Electroconvulsive Threshold Research Articles

The effects of cimetidine chronic treatment on conventional antiepileptic drugs in mice

The aim of this study was to evaluate the effects of 1-day, 7-day and 14-day administrations of cimetidine on the anticonvulsant activity of conventional antiepileptic drugs (AEDs; valproate, carbamazepine, phenytoin and phenobarbital) against maximal electroshock (MES)-induced convulsions in mice. Electroconvulsions were evoked in Albino Swiss mice by a current delivered via ear-clip electrodes. In addition, the effects of cimetidine, AEDs alone and their combinations were studied on performance and long-term memory tests. Pharmacokinetic changes in plasma and brain concentrations of AEDs after cimetidine administration were evaluated with immunofluorescence. Cimetidine (up to 100mg/kg) after 1-day administration did not affect the electroconvulsive threshold in animals. Moreover, in the 14-day treatment, cimetidine administered at a dose of 40mg/kg did not significantly change the electroconvulsive threshold in the MES-test, cimetidine administered 14-day (at 20mg/kg) significantly increased the anticonvulsant activity of carbamazepine, staying without effects after a 1-day and 7-day studies. In contrast, both the 7-day and 14-day administrations of cimetidine resulted in significant reductions of protective efficacy of the phenobarbital. Only valproate and phenytoin were not affected by cimetidine (20mg/kg) in all experimental period. Cimetidine administered 1-day, did not alter total brain concentrations and free plasma levels of all AEDs tested, whilst the 14-day study elevated carbamazepine plasma and brain concentration and reduced phenobarbital brain concentration. Cimetidine co-applied with AEDs did not impair performance of mice evaluated in the chimney test however, it worsened long-term memory in animals. Based on this preclinical study, a special caution is advised when treating epileptic patients with combinations of phenobarbital or carbamazepine with cimetidine.

Assessment of the anticonvulsant potency of various benzylamide derivatives in the mouse maximal electroshock-induced seizure threshold model.

The aim of this study was to assess the anticonvulsant potency of 6 various benzylamide derivatives [i.e., nicotinic acid benzylamide (Nic-BZA), picolinic acid 2-fluoro-benzylamide (2F-Pic-BZA), picolinic acid benzylamide (Pic-BZA), (RS)-methyl-alanine-benzylamide (Me-Ala-BZA), isonicotinic acid benzylamide (Iso-Nic-BZA), and (R)-N-methyl-proline-benzylamide (Me-Pro-BZA)] in the threshold for maximal electroshock (MEST)-induced seizures in mice. Electroconvulsions (seizure activity) were produced in mice by means of a current (sine-wave, 50Hz, 500V, strength from 4 to 18mA, ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). Nic-BZA, 2F-Pic-BZA, Pic-BZA, Me-Ala-BZA, Iso-Nic-BZA, and Me-Pro-BZA administered systemically (ip) in a dose-dependent manner increase the threshold for maximal electroconvulsions in mice. Linear regression analysis of Nic-BZA, 2F-Pic-BZA, Pic-BZA, MeAla-BZA, IsoNic-BZA, and Me-Pro-BZA doses and their corresponding threshold increases allowed determining threshold increasing doses by 20% (TID20 values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID20 values in the MEST test for Nic-BZA, 2F-Pic-BZA, Pic-BZA, Me-Ala-BZA, Iso-Nic-BZA, and Me-Pro-BZA were 7.45mg/kg, 7.72mg/kg, 8.74mg/kg, 15.11mg/kg, 21.95mg/kg and 28.06mg/kg, respectively. The studied benzylamide derivatives can be arranged with respect to their anticonvulsant potency in the MEST test as follows: Nic-BZA>2F-Pic-BZA>Pic-BZA>Me-Ala-BZA>Iso-Nic-BZA>Me-Pro-BZA.

