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 100 mg/kg significantly elevated the threshold for electroconvulsions in mice. TP4 at doses of 12.5, 25, 37.5 and 50 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP4 (50 mg/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 25 mg/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.     

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, 25 mA, 500 V, 50 Hz, 0.2 s 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 150 mg/kg significantly elevated the threshold for electroconvulsions in mice. IPPS at lower doses of 18.75 and 37.5 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, 37.5 mg/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 (18.75 mg/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.     

Imperatorin enhances the protective activity of conventional antiepileptic drugs against maximal electroshock-induced seizures in mice

The effects of imperatorin (8-isopentenyloxypsoralen; 9-(3-methylbut-2-enyloxy)-7H-furo[3,2-g]chromen-7-one) on the anticonvulsant activity of four conventional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) were studied in the mouse maximal electroshock seizure model. Results indicate that imperatorin (30 and 40 mg/kg, i.p.) significantly potentiated the anticonvulsant activity of carbamazepine against maximal electroshock-induced seizures by reducing its median effective dose (ED(50)) from 10.3 to 6.8 (by 34%; P<0.05) and 6.0 mg/kg (by 42%; P<0.01), respectively. Similarly, imperatorin (40 mg/kg, i.p.) markedly enhanced the antielectroshock action of phenobarbital and phenytoin, by lowering their ED(50) values from 19.6 to 12.2 mg/kg (by 38%; P<0.05-phenobarbital) and from 12.8 to 8.5 mg/kg (by 34%; P<0.05-phenytoin) in the maximal electroshock seizure test. In contrast, imperatorin (40 mg/kg, i.p.) did not affect the protective action of valproate against maximal electroshock-induced seizures in mice. Imperatorin at lower doses of 20 and 30 mg/kg had no significant effect on the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock seizure model. Pharmacokinetic evaluation of interaction between imperatorin (30 mg/kg, i.p.) and carbamazepine (6.8 mg/kg, i.p.) revealed a significant increase in total brain carbamazepine concentration after imperatorin administration, indicating a pharmacokinetic nature of interaction between these drugs. In cases of phenobarbital and phenytoin, imperatorin (40 mg/kg, i.p.) did not alter significantly total brain concentrations of phenytoin and phenobarbital in mice, and thus, the observed interactions in the maximal electroshock seizure test between imperatorin and phenobarbital or phenytoin were pharmacodynamic in nature. The present study demonstrates that imperatorin enhanced the antiseizure effects of carbamazepine, phenobarbital and phenytoin in the mouse maximal electroshock seizure model. However, the combination of imperatorin with carbamazepine, despite its beneficial effects in terms of seizure suppression in mice, was complicated by a pharmacokinetic increase in total brain carbamazepine concentration in experimental animals. In contrast, the combinations of imperatorin with phenytoin and phenobarbital, due to their beneficial antiseizure effects and no pharmacokinetic interactions between drugs in the brain compartment of experimental animals, deserve more attention and are of pivotal importance for epileptic patients as advantageous combinations from a clinical viewpoint.     

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 (ED50) 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 ED50 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 (TD50) 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 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, 25 mA, 500 V, 50 Hz, 0.2 s 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 10 mg/kg significantly elevated the threshold for electroconvulsions in mice. TP10 at doses of 2.5 and 5 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP10 (5 mg/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.     

Influence of chronic treatment with H1 receptor antagonists on the anticonvulsant activity of antiepileptic drugs.

