Threshold For Electroconvulsions In Mice Research Articles

Effect of acute and chronic exposure to lovastatin on the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Numerous studies indicate neuroprotective activity of statins, commonly used cholesterol lowering drugs in epilepsy and several other neurological diseases. Promising anti-convulsant and neuroprotective effects of statins, attributed to their anti-excitotoxic and anti-inflammatory action were reported in several animals’ seizure models.To determine the effects of acute (single) and chronic (once daily for 7 consecutive days) administration of lovastatin on the protective activity of four classical antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin and valproate in the mouse maximal electroshock seizure model.Seizure activity (maximal electroconvulsions) in mice were generated by alternating current delivered via ear-clip electrodes. Adverse-effect profile of lovastatin combinations with the tested antiepileptic drugs was assessed in the chimney test (motor performance). Total brain concentrations of antiepileptic drugs were evaluated with the fluorescence polarization immunoassay technique as a measure of the pharmacokinetic interaction between drugs.Lovastatin administered acutely or chronically (5–20 mg/kg) did not significantly affect the threshold for electroconvulsions in mice. Acute lovastatin (10 mg/kg) significantly enhanced the anticonvulsant effect of valproate, which was accompanied with a 34% significant increase in total brain concentration of valproate. Acute lovastatin in combination with phenytoin impaired motor performance by notably decreasing the TD50 value of phenytoin. Chronic lovastatin (10 mg/kg) markedly enhanced the anticonvulsant potential of phenytoin.Acute lovastatin increased anticonvulsant action of valproate but also significantly raised level of valproate in brain after combined administration suggesting pharmacokinetic nature of interaction. The combinations of chronic lovastatin combined with phenytoin can potentially enhance the anticonvulsant potency of phenytoin.

Influence of MPEP (a selective mGluR5 antagonist) on the anticonvulsant action of novel antiepileptic drugs against maximal electroshock-induced seizures in mice

The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)pyridine (MPEP — a selective antagonist for the glutamate metabotropic receptor subtype mGluR5) on the protective action of some novel antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) against maximal electroshock-induced seizures in mice. Brain concentrations of antiepileptic drugs were measured to determine whether MPEP altered pharmacokinetics of antiepileptic drugs. Intraperitoneal injection of 1.5 and 2mg/kg of MPEP significantly elevated the threshold for electroconvulsions in mice, whereas MPEP at a dose of 1mg/kg considerably enhanced the anticonvulsant activity of pregabalin and topiramate, but not that of lamotrigine or oxcarbazepine in the maximal electroshock-induced seizures in mice. Pharmacokinetic results revealed that MPEP (1mg/kg) did not alter total brain concentrations of pregabalin and topiramate, and the observed effect in the mouse maximal electroshock seizure model was pharmacodynamic in nature. Collectively, our preclinical data suggest that MPEP may be a safe and beneficial adjunct to the therapeutic effects of antiepileptic drugs in human patients.

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 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.

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.

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.

Influence of 5-(3-chlorophenyl)-4-(4-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione on the anticonvulsant action of 4 classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

BackgroundThe aim of this study was to determine the effects of 5-(3-chlorophenyl)-4-(4-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP10) on the protective action of 4 classical antiepileptic drugs – carbamazepine, phenobarbital, phenytoin and valproate – against maximal electroshock-induced seizures in mice. MethodsTonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by an electric current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured, together with total brain antiepileptic drug concentrations. ResultsTP10 administered intraperitoneally at 10mg/kg significantly elevated the threshold for electroconvulsions in mice. TP10 at doses of 2.5 and 5mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP10 (5mg/kg) significantly enhanced the anticonvulsant activity of valproate, but not that of carbamazepine, phenobarbital or phenytoin in the maximal electroshock seizure test in mice. Pharmacokinetic experiments revealed that TP10 significantly elevated total brain concentrations of valproate in mice. ConclusionThe enhanced anticonvulsant action of valproate by TP10 in the mouse maximal electroshock-induced seizure model was associated with a pharmacokinetic increase in total brain valproate concentrations in mice. The combinations of TP10 with carbamazepine, phenobarbital and phenytoin were neutral from a preclinical viewpoint.