Assessment of the Combined Treatment with Umbelliferone and Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Background/Aims: The aim of this study was to determine the effects of umbelliferone (7-hydroxycoumarin; UMB) on the anticonvulsant potency of four classical antiepileptic drugs (carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) and valproate (VPA)) in the mouse maximal electroshock-induced seizure (MES) model. Results: UMB administered systemically intraperitoneally (ip) in a dose of 150 mg/kg significantly elevated the threshold for maximal electroconvulsions (p < 0.05) in mice. Moreover, UMB (150 mg/kg) co-administered with PB and VPA significantly enhanced the anticonvulsant potency of these drugs by reducing their median effective doses (ED₅₀ values) from 35.39 to 21.78 mg/kg (p < 0.01) for PB, and from 281.4 to 215.5 mg/kg (p < 0.01) for VPA. In contrast, UMB (150 mg/kg, ip) had no significant effect on the antiseizure activity of CBZ and PHT in the mouse MES model. Neither total brain PB, nor total brain VPA concentrations were altered after ip administration of UMB, indicating a pharmacodynamic nature of interactions between the tested drugs. Conclusions: The selective potentiation of the anticonvulsant potency of PB and VPA by UMB, and lack of any pharmacokinetic interactions between drugs, make the combinations of UMB with PB or VPA worthy of consideration for epileptic patients who are refractory to standard antiepileptic treatment.

PP07.1 – 2308: Attenuation of the anticonvulsant effects of classical antiepileptic drugs against electroshock-induced convulsions in mice fed the ketogenic diet

Objective To investigate whether the KD could affect the anticonvulsant activity and pharmacokinetic properties of several AEDs in a model of generalized tonic-clonic epilepsy. Methods Male Swiss mice weighing 20–25 g were used for experiments. Mice were fed the KD for 2 weeks ( http://www.bioserv.com/product/F3666.html , 6:1 ratio of fat to protein + carbohydrates); control mice were receiving a standard rodent diet. The following AEDs were studied: carbamazepine, phenobarbital, phenytoin, and valproate. Electroconvulsions were induced by applying an alternating current via ear-clip electrodes in two methodologically different experimental approaches: maximal electroshock seizure threshold (MEST) test and maximal electroshock seizure (MES) test. Results The KD decreased the electroconvulsive threshold in the MEST test in mice, i.e. 47% decrease of the CS50 value from 7.29 to 3.86 mA, p Conclusion Though the KD has proven efficacy in clinical practice, it lowers the electroconvulsive threshold in the MEST test in mice. Moreover, the KD attenuates the anticonvulsant efficacy of the AEDs tested. This paradoxical effect of AEDs losing their anticonvulsant efficacy in mice fed the KD may be reflective of a higher energy state produced by the KD leading to a facilitated spread of electroconvulsions in the brain. It is concluded that that the MES and MEST tests may not be suitable for studying the anticonvulsant properties of the KD in mice.

Influence of N-(p-acetylphenyl)-p-isopropoxyphenylsuccinimide on the protective action of classical antiepileptic drugs against maximal electroshock-induced seizures in mice

The aim of this study was to determine the effects of N-(p-acetylphenyl)-p-isopropoxyphenylsuccinimide (APIPPS) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) in the maximal electroshock (MES)-induced seizures in mice. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Total brain AED concentrations were measured with fluorescence polarization immunoassay to ascertain whether any observed effects were consequent to a pharmacodynamic and/or a pharmacokinetic interaction between APIPPS and classical AEDs. Results indicate that APIPPS administered intraperitoneally at a dose of 150 mg/kg significantly elevated the threshold for electroconvulsions in mice. APIPPS at lower doses of 25, 50 and 100 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, APIPPS at 100 mg/kg significantly enhanced the anticonvulsant activity of PB and VPA, but not that of CBZ or PHT, in the MES test in mice. APIPPS at a dose of 50 mg/kg significantly potentiated the anticonvulsant action of VPA, but not that of PB in the mouse MES model. Pharmacokinetic experiment revealed that APIPPS did not alter total brain concentrations of PB or VPA in mice. Summing up, the enhanced anticonvulsant action of PB and VPA by APIPPS in the mouse MES model and lack of pharmacokinetic interactions between drugs, make the combinations of APIPPS with PB and VPA of importance for further experimental and clinical studies. The combinations of APIPPS with CBZ and PHT are neutral from a preclinical viewpoint.