The aim of this study was to evaluate the effects of chronic astemizole and ketotifen administration on the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced convulsions in mice. Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Brain and plasma levels of antiepileptics were measured by immunofluorescence. Astemizole (2 mg/kg) and ketotifen (8 mg/kg) significantly diminished the electroconvulsive threshold, being without effect upon this parameter at lower doses. Astemizole significantly reduced the anticonvulsant action of phenobarbital and diphenylhydantoin, but it did not affect that of carbamazepine and valproate. Moreover, ketotifen (at the subprotective dose of 4 mg/kg) remained without effect upon the protective activity of valproate, diphenylhydantoin or phenobarbital, but significantly diminished the anticonvulsant effect of carbamazepine. Histamine receptor antagonists combined with antiepileptic drugs, did not alter their brain and free plasma levels. Also, they did not influence adverse potential of carbamazepine, diphenylhydantoin and valproate while that of phenobarbital was significantly enhanced. Valproate, phenobarbital and diphenylhydantoin alone at their ED50s against maximal electroshock or combined with the histamine receptor antagonists disturbed long-term memory. The results of this study indicate that H1 receptor antagonists, should be used with caution in epileptic patients.     

Chronically administered fluoxetine enhances the anticonvulsant activity of conventional antiepileptic drugs in the mouse maximal electroshock model

Interactions between chronically administered fluoxetine and valproate, carbamazepine, phenytoin, or phenobarbital were studied in the maximal electroshock test in mice. Fluoxetine administered for 14 days at doses up to 20 mg/kg failed to affect the electroconvulsive threshold. Nevertheless the drug (at 15 and 20 mg) enhanced the anticonvulsant activity of valproate, carbamazepine, and phenytoin. When applied at 20 mg/kg, it potentiated the protective action of phenobarbital. Fluoxetine, antiepileptic drugs, and their combinations did not produce significant adverse effects evaluated in the chimney test (motor coordination) and passive-avoidance task (long-term memory). Chronically applied fluoxetine significantly increased the brain concentrations of valproate, carbamazepine, phenobarbital and phenytoin, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. In conclusion, long-term treatment with fluoxetine exhibited some favorable effects on the anticonvulsant properties of conventional antiepileptic drugs, resulting, however, from pharmacokinetic interactions.     

Influence of sexual hormone antagonists on the anticonvulsant action of conventional antiepileptic drugs against electrically- and pentylenetetrazol-induced seizures in mice.

The present results refer to the action of three gonadal steroid antihormones, tamoxifen (TXF, an estrogen antagonist), cyproterone acetate (CYP, an antiandrogen) and mifepristone (MIF, a progesterone antagonist) on seizure phenomena in mice. TXF and CYP at their lowest protective dose in the electroconvulsive threshold test, enhanced the antiseizure efficacy of some antiepileptic drugs. TXF (20 mg/kg) potentiated the protective activity of valproate, diphenylhydantoin and clonazepam, but not that of carbamazepine or phenobarbital, against maximal electroshock-induced convulsions in female mice. CYP (40 mg/kg) enhanced the anticonvulsant action of valproate, carbamazepine, diphenylhydantoin and clonazepam, but not that of phenobarbital, against maximal electroshock in male animals. MIF failed to affect the electroconvulsive threshold or the efficacy of antiepileptic drugs in maximal electroshock. The effect of TXF or CYP upon the electroconvulsive threshold and on the action of antiepileptics was not reversed by sex steroid hormones (estradiol, testosterone, progesterone). However, the TXF-induced elevation of the electroconvulsive threshold was abolished by bicuculline, N-methyl-D-aspartic acid and kainic acid, and partially reversed by aminophylline, strychnine being ineffective in this respect. The action of CYP on the threshold for electroconvulsions was partially reversed by bicuculline and aminophylline. Both glutamatergic agonists and strychnine remained ineffective in this respect. Moreover, the action of TXF or CYP on the activity of antiepileptics was not influenced by strychnine, and reversed to various extents by the remaining convulsants. In contrast to maximal electroshock, none of the three antihormones affected the protective action of antiepileptic drugs against pentylenetetrazol-induced seizures in mice. Neither TXF nor CYP altered the free plasma levels of antiepileptic drugs, so a pharmacokinetic interaction is not probable. The combined treatment of the two antihormones with antiepileptic drugs, providing 50% protection against maximal electroshock, did not affect motor performance in mice, and did not result in significant long-term memory deficits. Our data indicate that steroid receptor-mediated events may be indirectly associated with seizure phenomena in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs.     

