conclusion, the enhanced antielectroshock action of phenobarbital by AMIPPS and lack of pharmacokinetic interaction make the combination of AMIPPS with phenobarbital of pivotal importance for further experimental and clinical studies. Although AMIPPS potentiated the anticonvulsant action of valproate in the maximal electroshock seizure test, the caution is advised when combining these drugs due to the risk of pharmacokinetic interactions. The combinations of AMIPPS with carbamazepine and phenytoin are neutral from a preclinical viewpoint.

Characterization of the anticonvulsant activity of doxepin in various experimental seizure models in mice

In this paper, the anticonvulsant characteristics of doxepin were evaluated in numerous experimental seizure models, including maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, isoniazid (ISO)-, 3-mercaptopropionic acid (3-MP)-, bicuculline (BIC)-, thiosemicarbazide (THIO)-, and strychnine (STR)-induced seizures. In addition, the acute adverse-effect profile of doxepin with respect to impairment of motor coordination was assessed with a mouse rotarod test. The evaluation of the time-course and doseresponse relationships for doxepin provided evidence that the peak maximum anticonvulsant activity and acute adverse effects occurred 5 min after intraperitoneal (ip) administration. The results also revealed that doxepin had excellent anticonvulsant activity against maximal electroshock-induced seizures in mice with a median effect value (ED50) of 6.6mg/kg. The assessment of acute adverse effects in the rotarod test revealed that doxepin induced acute neurotoxicity, and its median toxic dose (TD50) was 26.4mg/kg. Additionally, doxepin showed anticonvulsant activity in several chemically-induced seizure models, including ISO, 3-MP, BIC, and THI. Based on this study, we can conclude that the antidepressant drug doxepin may be useful for treatment of depression in patients with epilepsy due to its short time to peak maximum anticonvulsant activity after ip administration (5min) and remarkable anticonvulsant activity (6.6mg/kg).

Synthesis and anticonvulsant activity of some new bishydrazones derived from 3,4-dipropyloxythiophene

A series of new 3,4-dipropyloxy-N 2,N 5-bis(substituted)thiophene-2,5-dicarbohydrazides ( 4– 30) were synthesized from ethyl thiodiglycolate and diethyloxalate through multistep reactions. Following Dieckmann–Komppa reaction, the required precursor 3,4-dihydroxythiophene-2,5-diester ( 1) was prepared. This was derivatized with propyl bromide and further converted to corresponding hydrazide ( 3), which was finally transformed to targeted hydrazones ( 4– 30) by conventional methods. The newly synthesized compounds were characterized using FT-IR, 1H and 13C NMR, EI-MS and elemental analyses. The anticonvulsant activity of all the title compounds was investigated against maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scMET) models and their neurotoxicity was also evaluated. Some of the selected compounds were subjected to 6 Hz test in order to evaluate their uncover activities. Compound 3,4-dipropyloxy-N 2,N 5-bis[1-(2-thienyl)ethylidene]thiophene-2,5-dicarbohydrazide ( 15) has emerged as a lead in this series with less neurotoxicity.

Osthole suppresses seizures in the mouse maximal electroshock seizure model

The aim of this study was to determine the anticonvulsant effects of osthole {[7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one] – a natural coumarin derivative} in the mouse maximal electroshock-induced seizure model. The antiseizure effects of osthole were determined at 15, 30, 60, and 120 min after its systemic (i.p.) administration. Time course of anticonvulsant action of osthole revealed that the natural coumarin derivative produced a clear-cut antielectroshock activity in mice and the experimentally-derived ED 50 values for osthole ranged from 259 to 631 mg/kg. In conclusion, osthole suppresses seizure activity in the mouse maximal electroshock-induced seizure model. It may become a novel treatment option following further investigation in other animal models of epilepsy and preclinical studies.

Effects of withdrawal from long-term diphenylhydantoin treatment on audiogenic and maximal electroshock-induced seizures in rats.

Rats withdrawal from long-term diphenylhydantoin treatment (DPH) were tested for their sensibility to convulsant stimuli. Animals were more sensitive to convulsions elicited by maximal electroshock and sound, respectively, at 48 and 72 h after drug removal. These results suggest that long-term DPH treatment might develop a central nervous system supersensitivity state.