Modafinil and its metabolites enhance the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model.

RationaleSeizures occur when the excitability of brain circuits is not sufficiently restrained by inhibitory mechanisms. Although modafinil is reported to reduce GABA-activated currents and extracellular GABA levels in the brain, the drug exerts anticonvulsant effects in animal studies.ObjectivesThe aim of this study was to determine the effects of modafinil and its metabolites (sulfone and carboxylic acid) on the anticonvulsant action of four classical antiepileptic drugs (AEDs)—carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA).MethodsAnticonvulsant activity was assessed with the maximal electroshock seizure threshold (MEST) test and MES test in mice. Brain concentrations of AEDs were measured to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects.ResultsIntraperitoneal injection of 75 mg kg−1 of modafinil or its metabolites significantly elevated the threshold for electroconvulsions in mice, whereas 50 mg kg−1 of each compound enhanced the anticonvulsant activity of CBZ, PHT, and VPA, but not that of PB. A 25-mg kg−1 dose of modafinil or its sulfone metabolite enhanced anticonvulsant activity of VPA. Modafinil and its metabolites (50 mg kg−1) did not alter total brain concentrations of PB and VPA but did elevate CBZ and PHT.ConclusionsEnhancement of anticonvulsant actions of VPA by modafinil in the mouse MES model is a pharmacodynamic effect. Collectively, our data suggest that modafinil may be a safe and beneficial adjunct to the therapeutic effects of AEDs in human patients.

Effect of cholecalciferol on the anticonvulsant action of some second generation antiepileptic drugs in the mouse model of maximal electroshock.

From a theoretical point of view, cholecalciferol (vitamin D3) as a precursor of calcitriol, a representative of secosteroids, may have neuroprotective properties and affect seizure phenomena. In the present study, interactions between cholecalciferol and three second generation antiepileptic drugs (oxcarbazepine, lamotrigine, and topiramate) were studied in the maximal electroshock test in mice. Effects of drugs on motor coordination, long-term memory and explorative behavior of animals were evaluated in the chimney test, passive-avoidance task and plus-maze test, respectively. Cholecalciferol applied ip at doses of 37.5-75μg/kg significantly raised the electroconvulsive threshold. Cholecalciferol, administered at the subthreshold dose of 18.75μg, potentiated the anticonvulsant activity of oxcarbazepine and lamotrigine, but did not change their brain concentrations, therefore the revealed interactions seem to be pharmacodynamic. Furthermore, the action of cholecalciferol was not dependent on its conversion to calcitriol. The anticonvulsant effect of topiramate was enhanced by cholecalciferol applied at the higher dose of 37.5μg/kg, at which it also increased the brain level of topiramate. As regards adverse effects, cholecalciferol, antiepileptic drugs, and their combinations did not significantly impair motor coordination or long-term memory in mice. Moreover, cholecalciferol did not show either anxiolytic or anxiogenic properties. Our findings show that cholecalciferol has not only its own anticonvulsant action but also enhances efficacy of certain antiepileptic drugs, at least in experimental conditions.

Seizure susceptibility to electroconvulsions or pentylenetetrazol after complete cerebral ischemia in rats due to cardiac arrest