Effect of 4-(4-bromophenyl)-5-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

The aim of this study was to determine the effects of 4-(4-bromophenyl)-5-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP4—a new S-triazole derivative possessing anticonvulsant properties in preclinical studies) on the protective action of four different classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice.Results indicate that TP4 administered intraperitoneally at doses of 75 and 100mg/kg significantly elevated the threshold for electroconvulsions in mice. TP4 at doses of 12.5, 25, 37.5 and 50mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP4 (50mg/kg) significantly enhanced the anticonvulsant activity of carbamazepine, phenobarbital and valproate, but not that of phenytoin in the maximal electroshock seizure test in mice. TP4 at 25mg/kg significantly potentiated the anticonvulsant action of carbamazepine, but not that of phenobarbital, phenytoin and valproate in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that TP4 significantly elevated total brain concentrations of carbamazepine and valproate, having no impact on total brain concentrations of phenobarbital in mice.In conclusion, the enhanced anticonvulsant action of phenobarbital by TP4 was probably pharmacodynamic in nature and, therefore, the combination of TP4 with phenobarbital is worthy of consideration while extrapolating the results from this study into clinical settings. The enhanced anticonvulsant action of carbamazepine and valproate by TP4 in the mouse maximal electroshock-induced seizure model was associated with pharmacokinetic increases in total brain concentrations of the antiepileptic drugs in mice. The combination of TP4 with phenytoin was neutral from a preclinical point of view.

Influence of N-hydroxymethyl-p-isopropoxyphenylsuccinimide on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Experimental epileptology is mainly focused on searching for some active compounds suppressing seizures that could become efficacious antiepileptic drugs. Accumulating evidence indicates that succinimide derivatives would be good candidates for novel antiepileptic drugs. Therefore, the aim of this study was to determine the effects of N-hydroxymethyl-p-isopropoxyphenyl-succinimide (HMIPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the maximal electroshock-induced seizure test in mice. 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, 0.2s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Results indicate that HMIPPS administered intraperitoneally at 100mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05). HMIPPS at doses of 12.5, 25 and 50mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, HMIPPS (50mg/kg) significantly enhanced the anticonvulsant activity of phenobarbital and valproate in the mouse maximal electroshock-induced seizure model by reducing their median effective doses (ED(50) values) from 23.25mg/kg to 16.82 mg/kg (P<0.01; for phenobarbital) and from 259.3mg/kg to 189.7 mg/kg (P<0.001; for valproate), respectively. In contrast, HMIPPS (50mg/kg) had no impact on the protective action of carbamazepine or phenytoin in the maximal electroshock seizure test in mice. HMIPPS (25mg/kg) significantly potentiated the anticonvulsant action of valproate by reducing its ED(50) value from 259.3mg/kg to 210.6 mg/kg (P>0.05), but not that of phenobarbital, phenytoin and carbamazepine in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that HMIPPS did not alter total brain concentrations of phenobarbital or valproate in mice. Moreover, none of the examined combinations of HMIPPS (50mg/kg) with carbamazepine, phenobarbital, phenytoin and valproate (at their ED(50) values from the maximal electroshock-induced seizure test) affected motor coordination in the chimney test, long-term memory in the passive avoidance task, and muscular strength in the grip-strength test in mice, indicating no possible acute adverse effects in animals. In conclusion, the enhanced anticonvulsant action of phenobarbital and valproate by HMIPPS in the mouse maximal electroshock-induced seizure model, lack of pharmacokinetic interactions and no potential acute adverse effects make the combinations of HMIPPS with phenobarbital and valproate worthy of consideration for further experimental and clinical studies. The combinations of HMIPPS with carbamazepine and phenytoin are neutral from a preclinical viewpoint.