Indapamide enhances the protective action of carbamazepine, phenobarbital, and valproate against maximal electroshock-induced seizures in mice

To determine the influence of indapamide on the protective action of numerous conventional and second-generation antiepileptic drugs (carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, topiramate and valproate) in the mouse maximal electroshock seizure model. Electroconvulsions were evoked in Albino Swiss mice by a current (sine-wave, 0.2 s stimulus duration) delivered via auricular electrodes. Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Indapamide (up to 3 mg/kg, i.p., 120 min before the test) neither altered the threshold for maximal electroconvulsions, nor protected the animals against maximal electroshock-induced seizures in mice. Moreover, indapamide (3 mg/kg, i.p.) significantly enhanced the anticonvulsant action of carbamazepine, phenobarbital and valproate, but not that of lamotrigine, oxcarbazepine or topiramate in the maximal electroshock seizure test in mice. Indapamide (1.5 mg/kg) had no impact on the anticonvulsant action of all studied antiepileptic drugs in the maximal electroshock seizure test in mice. Estimation of total brain antiepileptic drug concentrations revealed that the observed interaction between indapamide and phenobarbital was complicated by a significant pharmacokinetic increase in total brain concentrations of phenobarbital. In contrast, indapamide had no impact on the total brain concentrations of carbamazepine and valproate in mice. The selective potentiation of the anticonvulsant action of carbamazepine and valproate by indapamide and lack of any pharmacokinetic interactions between drugs, make the combinations of indapamide with carbamazepine or valproate of pivotal importance for epileptic patients taking these drugs together.

Spironolactone potentiates the protective action of some selected antiepileptic drugs against maximal electroshock-induced seizures in mice

Spironolactone potentiates the protective action of some selected antiepileptic drugs against maximal electroshock-induced seizures in mice

Verapamil enhances the anticonvulsant effect of oxcarbazepine in the maximal electroshock-induced seizure model in mice

Verapamil enhances the anticonvulsant effect of oxcarbazepine in the maximal electroshock-induced seizure model in mice

Isobolographic analysis of interactions between 1-methyl-1,2,3,4-tetrahydroisoquinoline and four conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

The anticonvulsant activity of 1-methyl-1,2,3,4-tetrahydroisoquinoline (MeTHIQ — an endogenous parkinsonism-preventing substance) administered alone and in combination with four conventional antiepileptic drugs (carbamazepine, phenytoin, phenobarbital and valproate) was determined in the mouse maximal electroshock-induced seizure model. The types of interactions of MeTHIQ with the antiepileptic drugs were characterized using isobolographic analysis. The isobolographic analysis revealed that the combination of MeTHIQ with phenobarbital at the fixed-ratios of 1:3, 1:1 and 3:1 exerted supra-additive (synergistic) interaction in the maximal electroshock-induced seizure test. In contrast, the combinations of MeTHIQ with carbamazepine, phenytoin and valproate exerted additive interaction for all three fixed-ratios (1:3, 1:1 and 3:1) tested in the maximal electroshock-induced seizure test. In conclusion, MeTHIQ produces a clear-cut anticonvulsant effect in the maximal electroshock-induced seizure test in mice. The supra-additive interaction of MeTHIQ with phenobarbital against maximal electroshock-induced seizures makes their combination of pivotal importance from a clinical viewpoint.

Isobolographic characterization of interactions of retigabine with carbamazepine, lamotrigine, and valproate in the mouse maximal electroshock-induced seizure model

The aim of this study was to characterize the pharmacodynamic, pharmacokinetic, and adverse-effect profiles of retigabine (RTG) in combination with carbamazepine (CBZ), lamotrigine (LTG), and valproate (VPA). The isobolographic analysis for parallel and nonparallel dose-response effects was used in the mouse maximal electroshock seizure (MES) model for evaluation of pharmacodynamic interaction. Potential adverse-effect profiles of interactions of RTG with CBZ, LTG, and VPA at the fixed ratio of 1:1 in the MES test were evaluated in the chimney (motor performance), passive avoidance (long-term memory), and grip strength (muscular strength) tests. Free plasma and total brain concentrations of CBZ, LTG, and VPA were determined by immunofluorescence and chromatography to assess pharmacokinetic interaction. In the MES model, RTG administered singly had its dose-response relationship curve (DRRC) parallel to that for VPA and nonparallel to that for CBZ and LTG. With isobolography for parallel DRRCs, the combination of RTG with VPA at fixed ratios of 1:3, 1:1, and 3:1 exerted supraadditive (synergistic) interaction. Isobolography for nonparallel DRRCs revealed that the combinations of RTG with CBZ and LTG at the fixed ratio of 1:1 produced additive interaction. In all combinations, neither motor coordination, long-term memory, nor muscular strength were affected. Only the combination of RTG with VPA at the fixed ratio of 3:1 was complicated by a pharmacokinetic increase in both free plasma and total brain VPA concentrations. All remaining combinations of RTG with VPA, CBZ, and LTG were pharmacodynamic in nature. RTG synergistically interacted with VPA and exerted additive interaction with CBZ and LTG in the mouse MES model.