Influence of MK-801 on the anticonvulsant activity of antiepileptics

MK-801 (a potent non-competitive antagonist of N-methyl-D-aspartic acid-mediated events) in subcutanteous doses of 0.1 and 0.2 mg/kg increased the threshold for electroconvulsions and in doses of 0.0031 and 0.0125 mg/kg enhanced the protective activity of valproate against maximal electroshock-induced convulsions in mice. Valproate-induced side-effects (evaluated by means of dark-avoidance acquisition and retention testing and the chimney test) at its ED₅₀, against maximal electroshock (i.e. 268 mg/kg) were pronounced whereas they were absent in the case of a combined treatment with MK-801 (0.0125 mg/kg) and valproate (91 mg/kg). This treatment provided 50% protection against maximal electroshock-induced seizures. Moreover. MK-801 (0.0125 and 0.05 mg/kg) potentiated the anticonvulsant action of phenobarbital, reducing phenobarbital-induced motor impairment totally at 0.05 mg/kg, but did not influence the protection offered by carbamazepine and diphenylhydantoin at 0.05 mg/kg. The N-methyl-D-aspartic acid antagonist did not affect the total plasma levels of either valproate or phenobarbital (as measured by immunofluorescence), so a pharmacokinetic interaction, in terms of total plasma levels at least, is unlikely to be involved in the observed effects. The finding that the combined treatment of MK-801 with valproate or phenobarbital, apart from the distinct potentiation of their anticonvulsant activities, is devoid of side-effects should be carefully considered.     

Nefopam enhances the protective activity of antiepileptics against maximal electroshock-induced convulsions in mice

Nefopam is a centrally acting non-opioid analgesic with a mechanism of action that is not completely understood. Adverse effects associated with the therapeutic use and overdose of nefopam are mainly associated with the central nervous system, such as hallucinations, cerebral edema and convulsions. The aim of this study was to assess the effect of nefopam on the electrical threshold and its influence on the protective activity of antiepileptic drugs in the maximal electroshock test in mice. A 5 mg/kg dose of nefopam significantly elevated the electric seizure threshold, while a dose of 1 mg/kg failed to protect mice against electroconvulsion. At a subthreshold dose of 1 mg/kg, nefopam significantly enhanced the anticonvulsant activity of valproate against electroconvulsions. The protective activity of phenobarbital and phenytoin was significantly enhanced by co-administration of nefopam at the 5 mg/kg dose, but this same dose of nefopam failed to affect the protective activity of carbamazepine. In conclusion, nefopam exerts an anticonvulsive effect when given alone and significantly enhances the protective activity of certain antiepileptic agents against electroconvulsions induced in mice.     

Anticonvulsant action of chlormethiazole is prevented by subconvulsive amounts of strychnine and aminophylline but not by bicuculline and picrotoxin

The anticonvulsant action of chlormethiazole was evaluated with the use of subthreshold doses of convulsants affecting the purinergic, glycinergic and gamma-aminobutyric acid (GABA)-mediated transmission, i.e. aminophylline, strychnine, bicuculline and picrotoxin in the model of generalized tonic-clonic convulsions. Chlormethiazole protected mice against maximal electroshock-induced seizures with an ED50 of 130.8 mg/kg. Aminophylline (100 mg/kg) and strychnine (0.4 mg/kg) reversed the protective action of chlormethiazole against electroconvulsions raising the ED50 values of this drug to 218.6 and 208.6 mg/kg, respectively. In contrast, GABA antagonists, bicuculline and picrotoxin, neither affected the protection provided by chlormethiazole nor did they alter the protective activity of valproate, phenobarbital, diphenylhydantoin and carbamazepine against electroconvulsions. Our results indicate that (a) the anticonvulsant activity of chlormethiazole might be related to its interaction with strychnine-sensitive glycinergic as well as purinergic neurotransmission, (b) purinergic and strychnine-sensitive glycinergic events contribute more prominently than GABAergic ones to the anticonvulsant activity of the drugs providing protection against maximal electroshock-induced convulsions.     