Effects of three N-(carboxyanilinomethyl) derivatives of p-isopropoxyphenylsuccinimide on the anticonvulsant action of carbamazepine, phenobarbital, phenytoin and valproate in the mouse maximal electroshock-induced seizure model

The aim of the study was to determine the influence of N-( ortho-carboxyanilinomethyl)-p-isopropoxyphenylsuccinimide [ o-CAMIPPS], N-( meta-carboxyanilinomethyl)-p-isopropoxyphenylsuccinimide [ m-CAMIPPS], and N-( para-carboxyanilinomethyl)-p-isopropoxyphenylsuccinimide [ p-CAMIPPS] on the protective activity of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure model. The results indicate that all tested succinimide derivatives administered intraperitoneally at doses of 75 and 150 mg/kg significantly elevated the threshold for electroconvulsions in mice. Succinimide derivatives at a dose of 37.5 mg/kg had no effect on the threshold for electroconvulsions in mice. Furthermore, o-CAMIPPS (37.5 mg/kg) significantly reduced the anticonvulsant activity of carbamazepine, but not that of phenobarbital, phenytoin and valproate in the maximal electroshock-induced seizures in mice. Anticonvulsant efficacy of carbamazepine, phenobarbital, phenytoin and valproate in the maximal electroshock-induced seizures in mice was not changed after administration of m-CAMIPPS or p-CAMIPPS. Pharmacokinetic experiment revealed that o-CAMIPPS significantly increased total brain concentrations of carbamazepine in mice. In conclusion, the reduced anticonvulsant action of carbamazepine by o-CAMIPPS in the maximal electroshock-induced seizures, despite the increased total brain carbamazepine concentrations after combined administration of carbamazepine with o-CAMIPPS, may suggest the antagonistic interaction between drugs. The combinations of m-CAMIPPS or p-CAMIPPS with carbamazepine, phenobarbital, phenytoin and valproate were neutral from a preclinical viewpoint.

Effect of sildenafil on the anticonvulsant action of classical and second‐generation antiepileptic drugs in maximal electroshock‐induced seizures in mice

The goal of the present study was to evaluate the effects of sildenafil on the threshold for electrically induced seizures in mice. In addition, interactions between sildenafil and classical and second-generation antiepileptic drugs (AEDs), that is, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC) were evaluated. Two electroconvulsive tests were used: maximal electroshock seizure threshold (MEST) and maximal electroshock seizure (MES) tests in mice. Acute adverse effects of the studied combinations were investigated in the chimney test, step-through passive avoidance task, and grip-strength test. Total brain and free plasma concentrations of AEDs were also determined. Sildenafil raised the threshold for electroconvulsions in a dose-dependent manner. It also increased the anticonvulsant activity of CBZ, VPA, and TPM in the MES test, whereas the activity of the remaining AEDs was not significantly changed. Sildenafil increased total brain and free (protein unbound) plasma CBZ concentrations and total brain VPA concentration. Neither sildenafil nor its coadministration with the studied AEDs affected motor coordination and long-term memory in mice. Interestingly, sildenafil dose-dependently enhanced the skeletal muscle strength in mice, although combinations of sildenafil with AEDs were ineffective in this respect. Sildenafil significantly raised the threshold for electroconvulsions in mice without any impairment of motor performance and long-term memory, but it enhanced muscle strength. Treatment of patients on CBZ or VPA with sildenafil may not be recommended due to pharmacokinetic interactions. Coadministration of sildenafil with other AEDs, especially with TPM, seems to be a reasonable choice.