Synthesis and anticonvulsant activity of some substituted 1,2,4-thiadiazoles

A series of new substituted 1,2,4-thiadiazoles were synthesized by appropriate route and screened for anticonvulsant, neurotoxic and sedative-hypnotic activity. The structures of the synthesized compounds were confirmed by IR spectroscopy, 13C NMR and elemental (nitrogen and sulphur) analysis. After i.p. injection of the compounds to mice or rate at doses of 30, 100, and 300 mg/kg, body weights were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models after 0.5 and 4 h. Rotorod method and phenobarbitone-induced hypnosis potentiation study were employed to examine neurotoxicity and sedative-hypnotic activity, respectively. All the compounds except 4g showed protection against MES screen after 0.5 h. Compounds 3a– c, 4a– c were active at 100 mg/kg dose i.p., whereas remaining compounds showed activity at 300 mg/kg. All 14 compounds except 3 g showed neurotoxicity at 100 and 300 mg/kg after 0.5 h. Compounds 3b and 4b showed NT after 4 h. Two compounds 3b and 4g showed significant ( p < 0.05) percentage increase in sleeping time i.e. 67% and 59%, respectively. It may be concluded that the synthesized compounds were potent against MES-induced seizures than ScPTZ induced and showed low potency as sedative-hypnotic agent which is advantageous.

Design and synthesis of 6-amino-1,4-oxazepane-3,5-dione derivatives as novel broad spectrum anticonvulsants

Based on the structural estimations of the typical anticonvulsant drugs, a series of 6-amino-1,4-oxazepane-3,5-dione derivatives, novel structures of 7-membered heterocyclic imides, which were hybridized with pharmacophores such as cyclic imide and N-CO-C-N group in their molecule were designed and synthesized. Their anticonvulsant activities were evaluated by the maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (PTZ) tests. Almost all the designed compounds except 1c and 1f showed comparable anticonvulsant activities in at least one of the anticonvulsant tests. Moreover, some of the tested compounds exhibited moderate anticonvulsant activities in both MES and PTZ tests. From these results, 6-amino-1,4-oxazepane-3,5-dione derivatives could be recommended as novel structures of broad spectrum anticonvulsants.

Effects of amlodipine, diltiazem, and verapamil on the anticonvulsant action of topiramate against maximal electroshock-induced seizures in micePresented in part at the 11th Congress of the European Federation of Neurological Societies, Brussels, Belgium, 25–28 August 2007.

To assess the effect of 3 calcium channel antagonists (amlodipine, diltiazem, and verapamil) on the anticonvulsant action of topiramate (a new generation antiepileptic drug) in the mouse maximal electroshock seizure (MES) model. Amlodipine (20 mg/kg) significantly enhanced the anticonvulsant activity of topiramate in the MES test in mice, reducing its ED50 value from 54.83 to 33.10 mg/kg (p < 0.05). Similarly, diltiazem (5 and 10 mg/kg) markedly potentiated the antiseizure action of topiramate against MES, lowering its ED50 value from 54.83 to 32.48 mg/kg (p < 0.05) and 28.68 mg/kg (p < 0.01), respectively. In contrast, lower doses of amlodipine (5 and 10 mg/kg) and diltiazem (2.5 mg/kg) and all doses of verapamil (5, 10, and 20 mg/kg) had no significant impact on the antiseizure action of topiramate. Pharmacokinetic verification of the interaction of topiramate with amlodipine and diltiazem revealed that neither amlodipine nor diltiazem affected total brain topiramate concentration in experimental animals, and thus, the observed interactions were concluded to be pharmacodynamic in nature. The favorable combinations of topiramate with amlodipine or diltiazem deserve more attention from a clinical viewpoint because the enhanced antiseizure action of topiramate was not associated with any pharmacokinetic changes in total brain topiramate concentration.

Newer GABA derivatives for the treatment of epilepsy including febrile seizures: A bioisosteric approach

The present study aims at design and synthesis of newer γ-aminobutyric acid (GABA) derivatives with the combination of thiosemicarbazone and GABA pharmacophores in order to develop newer anticonvulsants. The reported compounds were designed as bioisosteric analogues of GABA semicarbazones. The structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and subcutaneous picrotoxin (scPIC)-induced seizure threshold tests. A model involving 22-day old rat pups was also employed to further screen the effects of the test compounds against hyperthermia-induced febrile seizures. Only compounds 1 and 11 were found to be active in the MES test. Most of the compounds were found to be effective in the scPIC and febrile seizure models and very few compounds showed protection in scPTZ and scSTY models. This is the first report on these new GABA derivatives effective in the treatment of febrile seizures.