7-Nitroindazole enhances dose-dependently the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

7-Nitroindazole (7NI, a nitric oxide synthase [NOS] inhibitor) administered intraperitoneally (ip), 30 min before the test, at doses ranging between 50-200 mg/kg, raised the threshold for electroconvulsions in mice. Linear regression analysis revealed that the doses increasing the threshold by 50% (TID50) and 100% (TID100) over the control value for 7NI were 115.2 and 173.4 mg/kg, respectively. Moreover, 7NI dose-dependently potentiated the anticonvulsant effects of four conventional antiepileptic drugs (AEDs: carbamazepine - CBZ, phenobarbital - PB, phenytoin - PHT, and valproate - VPA) in the mouse maximal electroshock-induced seizure (MES) model. 7NI at 50 mg/kg enhanced only the anticonvulsant effect of PB, whereas the drug at 75 and 100 mg/kg potentiated the antiseizure effects of PB, PHT and VPA, but not those of CBZ against MES-induced seizures. Only 7NI at 150 mg/kg enhanced considerably the antielectroshock action of all studied AEDs in the MES test. Pharmacokinetic evaluation of interactions between 7NI and the investigated AEDs revealed that 7NI (150 mg/kg; ip) did not alter total brain concentrations of conventional AEDs in mice. L-arginine (L-Arg - a natural precursor of NO; administered ip, 500 mg/kg, 60 min before electroconvulsions) did not reverse the activity of 7NI (150 mg/kg), but in contrast, it significantly potentiated the anticonvulsant action of conventional AEDs combined with 7NI (150 mg/kg). Pharmacokinetic increase in total brain AED concentrations was observed for the combinations of L-Arg (500 mg/kg) with 7NI (150 mg/kg) and PHT (by 32%; p<0.01) or VPA (by 22%; p<0.05). Neither total brain CBZ nor PB concentrations were altered following the co-administration of L-Arg (500 mg/kg) with 7NI (150 mg/kg). 7NI at doses of 100-200 mg/kg significantly impaired spontaneous ambulatory activity in mice subjected to the Y-maze task. The NOS inhibitor at doses of 50 and 75 mg/kg had no significant effect on locomotor activity of animals, although the number of arm entries within the 5 min of observational time was reduced. Finally, it can be concluded that the enhancement of anticonvulsive efficacy of CBZ, PB, PHT and VPA by 7NI alone or in combination with L-Arg in the MES test, deserves more attention and further neurochemical studies are required to elucidate the exact role of NO in the brain.     

Synthetic cannabinoid WIN 55,212-2 mesylate enhances the protective action of four classical antiepileptic drugs against maximal electroshock-induced seizures in mice

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN — a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, and valproate) in the mouse maximal electroshock seizure (MES) model. The results indicate that WIN (10 mg/kg, i.p.) significantly enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test in mice. WIN (5 mg/kg) potentiated the anticonvulsant action of carbamazepine and valproate, but not that of phenytoin or phenobarbital in the MES test in mice. However, WIN administered alone and in combination with carbamazepine, phenytoin, phenobarbital and valproate significantly reduced muscular strength in mice in the grip-strength test. In the passive avoidance task, WIN in combination with phenobarbital, phenytoin and valproate significantly impaired long-term memory in mice. In the chimney test, only the combinations of WIN with phenobarbital and valproate significantly impaired motor coordination in mice. In conclusion, WIN enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test. However, the utmost caution is advised when combining WIN with classical antiepileptic drugs due to impairment of motor coordination and long-term memory and/or reduction of skeletal muscular strength that might appear during combined treatment.     