Effect of p-isopropoxyphenylsuccinimide monohydrate on the anticonvulsant action of carbamazepine, phenobarbital, phenytoin and valproate in the mouse maximal electroshock-induced seizure model

This study was designed to determine the effects of p-isopropoxyphenylsuccinimide monohydrate (IPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure model.Tonic 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. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Results indicate that IPPS administered intraperitoneally (ip) at doses of 75 and 150mg/kg significantly elevated the threshold for electroconvulsions in mice. IPPS at lower doses of 18.75 and 37.5mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, 37.5mg/kg IPPS significantly enhanced the anticonvulsant activity of phenytoin and valproate, but not that of carbamazepine or phenobarbital, in the maximal electroshock seizure test in mice. IPPS (18.75mg/kg) had no impact on the antiseizure action of phenytoin and valproate against maximal electroshock-induced seizures in mice. Pharmacokinetic experiments revealed that IPPS did not alter total brain concentrations of phenytoin or valproate in mice.In conclusion, the enhanced anticonvulsant action of phenytoin and valproate by IPPS in the mouse maximal electroshock-induced seizure model and lack of pharmacokinetic interactions make the combinations of IPPS with phenytoin and valproate of pivotal importance for further experimental and clinical studies. The combinations of IPPS with carbamazepine and phenobarbital are neutral from a preclinical viewpoint.

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.

Influence of aminophylline on the anticonvulsive action of gabapentin in the mouse maximal electroshock seizure threshold model

Accumulating evidence indicates that aminophylline [theophylline(2) x ethylenediamine] markedly attenuates the anticonvulsant action of conventional antiepileptic drugs in experimental animal models of epilepsy and evokes severe seizure activity in patients treated with this methylxanthine. The objective of this study was to determine the influence of acute (single) and chronic (twice daily for 14 consecutive days) treatments with aminophylline on the anticonvulsant potential of gabapentin (a second-generation antiepileptic drug) in the mouse maximal electroshock seizure threshold model. Additionally, the effects of acute and chronic administration of aminophylline on the adverse effect potential of gabapentin in terms of motor coordination impairment were assessed in the chimney test. To evaluate pharmacokinetic characteristics of interaction between drugs, total brain concentrations of gabapentin and theophylline were estimated with high-pressure liquid chromatography and fluorescence polarization immunoassay, respectively. Results indicated that gabapentin (at doses of 75 and 100 mg/kg, i.p.) increased the threshold for electroconvulsions in mice. Aminophylline in non-convulsive doses of 50 and 100 mg/kg (i.p.), both in acute and chronic experiments, did not attenuate the anticonvulsant potential of gabapentin in the maximal electroshock seizure threshold test in mice. Similarly, aminophylline at a dose of 100 mg/kg had no impact on the adverse effect potential of gabapentin in the chimney test. Pharmacokinetic evaluation of total brain concentrations of gabapentin and theophylline revealed no significant changes in total brain concentrations of the drugs after both, acute and chronic applications of aminophylline in combination with gabapentin. The data show that aminophylline did not alter the ability of gabapentin to protect mice against seizures induced by electroconvulsive shock. The observed interaction between gabapentin and aminophylline in both acute and chronic experiments was pharmacodynamic in nature.

Time–course and dose–response relationships of imperatorin in the mouse maximal electroshock seizure threshold model

This study was designed to evaluate the anticonvulsant effects of imperatorin (a furanocoumarin isolated from fruits of Angelica archangelica) in the mouse maximal electroshock seizure threshold model. The threshold for electroconvulsions in mice was determined at several times: 15, 30, 60 and 120 min after i.p. administration of imperatorin at increasing doses of 10, 20, 30, 40, 50 and 100 mg/kg. The evaluation of time–course relationship for imperatorin in the maximal electroshock seizure threshold test revealed that the agent produced its maximum antielectroshock action at 30 min after its i.p. administration. In this case, imperatorin at doses of 50 and 100 mg/kg significantly raised the threshold for electroconvulsions in mice by 38 and 68% ( P < 0.05 and P < 0.001), respectively. The antiseizure effects produced by imperatorin at 15, 60 and 120 min after its systemic (i.p.) administration were less expressed than those observed for imperatorin injected 30 min before the maximal electroshock seizure threshold test. Based on this study, one can conclude that imperatorin produces the anticonvulsant effect in the maximal electroshock seizure threshold test in a dose-dependent manner.