BackgroundExperimental data provide evidence on the induction of a susceptibility to audiogenic seizures in rats surviving cardiac arrest and subsequent global brain ischemia. The aim of this study was to find out whether cardiac arrest in rats could affect seizure susceptibility in the long-term period of one and two months, following this event. Seizure susceptibility was evaluated against electroconvulsions and pentylenetetrazol-induced seizures. MethodsExperiments were conducted on 34 rats surviving cardiac arrest and 34 sham-operated animals which also had surgery but their hearts were not stopped. The threshold for electroconvulsions and pentylenetetrazol was calculated in 3 groups of 5–6 rats. The endpoint for electroconvulsions was the tonic hindlimb extension and for pentylenetetrazol-generalized clonic seizure. ResultsThe results indicate that cardiac arrest did not modify the threshold for electroconvulsions either one or two months, following the surgery. On the other hand, a significant reduction in the seizure threshold for pentylenetetrazol was noted one month after cardiac arrest. The median convulsive dose of pentylenetetrazol was decreased from 52.47mg/kg (sham-operated rats) to 34.03mg/kg of the convulsant for the induction of clonic seizure activity. This effect was not observed at two months after cardiac arrest. ConclusionsIt is evident that global brain ischemia is associated with a transient reduction in the convulsive threshold for pentylenetetrazol whilst the threshold for electroconvulsions remains unchanged.

Effect of N-(p-ethoxycarbonylphenylmethyl) -p-isopropoxyphenylsuccinimide on the anticonvulsant action of four classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Introduction and objective. The purpose of this study was to determine the effects of N-(p-ethoxycarbonylphenylmethyl)p-isopropoxyphenylsuccinimide (ECPM-IPPS), a new succinimide derivative, on the protective action of four classical antiepileptic drugs (AEDs): carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT) and valproate (VPA) in the mouse maximal electroshock (MES)-induced tonic seizure model. Materials and methods. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via ear-clip electrodes. Results. ECPM-IPPS administered (i.p.) at a dose of 150 mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05). Lower doses of ECPM-IPPS (50 and 100 mg/kg) had no significant impact on the threshold for electroconvulsions in mice. Moreover, ECPM-IPPS (100 mg/kg) did not significantly affect the anticonvulsant potency of CBZ, PB, PHT and VPA in the MES test in mice. Conclusions. ECPM-IPPS elevated the threshold for electroconvulsions in mice in a dose-dependent manner. However, ECPM-IPPS (100 mg/kg) did not affect the anticonvulsant action of various classical AEDs in the mouse MES model, making the combinations of ECPM-IPPS with CBZ, PB, PHT and VPA neutral, from a preclinical point of view.

SYM 2206 (a potent non-competitive AMPA receptor antagonist) elevates the threshold for maximal electroshock-induced seizures in mice

Abstract The aim of this study was to determine the effect of SYM 2206 (a potent non-competitive AMPA receptor antagonist) on the threshold for maximal electroshock (MEST)-induced seizures in mice. Electroconvulsions were produced in mice by means of a current (sinewave, 50 Hz, maximum 500 V, strength from 4 to 14 mA, 0.2-s stimulus duration, tonic hind limb extension taken as the endpoint) delivered via ear-clip electrodes. SYM 2206 administered systemically (i.p.), 30 min before the MEST test, at doses of 2.5 and 5 mg/kg, did not alter the threshold for maximal electroconvulsions in mice. In contrast, SYM 2206 at doses of 10 and 20 mg/kg significantly elevated the threshold for maximal electroconvulsions in mice (P&lt;0.01 and P&lt;0.001). Linear regression analysis of SYM 2206 doses and their corresponding threshold increases allowed for the determination of threshold increasing doses by 20% and 50% (TID20 and TID50 values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID20 and TID50 values for SYM 2206 were 4.25 and 10.56 mg/kg, respectively. SYM 2206 dose-dependently increased the threshold for MEST-induced seizures, suggesting the anticonvulsant action of the compound in this seizure model in mice.