Acute and chronic treatment with mianserin differentially affects the anticonvulsant activity of conventional antiepileptic drugs in the mouse maximal electroshock model

Rationale Epilepsy often coexists with depression. Therefore, the probability of simultaneous treatment with antiepileptics and antidepressants and the possibility of interactions between them are relatively high. Objective The effects of acute and chronic administration of mianserin on the protective activity of valproate (VPA), carbamazepine, phenytoin, and phenobarbital were evaluated in the maximal electroshock in mice. Materials and methods Animals were subjected to electroconvulsions. Undesired effects were evaluated in the chimney test (motor impairment) and passive-avoidance task (memory deficit). Brain concentrations of antiepileptic drugs were assessed by immunofluorescence. Results When given acutely, mianserin (at doses greater than or equal to 20 mg/kg) significantly raised the electroconvulsive threshold. The antidepressant, at the subanticonvulsant doses, enhanced the anticonvulsant action of carbamazepine, phenytoin, and VPA. Mianserin administered chronically at 30 mg/kg significantly decreased the electroconvulsive threshold. In contrast to acute treatment, the antidepressant at subeffective doses diminished the anticonvulsant activity of VPA and phenytoin. Mianserin given either acutely or chronically did not affect the brain concentrations of antiepileptic drugs, so a pharmacokinetic contribution to the observed interactions is not probable. Acute and chronic treatment with mianserin and its combinations with antiepileptic drugs did not impair either motor coordination or long-term memory. Conclusion Although acute application of mianserin may potentiate the anticonvulsant action of some antiepileptics, its chronic administration can lead to the opposite effect. Therefore, as far as the presented results can be transferred to clinical conditions, the antidepressant therapy with mianserin should be limited or even avoided in epileptic patients.     

Effect of acutely and chronically administered venlafaxine on the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock model

The influence of acute and chronic treatments with intraperitoneal venlafaxine, a selective serotonin/norepinephrine reuptake inhibitor, on the anticonvulsant activity of selected antiepileptic drugs was studied in the maximal electroshock test in mice. Venlafaxine (12.5 and 25 mg/kg), given either acutely or chronically, significantly increased the electroconvulsive threshold. Moreover, both acute and chronic venlafaxine, applied at the highest subprotective dose of 6.25 mg/kg, enhanced the anticonvulsant effect of valproate, without affecting the protective action of carbamazepine, phenobarbital and phenytoin. The antidepressant did not affect brain concentration of valproate, indicating that the interaction between the two drugs seems pharmacodynamic in nature. Despite the lack of effect on the antielectroshock action of the remaining antiepileptics, acute venlafaxine increased the brain concentration of phenobarbital, while chronic venlafaxine reduced the brain level of phenytoin. In terms of adverse effects, acute/chronic venlafaxine and antiepileptic drugs alone, as well as their combinations, did not produce significant motor or long-term memory deficits in mice. Summing up, it seems that venlafaxine may be considered as a safe drug for the clinical use in patients with epilepsy and depressive disorders.     

Influence of orphenadrine upon the protective activity of various antiepileptics in the maximal electroshock-induced convulsions in mice

Orphenadrine is an anticholinergic drug used in the treatment of Parkinson’s disease, and is also known to exert nonspecific antagonistic activity at the phencyclidine binding site of the N-methyl-D-aspartate (NMDA) receptor. The aim of this study was to assess the anticonvulsant properties of orphenadrine and to evaluate its effect on the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced seizures in mice. Orphenadrine given at a dose of 5.65 mg/kg elevated the electrical seizure threshold from 5.7 (5.4 – 6.1) to 6.8 (6.3–7.3) mA, while a dose of 2.8 mg/kg was ineffective. The ED₅₀ values of orphenadrine administered 10,30 and 120 min before maximal electroshock-induced convulsions were 16.8 (11.3–25.1), 17.8 (15.7–20.0) and 25.6 (23.3–28.3) mg/kg, respectively. Orphenadrine at a sub-threshold dose of 2.8 mg/kg significantly enhanced the anticonvulsant activity of valproate by reducing its ED₅₀ value from 315.8 (270.0–369.4) to 245.9 (207.1–292.0) mg/kg without affecting the free plasma levels of valproate. However, orphenadrine failed to enhance the protective activity of carbamazepine, phenytoin, phenobarbital, lamotrigine, topiramate, or oxcarbazepine against maximal electroshock-induced seizures.     

