Marta Andres-Mach

Anticonvulsant and acute neurotoxic effects of imperatorin, osthole and valproate in the maximal electroshock seizure and chimney tests in mice: A comparative study

The aim of this study was to determine and compare the anticonvulsant and acute adverse (neurotoxic) effects of imperatorin and osthole (two natural coumarin derivatives) with valproate (a classical antiepileptic drug) in the maximal electroshock seizure and chimney tests in mice. The anticonvulsant and acute adverse effects of imperatorin, osthole and valproate were determined at 15, 30, 60 and 120 min after their systemic (i.p.) administration. The evaluation of time-course and dose-response relationships for imperatorin, osthole and valproate in the maximal electroshock seizure test revealed that the compounds produced a clear-cut antielectroshock action in mice and the experimentally derived ED(50) values for imperatorin ranged between 167 and 290 mg/kg, those for osthole ranged from 253 to 639 mg/kg, whereas the ED(50) values for valproate ranged from 189 to 255 mg/kg. The evaluation of acute neurotoxic effects in the chimney test revealed that the TD(50) values for imperatorin ranged between 329 and 443 mg/kg, the TD(50) values for osthole ranged from 531 to 648 mg/kg, while the TD(50) values for valproate ranged from 363 to 512 mg/kg. The protective index (as a ratio of TD(50) and ED(50) values) for imperatorin ranged between 1.13 and 2.60, for osthole ranged from 0.83 to 2.44, and for valproate ranged between 1.72 and 2.00. In conclusion, both natural coumarin derivatives deserve more attention from a preclinical point of view as compounds possessing some potentially favorable activities in terms of suppression of seizures, quite similar to those reported for valproate.

Osthole suppresses seizures in the mouse maximal electroshock seizure model.

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

Anticonvulsant effects of four linear furanocoumarins, bergapten, imperatorin, oxypeucedanin, and xanthotoxin, in the mouse maximal electroshock-induced seizure model: a comparative study

The aim of this study was to determine and compare the anticonvulsant activities of four natural furanocoumarins [bergapten (5-methoxypsoralen), imperatorin (8-isopentenyloxypsoralen), oxypeucedanin (5-epoxy-isopentenyloxypsoralen) and xanthotoxin (8-methoxypsoralen)] in the maximal electroshock-induced seizure test in mice. The anticonvulsant effects of bergapten, imperatorin, oxypeucedanin, and xanthotoxin were evaluated at 15, 30, 60 and 120 min after their systemic (intraperitoneal) administration. Tonic hind limb extension (seizure activity) was evoked in adult albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. The time courses of protection by bergapten, imperatorin, oxypeucedanin and xanthotoxin against maximal electroshock-induced seizures revealed that 300 mg/kg imperatorin and xanthotoxin (C-8 substituted derivatives of psoralen) exerted strong anticonvulsant activity, whereas 300 mg/kg bergapten and oxypeucedanin (C-5 substituted derivatives of psoralen) did not produce any anticonvulsant activity in this model. In conclusion, imperatorin and xanthotoxin protected the animals against maximal electroshock-induced seizures, whereas bergapten and oxypeucedanin, despite their chemical and structural similarities to xanthotoxin and imperatorin, exerted no anticonvulsant activity in this seizure test.

Pharmacodynamic and pharmacokinetic interaction profiles of levetiracetam in combination with gabapentin, tiagabine and vigabatrin in the mouse pentylenetetrazole-induced seizure model: An isobolographic analysis