Effect of N-(m-bromoanilinomethyl)-p-isopropoxyphenylsuccinimide on the anticonvulsant action of four classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Abstract The purpose of this study was to determine the effects of N-(m-bromoanilinomethyl)- p-isopropoxyphenylsuccinimide (BAM-IPPS - a new succinimide derivative) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) in the mouse maximal electroshock (MES)-induced tonic seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via ear-clip electrodes. BAM-IPPS administered (i.p.) at a dose of 150 mg/kg significantly elevated the threshold for electroconvulsions in mice (P&lt;0.05). Lower doses of BAM-IPPS (50 and 100 mg/kg) had no significant impact on the threshold for electroconvulsions in mice. Moreover, BAM-IPPS (100 mg/kg) did not significantly affect the anticonvulsant potency of CBZ, PB, PHT and VPA in the mouse MES model. BAM-IPPS elevated the threshold for electroconvulsions in mice in a dosedependent manner. However, BAM-IPPS (100 mg/kg) did not affect the anticonvulsant action of various classical AEDs in the mouse MES model, making the combinations of BAM-IPPS with CBZ, PB, PHT and VPA neutral, from a preclinical point of view.

Reboxetine and its influence on the action of classical antiepileptic drugs in the mouse maximal electroshock model

BackgroundOur previous studies revealed that different classes of antidepressant drugs differently affect seizure phenomena. Continuing our research in this field, in the present study we wanted to investigate the influence of acute and chronic treatment with reboxetine, a selective norepinephrine reuptake inhibitor, on the anticonvulsant action of classical antiepileptic drugs. MethodsExperiments were conducted in the model of electroconvulsive threshold and maximal electroshock in mice. Motor coordination was evaluated in the chimney test and long term memory in the step-through passive avoidance task. Brain concentrations of antiepileptic drugs were detected by fluorescence polarization immunoassay. ResultsAcute treatment with reboxetine (8–16mg/kg) significantly raised the electroconvulsive threshold. In contrast, chronic reboxetine (2–16mg/kg) did not affect this parameter. Single administration of the antidepressant applied at its subthreshold doses enhanced the action of valproate, carbamazepine and phenobarbital. The antielectroshock effect of phenytoin was also potentiated by acute reboxetine, but only at doses increasing the threshold. Repeated administration of reboxetine (8–12mg/kg) enhanced the anticonvulsant action of carbamazepine, but not that of three remaining antiepileptic drugs. Neither acute nor chronic reboxetine changed the brain concentrations of valproate, carbamazepine, phenytoin or phenobarbital. Therefore, all revealed interactions seem to be pharmacodynamic. In terms of undesired effects, acute/chronic reboxetine and its combinations with classical antiepileptic drugs did not significantly impair motor performance or long-term memory in mice. ConclusionsAs far as the obtained data can be extrapolated into clinical conditions, it seems that reboxetine may be safely used in the treatment of depressive disorders in epileptic patients.

Interaction of famotidine, an H2 histamine receptor antagonist, with conventional antiepileptic drugs in mice

H2 histamine receptors are localized postsynaptically in the CNS. The aim of this study was to evaluate the effects of acute (1 day) and prolonged (7 day) administration of the H2 histamine receptor antagonist, famotidine, on the anticonvulsant activity of conventional antiepileptic drugs (AEDs; valproate, carbamazepine, diphenylhydantoin and phenobarbital) against maximal electroshock (MES)-induced seizures in mice. In addition, the effects of these drugs alone or in combination with famotidine were studied on motor performance and long-term memory. The influence of H2 receptor antagonist on brain concentrations and free plasma levels of the antiepileptic drugs was also evaluated. After acute or prolonged administration of famotidine (at dose of 10mg/kg) the drug raised the threshold for electroconvulsions. No effect was observed on this parameter at lower doses. Famotidine (5mg/kg), given acutely, significantly enhanced the anticonvulsant activity of valproate, which was expressed by a decrease in ED50. After the 7-day treatment, famotidine (5mg/kg) increased the anticonvulsant activity of diphenylhydantoin against MES. Famotidine (5mg/kg), after acute and prolonged administration, combined with valproate, phenobarbital, diphenylhydantoin and carbamazepine did not alter their free plasma levels. In contrast, brain concentrations of valproate were elevated for 1-day treatment with famotidine (5mg/kg). Moreover, famotidine co-applied with AEDs, given prolonged, worsened motor coordination in mice treated with carbamazepine or diphenylhydantoin. In contrast this histamine antagonist, did not impair the performance of mice evaluated in the long-term memory task. The results of this study indicate that famotidine modifies the anticonvulsant activity of some antiepileptic drugs.