Influence of antazoline and ketotifen on the anticonvulsant activity of conventional antiepileptics against maximal electroshock in mice.

Experimental studies have indicated that the central histaminergic system plays an important role in the inhibition of seizures through the stimulation of histamine H1 receptors. H1 receptor antagonists, including classical antiallergic drugs, occasionally may induce convulsions in healthy children and patients with epilepsy. The purpose of this study was to investigate the effects of antazoline and ketotifen (two H1 receptor antagonists) on the anticonvulsant activity of antiepileptic drugs against maximal electroshock (MES)-induced convulsions in mice. The following antiepileptic drugs were used: valproate, carbamazepine, diphenylhydantoin and phenobarbital. In addition, the effects of antiepileptic drugs alone or in combination with antazoline or ketotifen were studied on long-term memory (tested in the passive avoidance task) and motor performance (evaluated in the chimney test), acutely and after 7-day treatment with these H1 receptor antagonists. The influence of antazoline and ketotifen on the free plasma and brain levels of the antiepileptics was also evaluated. Antazoline (at 0.5 mg/kg), given acutely and after 7-day treatment, significantly diminished the electroconvulsive threshold. Similarly, ketotifen, after acute and chronic doses of 8 mg/kg markedly reduced the threshold for electroconvulsions. In both cases, antazoline and ketotifen were without effect upon this parameter at lower doses. Antazoline (0.25 mg/kg) significantly raised the ED50 value of carbamazepine against MES (both, acutely and after 7-day treatment). Furthermore antazoline (0.25 mg/kg) also reduced the anticonvulsant activity of diphenylhydantoin, but only after repeated administration, without modifying the brain and free plasma level of this drug. Moreover, valproate and phenobarbital did not change their protective activity when combined with antazoline. Ketotifen (4 mg/kg) possessed a biphasic action, acutely it enhanced the anticonvulsant action of carbamazepine and phenobarbital while, following 7-day treatment, reduced the antiseizure activity of carbamazepine. Ketotifen did not affect the free plasma or brain levels of antiepileptics tested. Only acute antazoline (0.25 mg/kg) applied with valproate impaired the performance of mice evaluated in the chimney test. Ketotifen (4 mg/kg) co-administered with conventional antiepileptic drugs impaired motor coordination in mice treated with valproate, phenobarbital or diphenylhydantoin. Acute and chronic antazoline (0.25 mg/kg) alone or in combination with antiepileptic drugs did not disturb long-term memory, tested in the passive avoidance task. Similarly, ketotifen (4 mg/kg) did not impair long-term memory, acutely and after 7-day treatment. However, valproate alone or in combination with chronic ketotifen (4 mg/kg) worsened long-term memory. The results of this study indicate that H1 receptor antagonists, crossing the blood brain barrier, should be used with caution in epileptic patients. This is because antazoline reduced the protective potential of diphenylhydantoin and carbamazepine. Also, ketotifen reduced the protection offered by carbamazepine and elevated the adverse activity of diphenylhydantoin, phenobarbital and valproate.     