1-Methyl-1,2,3,4-tetrahydroisoquinoline enhances the anticonvulsant action of carbamazepine and valproate in the mouse maximal electroshock seizure model

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ – an endogenous parkinsonism-preventing substance) administered intraperitoneally at a dose of 20 mg/kg considerably elevated the threshold for electroconvulsions in mice from 6.4 to 8.4 mA ( P < 0.05). In contrast, the agent administered at 5 and 10 mg/kg had no significant impact on the electroconvulsive threshold in mice. Moreover, 1-MeTHIQ (at a subthreshold dose of 10 mg/kg) potentiated the anticonvulsant action of valproate (VPA) against maximal electroshock (MES)-induced seizures in mice, reducing its median effective dose (ED 50) from 232 to 170 mg/kg ( P < 0.001). Similarly, 1-MeTHIQ (at 10 mg/kg) enhanced the antielectroshock activity of carbamazepine (CBZ) in mice, decreasing its ED 50 from 10.8 to 7.8 mg/kg ( P < 0.05). In contrast, 1-MeTHIQ (at 10 mg/kg) did not affect the anticonvulsant action of phenytoin and phenobarbital against MES-induced seizures in mice. The evaluation of acute neurotoxic effects of the studied antiepileptic drugs (AEDs) in combination with 1-MeTHIQ, as regards motor coordination impairment in the chimney test, revealed no significant changes in median toxic doses (TD 50) of conventional AEDs after systemic administration of 1-MeTHIQ (up to 10 mg/kg). Pharmacokinetic characterization of interactions between 1-MeTHIQ (10 mg/kg) and VPA (170 mg/kg) or CBZ (7.8 mg/kg) revealed no significant changes in total brain concentrations of CBZ and VPA, indicating that the observed enhancement of antiseizure effects of CBZ and VPA by 1-MeTHIQ was pharmacodynamic in nature. Based on our preclinical study, it may be concluded that 1-MeTHIQ exerts the anticonvulsant effects increasing the threshold for electroconvulsions and potentiating the antiseizure action of CBZ and VPA against maximal electroshock. The antiseizure properties of 1-MeTHIQ (an endogenous parkinsonism-preventing substance) and its exact physiological role in the brain need extensive examination in further neuropharmacological studies.

Influence of the combined treatment of LY 300164 (an AMPA/kainate receptor antagonist) with adenosine receptor agonists on the electroconvulsive threshold in mice

7-Acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7 H-1,3-dioxolo-4,5 H-2,3-benzodiazepine hydrochloride (LY 300164; a selective noncompetitive AMPA/kainate antagonist; 2 mg/kg) and N 6-2-(4-aminophenyl)ethyl-adenosine (APNEA; a nonselective adenosine A 1/A 3 receptor agonist; 2 and 3 mg/kg) significantly raised the threshold for electroconvulsions in mice. In contrast, 5′- N-ethylcarboxamidoadenosine (NECA; a nonselective adenosine A 1/A 2 receptor agonist; up to 1 mg/kg) did not affect the electroconvulsive threshold. The combined treatment of LY 300164 with NECA or APNEA was superior to single-drug medication as regards their protective action in this seizure model. Moreover, the combinations of LY 300164 with either NECA or APNEA were devoid of motor impairment, although they produced a significant long-term memory deficit. Measurement of the plasma levels of LY 300164 alone and in combination with APNEA or NECA did not suggest pharmacokinetic phenomena as an explanation for the interaction between these drugs. APNEA did not influence the plasma concentration of LY 300164. Moreover, NECA even significantly decreased the plasma levels of the AMPA/kainate antagonist. The present study clearly indicates a strong positive interaction in terms of anticonvulsant activity between LY 300164 and the drugs acting via adenosine receptors.