A locus on mouse Ch10 influences susceptibility to limbic seizure severity: fine mapping andin silicocandidate gene analysis

Identification of genes contributing to mouse seizure susceptibility can reveal novel genes or pathways that provide insight into human epilepsy. Using mouse chromosome substitution strains and interval-specific congenic strains (ISCS), we previously identified an interval conferring pilocarpine-induced limbic seizure susceptibility on distal mouse chromosome 10 (Ch10). We narrowed the region by generating subcongenics with smaller A/J Ch10 segments on a C57BL/6J (B6) background and tested them with pilocarpine. We also tested pilocarpine-susceptible congenics for 6-Hz ECT (electroconvulsive threshold), another model of limbic seizure susceptibility, to determine whether the susceptibility locus might have a broad effect on neuronal hyperexcitability across more than one mode of limbic seizure induction. The ISCS Line 1, which contained the distal 2.7 Mb segment from A/J (starting at rs29382217), was more susceptible to both pilocarpine and ECT. Line 2, which was a subcongenic of Line 1 (starting at rs13480828), was not susceptible, thus defining a 1.0 Mb critical region that was unique to Line 1. Bioinformatic approaches identified 45 human orthologs within the unique Line 1 susceptibility region, the majority syntenic to human Ch12. Applying an epilepsy network analysis of known and suspected excitability genes and examination of interstrain genomic and brain expression differences revealed novel candidates within the region. These include Stat2, which plays a role in hippocampal GABA receptor expression after status epilepticus, and novel candidates Pan2, Cdk2, Gls2 and Cs, which are involved in neural cell differentiation, cellular remodeling and embryonic development. Our strategy may facilitate discovery of novel human epilepsy genes.

Effect of amlodipine on the antiepileptic action of lamotrigine, gabapentin and topiramate on maximal electroshock induced seizures in mice

Background: The development of newer classes of antiepileptic drugs has created several opportunities for the treatment of epilepsy. Aims & Objective: The present study was designed to assess the$effect of amlodipine on the antiepileptic action of lamotrigine, gabapentin and topiramate in the mouse maximal electroshock-induced seizure model. Materials and Methods: 300 Adult male mice were divided into 8 groups: (1) control to determine CS50; (2) amlodipine at doses of 5 mg/kg, 10 mg/kg and 20 mg/kg; (3) to determine ED50 of lamotrigine alone; (4) to determine ED50 of lamotrigine after amlodipine; (5) to determine ED50 of gabapentin alone; (6) to determine ED50 of gabapentin after amlodipine; (7) to determine ED50 of topiramate alone; (8) to determine ED50 of topiramate after amlodipine. Results: It was found that amlodipine (up to 20 mg/kg), did not affect the electroconvulsive threshold in mice thus, it has no anticonvulsant effect. Moreover, amlodipine at doses of 10 and 20 mg/kg significantly enhanced the antiseizure action of the three anti convulsant drugs. Amlodipine through the blockade of N- and P/Q type calcium channels enhances the effects of lamotrigine related to the reduction of glutamate release from neurons. It binds to the alpha2 sigma subunit of voltage gated calcium channels, this may explain the observed interaction between gabapentin and amlodipine in the maximal electroshock-induced seizures in mice. Topiramate inhibits voltage-dependent sodium and L-type calcium channels. Its effect on calcium channels may explain the interaction with amlodipine. Conclusion: Amlodipine potentiates the anticonvulsant action of lamotrigine, gabapentin and topiramate.