The interactions of atorvastatin and fluvastatin with carbamazepine, phenytoin and valproate in the mouse maximal electroshock seizure model

The aim of this study was to determine the influence of acute (single) and chronic (once daily for 7 consecutive days) treatments with atorvastatin and fluvastatin on the anticonvulsant potential of three antiepileptic drugs: carbamazepine, phenytoin and valproate in the mouse maximal electroshock-induced seizure model. Additionally, the effects of acute and chronic administration of both statins on the adverse effect potential of three antiepileptic drugs were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). To evaluate the pharmacokinetic characteristics of interaction between antiepileptic drugs and statins, the total brain concentrations of antiepileptic drugs were estimated with the fluorescence polarization immunoassay technique. Results indicate that atorvastatin at doses up to 80mg/kg in chronic experiment attenuated the anticonvulsant potential of carbamazepine by increasing its ED(50) value against maximal electroconvulsions. Acute fluvastatin (80mg/kg) enhanced the anticonvulsant potential of carbamazepine and valproate by decreasing their ED(50) values. Acute fluvastatin (80mg/kg) also markedly increased the total brain carbamazepine concentration by 61% in a pharmacokinetic reaction. Atorvastatin (acute and chronic) and fluvastatin (chronic) in combinations with valproate impaired long-term memory in mice. Both statins in combinations with all three antiepileptic drugs had no impact on their adverse effects in the chimney test. Based on this preclinical study, one can conclude that chronic administration of atorvastatin reduces the anticonvulsant action of carbamazepine and acute fluvastatin can enhance the anticonvulsant potency of the carbamazepine and valproate. The former interaction was pharmacokinetic in nature.     

Antiparkinsonian drugs memantine and trihexyphenidyl potentiate the anticonvulsant activity of valproate against maximal electroshock-induced seizures.

Memantine increased the threshold for electroconvulsions, when administered at 1.0-6.0 mg/kg (i.p.) and given in subthreshold doses of 0.0156, 0.0625, 0.125 and 0.5 mg/kg (i.p.) potentiated the protective efficacy of valproate, against maximal electroshock (50 mA)-induced seizures in mice, lowering the ED50 from 235 to 197, 172, 164 and 130 mg/kg, respectively. Trihexyphenidyl, applied in doses of 30 and 50 mg/kg (i.p.), did not influence the electroconvulsive threshold per se but when combined with valproate, strongly enhanced its anticonvulsant activity against maximal electroshock-induced seizures lowering the ED50 from 206 to 103 and 46 mg/kg, respectively. The chimney test and retention testing in mice revealed that administration of memantine at 0.5 mg/kg (i.p.) or trihexyphenidyl at 30 mg/kg (i.p.) together with valproate in doses of 130 or 103 mg/kg (i.p.), respectively, resulted in motor impairment and caused impairment of long-term memory, similar to the effects of valproate alone, when applied at its ED50 against maximal electroshock. Neither memantine nor trihexyphenidyl altered the total level of valproate in plasma. It may be concluded that the potentiation of the anticonvulsant activity of valproate, by memantine and trihexyphenidyl, is not associated with a pharmacokinetic interaction.     

Cholecalciferol enhances the anticonvulsant effect of conventional antiepileptic drugs in the mouse model of maximal electroshock

The interactions between cholecalciferol, a precursor of the active form of Vitamin D(3), and conventional antiepileptic drugs (valproate, carbamazepine, phenytoin, and phenobarbital) were studied in the maximal electroshock test in mice. Vitamin D(3) applied i.p. at doses of 37.5 and 75 mug/kg, but not at 18.75 mug/kg, significantly raised the electroconvulsive threshold. Furthermore, cholecalciferol (at its highest subthreshold dose of 18.75 mug) potentiated the anticonvulsant activity of phenytoin and valproate. The action of carbamazepine and phenobarbital was also enhanced by Vitamin D(3), but when it was given at the higher dose of 37.5 mug/kg. Cholecalciferol, antiepileptic drugs, and their combinations did not produce significant adverse effects evaluated in the chimney test (motor coordination) and passive-avoidance task (long-term memory). Cholecalciferol did not significantly increase the brain concentrations of conventional antiepileptics, indicating a pharmacodynamic nature of revealed interactions. Our findings show that cholecalciferol may play an anticonvulsant role in the brain and can influence the efficacy of antiepileptic drugs, at least in experimental conditions.