Interaction of the neurosteroid alphaxalone with conventional antiepileptic drugs in different types of experimental seizures

A number of neurosteroids exert antiseizure and/or neuroprotective properties. The aim of this study was to evaluate the effect of the neurosteroid alphaxalone on the protective action of conventional antiepileptics in four seizure tests. Alphaxalone (up to 5 mg/kg) did not exert a significant action against amygdala-kindled seizures in rats, or against pentetrazole- or aminophylline-induced convulsions in mice. The neuroactive steroid at the dose of 2.5 mg/kg significantly raised the threshold for electroconvulsions in mice. At 2.5 mg/kg, alphaxalone diminished the protective activity of valproate against maximal electroshock and at 2.5–5 mg/kg against pentetrazole-induced seizures in mice. However, alphaxalone (2.5 mg/kg) did not affect the protective activity of carbamazepine, diphenylhydantoin, phenobarbital or clonazepam against maximal electroshock and at 5 mg/kg did not affect that of phenobarbital, clonazepam and ethosuximide against pentetrazole-induced convulsions. Insignificant results were also obtained in the case of co-administration of alphaxalone with phenobarbital, valproate, clonazepam and carbamazepine against aminophylline-evoked seizures in mice. Also, in the kindling model of epilepsy, combinations of the neuroactive steroid (2.5 mg/kg) with valproate, carbamazepine, phenobarbital, diphenylhydantoin or clonazepam at their subprotective doses did not result in pro- or anticonvulsant activity. Valproate (284 mg/kg; the dose used in combination with alphaxalone) produced significant memory deficits in mice. Alphaxalone (2.5 mg/kg), valproate (at its ED50 value of 226 mg/kg) and the combination of valproate (284 mg/kg) with alphaxalone (2.5 mg/kg) did not affect long-term memory, evaluated in the passive avoidance task with mice. Alphaxalone administered alone or in combination with valproate caused no motor impairment in experimental animals. Finally, alphaxalone (2.5 and 5 mg/kg) significantly increased the free plasma levels of valproate, strongly indicating that the neuroactive steroid-induced reduction of the protective activity of valproate is not related to pharmacokinetic phenomena. Summing up, alphaxalone does not seem to be a promising candidate for adjunctive treatment of epilepsy.

2-Chloroadenosine, a preferential agonist of adenosine A 1 receptors, enhances the anticonvulsant activity of carbamazepine and clonazepam in mice

2-Chloroadenosine (0.25–1 mg/kg) significantly raised the threshold for electroconvulsions in mice. This preferential adenosine A 1 receptor agonist (at 0.125 mg/kg) significantly potentiated the protective activity of carbamazepine against maximal electroshock-induced seizures in mice. 2-Chloroadenosine (1 mg/kg) showed also anticonvulsive efficacy against pentylenetetrazol-evoked seizures, raising the CD 50 value for pentylenetetrazol from 77.2 to 93.7 mg/kg. The drug (at 0.5 mg/kg) significantly enhanced the protective action of clonazepam in this test, decreasing its ED 50 value from 0.033 to 0.011 mg/kg. Moreover, aminophylline, a non-selective adenosine receptor antagonist (5 mg/kg), and 8-cyclopentyl-1,3-dimethylxanthine (8-CPX), a selective A 1 adenosine receptor antagonist (5 mg/kg) reversed the 2-chloroadenosine (0.125 mg/kg)-induced enhancement of the protective activity of carbamazepine and clonazepam. 2-Chloroadenosine administered alone or combined with antiepileptic drugs, caused neither motor nor long-term memory impairment. Finally, the adenosine A 1 agonist did not change the free plasma concentration of antiepileptics, so a pharmacokinetic factor is not probable. Summing up, 2-chloroadenosine potentiated the protective activity of both carbamazepine and clonazepam, which seems to be associated with the enhancement of purinergic transmission mediated through adenosine A 1 receptors.