Ivabradine (a hyperpolarization activated cyclic nucleotide-gated channel blocker) elevates the threshold for maximal electroshock-induced tonic seizures in mice

BackgroundThe aim of this study was to determine the effect of ivabradine (a hyperpolarization activated cyclic nucleotide-gated channel (HCN) blocker) on the threshold for maximal electroshock (MEST)-induced tonic seizures in mice. MethodsElectroconvulsionswere produced inmice bymeans of a current (sine-wave, 50Hz,maximum500V, strength from3–10mA, ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). ResultsIvabradine administered intraperitoneally (ip), 60min before the MEST test, at doses of 5 and 10mg/kg, did not alter the threshold for maximal electroconvulsions in mice. In contrast, ivabradine at doses of 15 and 20mg/kg significantly elevated the threshold for maximal electroconvulsions in mice (p<0.05 and p<0.001, respectively). Linear regression analysis of ivabradine doses and their corresponding threshold increases allowed determination of the threshold increasing doses by 20 and 50% (TID20 and TID50 values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID20 and TID50 values for ivabradine were 8.70 and 18.29mg/kg, respectively. ConclusionsBased on this preclinical study, one can ascertain that ivabradine dose-dependently increased the threshold for MEST-induced seizures, suggesting the antiseizure activity of the compound in this seizure model in mice.

Evaluation of anxiolytic-like, anticonvulsant, antidepressant-like and antinociceptive properties of new 2-substituted 4-hydroxybutanamides with affinity for GABA transporters in mice

PurposeThe inhibition of plasma membrane GABA transporters (GATs) is responsible for anxiolytic-like, anticonvulsant, antinociceptive and antidepressant-like effects in mice. It also influences animals' motor coordination and their sensitivity to ethanol. The aim of this study was to assess the pharmacological activity of two novel 2-substituted 4-hydroxybutanamides (BM 130 and BM 131) in some screening models. An attempt has been made to establish the relationship between the inhibition of GAT subtype and the observed in vivo activity. MethodsThe affinity for GAT subtypes was evaluated by means of [3H]GABA uptake assay. It indicated that BM 130 inhibited GAT1 and GAT2, whereas BM 131 inhibited GAT1 and GAT3. In mice anxiolytic-like, antidepressant-like, anticonvulsant and antinociceptive properties of the test compounds were assessed. Their influence on motor coordination, locomotor activity and the ability to potentiate effects of subnarcotic doses of ethanol was also tested. ResultsBoth compounds administered intraperitoneally exerted a significant anxiolytic-like effect in the four plate test with ED50 values 3.4 and 7.9mg/kg, respectively. At 30mg/kg they reduced duration of immobility in the forced swim test for 33% and 19%, respectively. They had no effect on electroconvulsive threshold or pain reactivity in the hot plate assay but they were antinociceptive in the acetic acid-induced writhing test (ED50 values were 12.7 and 18.6mg/kg, respectively) and in both phases of the formalin test (ED50 values in the first phase were 10.2 and 2.1mg/kg for BM 130 and BM 131, respectively). No motor adverse effects were observed in mice pretreated with the test compounds in the rotarod or chimney tests but BM 131 caused a transient but statistically significant decrease of animals' locomotor activity. ConclusionsIn mice BM 130 and BM 131 have anxiolytic-like, antidepressant-like and antinociceptive properties which can be attributed to their affinity for not only mGAT1 but also mGAT2–4.

Effects of N-(morpholinomethyl)- p-isopropoxyphenylsuccinimide on the protective action of different classical antiepileptic drugs against maximal electroshock-induced tonic seizures in mice

BackgroundThe aim of this study was to determine the effects of N-(morpholinomethyl)-p-isopropoxy-phenylsuccinimide (MMIPPS) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) against maximal electroshock (MES)-induced seizures in mice. MethodsTonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Total brain concentrations of AEDs were measured to determine the characteristics of interaction between MMIPPS and classical AEDs in the mouse MES model. ResultsMMIPPS administered intraperitoneally (ip) at 100mg/kg significantly elevated the threshold for electroconvulsions in mice (p<0.01). MMIPPS at doses of 25 and 50mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, MMIPPS (50mg/kg) significantly enhanced the anticonvulsant activity of PB and VPA(p<0.05), but not that of CBZ or PHT, in the MES test in mice. Pharmacokinetic studies revealed that MMIPPS (50mg/kg) did not alter total brain concentrations of PB, but significantly elevated total brain concentrations of VPA in mice (p<0.05). ConclusionsThe enhanced anticonvulsant action of PB byMMIPPS in themouseMESmodel and lack of any pharmacokinetic interaction between drugs make the combination of MMIPPS with PB of pivotal importance for further experimental and clinical studies. Pharmacokinetic increase in total brain VPAconcentration seems to be responsible for the enhanced anticonvulsant action of VPAby MMIPPS in the mouse MES model. The combinations of MMIPPS with CBZ and PHT are neutral from a preclinical viewpoint.