Interactions of MRZ 2/576 with Felbamate, Lamotrigine, Oxcarbazepine and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

This study focused on the evaluation of interactions between MRZ 2/576 (8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridazino(4,5-b)quinoline-5-oxide choline salt), an N-methyl-D-aspartate (NMDA) receptor antagonist acting at the NMDA receptor/glycine_B site and four newer antiepileptic drugs (felbamate, lamotrigine, oxcarbazepine, and topiramate) in the mouse maximal electroshock seizure model. Results indicate that MRZ 2/576 administered intraperitoneally, 5 min before the test, exerted a clear-cut anticonvulsant effect in the maximal electroshock seizure test in mice and its ED₅₀ value was 13.71 (11.95–15.73) mg/kg. In the subthreshold method, MRZ 2/576 (administered intraperitoneally, at a subthreshold dose of 5 mg/kg) significantly enhanced the anticonvulsant action of felbamate, oxcarbazepine and topiramate, by reducing their ED₅₀ values from 73.0 to 53.8 mg/kg (p < 0.05) for felbamate, from 10.77 to 7.48 mg/kg (p < 0.05) for oxcarbazepine, and from 49.3 to 28.7 mg/kg (p < 0.01) for topiramate. In contrast, MRZ 2/576 (5 mg/kg, i.p.) did not significantly affect the antiseizure effects of lamotrigine in the maximal electroshock seizure test in mice. Isobolographic transformation of data revealed that MRZ 2/576 (5 mg/kg, i.p.) exerted barely additive interactions with all investigated antiepileptic drugs in the maximal electroshock seizure test. In conclusion, the isobolographic analysis revealed that MRZ 2/576 additively cooperates with newer antiepileptic drugs in terms of suppression of maximal electroshock-induced seizures in mice.

Synthesis, anticonvulsant, antimicrobial and analgesic activity of novel 1,2,4-dithiazoles

A series of 1,2,4-dithiazole were synthesized from 1,2,4-thiadiazoles in the presence of CS2 and evaluated for their antimicrobial, anticonvulsant, analgesic and neurotoxicity potential. The compounds provided significant protection against maximal electroshock-induced seizures and seizures induced by 300 mg/kg of subcutaneous pentylenetetrazole administration. The designed compounds (3a-g) were screened in vitro for antibacterial activity against Staphylococcus aureus Escherichia coli, Bacillus subtilis and Pseudomonas aeruginosa and antifungal activity in fungal strains of Candida albicans and Aspergillus niger. Synthesized compounds exhibited moderate antibacterial and antifungal activity. N,N -Di-naphthalen-1-yl-N -(thioxo-5H -[1,2,4]dithiazol-3-yl)-guanidine and N,N -Bis-(4-fluoro-phenyl)-N -(5-thioxo-5H -[1,2,4]dithiazol-3-yl)-guanidine showed analgesic activity by tail flick method.

Maximal electroshock induces changes in some markers of oxidative stress in mice

The oxidative/antioxidative status was investigated in maximal electroshock-induced seizures in mice, a well established model of generalized seizures in humans. Mice were given a single electroshock resulting in tonic convulsions. Total antioxidant capacity (TAC), lipid peroxidation intensity and glutathione peroxidase (GSH-Px) activity was measured spectrophotometrically in the brain, plasma and erythrocytes collected from mice sacrificed at different time points after stimulation. For comparison, sham-stimulated and subeffectively stimulated (no tonic seizures) mice were used. Tonic seizures caused an immediate increase in GSH-Px activity in the brain and during the following three hours the enzyme activity decreased below control values. Similar changes were seen after subconvulsive stimulations, however, a significant increase occurred only one hour after electroshock. A marked TAC reduction in the brain was observed three hours after subconvulsive stimulations. Nevertheless, no significant changes in TAC after tonic seizures were noted. TAC in plasma was significantly reduced three hours after both subconvulsive and convulsive stimulation. Marked reduction of lipid peroxidation intensity in the brain and plasma was recorded after both modes of stimulation. In conclusion, pronounced changes in oxidative/antioxidative status in mice following electroshock are caused by both convulsive and subconvulsive stimuli. Participation of oxidative stress in seizures and pathophysiology of epilepsy awaits further clarification.