Effect of acute and chronic tianeptine on the action of classical antiepileptics in the mouse maximal electroshock model

BackgroundThe aim of the study was to analyze the influence of acute and chronic treatment with tianeptine, an antidepressant selectively accelerating presynaptic serotonin reuptake, on the protective activity of classical antiepileptic drugs in the maximal electroshock test in mice. MethodsElectroconvulsions were produced by means of an alternating current (50Hz, 25mA, 0.2 s) delivered via ear-clip electrodes. Motor impairment and long-term memory deficits in animals were quantified in the chimney test and in the passive-avoidance task, respectively. Brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay. ResultsAcute and chronic treatment with tianeptine (25–50mg/kg) did not affect the electroconvulsive threshold. Furthermore, tianeptine applied in both acute and chronic protocols enhanced the anticonvulsant action of valproate and carbamazepine, but not that of phenytoin. Neither acute nor chronic tianeptine changed the brain concentrations of valproate, carbamazepine or phenytoin. On the other hand, both single and chronic administration of tianeptine diminished the brain concentration of phenobarbital. In spite of this pharmacokinetic interaction, the antidepressant enhanced the antielectroshock action of phenobarbital. In terms of adverse effects, acute/chronic tianeptine (50mg/kg) and its combinations with classic antiepileptic drugs did not impair motor performance or long-term memory in mice. ConclusionThe obtained results justify the conclusion that tianeptine may be beneficial in the treatment of depressive disorders in the course of epilepsy.

Trazodone reduces the anticonvulsant action of certain classical antiepileptics in the mouse maximal electroshock model

BackgroundThe aim of the study was to examine effects of an acute and chronic treatment with trazodone, a serotonin antagonist and reuptake inhibitor (SARI), on the protective activity of four classical antiepileptic drugs provided in the maximal electroshock test in mice. MethodsElectroconvulsions were produced in mice by means of an alternating current (50Hz, 25mA, 0.2s) and delivered via earclip electrodes. Motor impairment in animals were assessed in the chimney test, and long-term memory deficits were quantified in the passive-avoidance task. Brain concentrations of antiepileptic drugs were analyzed by fluorescence polarization immunoassay. ResultsThe obtained results showed that a single administration of trazodone (up to 40mg/kg) did not influence the electroconvulsive threshold. In contrast, chronic treatment with the antidepressant (40mg/kg) significantly increased this parameter. Furthermore, both single and chronic administration of trazodone reduced the anticonvulsant effect of phenytoin and carbamazepine against the maximal electroshock. However, the antidepressant remained without effect on the anticonvulsant action of valproate and phenobarbital. Some interactions between trazodone and antiepileptic drugs may have a pharmacodynamic background. Both, acute and chronic treatment with the antidepressant diminished the brain concentration of phenytoin. Chronic trazodone lowered the brain levels of carbamazepine and phenobarbital. Moreover, acute and chronic trazodone increased the valproate concentration in the brain. As regards undesired effects, acute and chronic trazodone (40mg/kg), alone and in combination with phenytoin, significantly impaired long-term memory in tested animals, evaluated in the passive avoidance task. Acute trazodone (40mg/kg) alone and combined with phenytoin produced also significant motor deficits in mice, as measured in the chimney test. ConclusionThe obtained results allow to conclude that trazodone is not a good candidate for an antidepressant drug in epileptic patients.