To characterize the interactions between levetiracetam and the antiepileptic drugs gabapentin, tiagabine, and vigabatrin in suppressing pentylenetetrazole-induced clonic seizures in mice, type II isobolographic analysis was used. Clonic seizures were evoked in Albino Swiss mice by subcutaneous injection of pentylenetetrazole at its CD(97)(98 mg/kg). Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 were supra-additive (synergistic) in terms of seizure suppression whilst the combination at the fixed-ratio of 4:1 was additive. Tiagabine with levetiracetam and vigabatrin with levetiracetam at the fixed-ratios of 1:25, 1:50, 1:100, 1:200, and 1:400 and at 2:1, 3:1, 4:1, 6:1, 8:1, and 16:1 were additive, respectively. No acute adverse effects were observed. Measurement of total brain antiepileptic drug concentrations revealed that levetiracetam in combination with gabapentin at the fixed-ratio of 1:4 significantly elevated (21%) total brain gabapentin concentrations. In contrast, levetiracetam was without affect on tiagabine or vigabatrin concentrations and co-administration with gabapentin, tiagabine or vigabatrin had no effect on levetiracetam brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse pentylenetetrazole model. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 appears to be particularly favorable combination exerting supra-additive interaction in suppressing pentylenetetrazole-induced seizures, although there is a pharmacokinetic contribution to the interaction between levetiracetam and gabapentin at the fixed-ratio of 1:4. Levetiracetam in combination with tiagabine and vigabatrin appear to be neutral combinations producing only additivity in the mouse pentylenetetrazole model.

Levetiracetam and felbamate interact both pharmacodynamically and pharmacokinetically: An isobolographic analysis in the mouse maximal electroshock model

Summary:  Purpose: Polytherapy with two or more antiepileptic drugs (AEDs) is generally required for approximately 30% of patients with epilepsy, who do not respond satisfactorily to monotherapy. The potential usefulness of AED combinations, producing synergistic anticonvulsant efficacy and minimal adverse effects, is therefore of significant importance. The present study sought to ascertain the potential usefulness of levetiracetam (LEV) and felbamate (FBM) in combination in the mouse maximal electroshock (MES)‐induced seizure model.

Effects of WIN 55,212-2 mesylate (a synthetic cannabinoid) on the protective action of clonazepam, ethosuximide, phenobarbital and valproate against pentylenetetrazole-induced clonic 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 (AEDs: clonazepam [CZP], ethosuximide [ETS], phenobarbital [PB], and valproate [VPA]) in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model. WIN (15 mg/kg, i.p.) significantly enhanced the anticonvulsant action of ETS, PB and VPA, but not that of CZP against PTZ-induced clonic seizures. The ED(50) values of ETS, PB and VPA were reduced from 148.0, 13.9 and 137.1mg/kg to 104.0, 8.3 and 85.6 mg/kg, respectively (P<0.05). WIN (5 and 10mg/kg, i.p.) had no impact on the anticonvulsant action of all studied AEDs against PTZ-induced clonic seizures. WIN (15 mg/kg, i.p.) significantly elevated total brain concentrations of ETS and VPA, but not those of CZP and PB in mice. Moreover, WIN combined with CZP, ETS, PB and VPA significantly impaired motor performance, long-term memory and muscular strength in mice subjected to the chimney, passive avoidance and grip-strength tests, respectively. Pharmacodynamic enhancement of the anticonvulsant action of PB by WIN against PTZ-induced clonic seizures is favorable from a preclinical viewpoint. Advantageous effects of WIN in combination with ETS and VPA against PTZ-induced seizures were pharmacokinetic in nature. However, WIN combined with CZP, ETS, PB and VPA impaired motor coordination and long-term memory as well as reduced skeletal muscular strength in the experimental animals.

Isobolographic characterization of the anticonvulsant interaction profiles of levetiracetam in combination with clonazepam, ethosuximide, phenobarbital and valproate in the mouse pentylenetetrazole-induced seizure model

This study was designed so as to characterize the interactions between levetiracetam (LEV) and the conventional antiepileptic drugs (AEDs) clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced clonic seizures in mice by use of type II isobolographic analysis. Adverse-effect profiles of the drugs in combination were determined and brain AED concentrations were measured. The combinations of VPA and ETS with LEV at the fixed-ratio of 1:2, CZP with LEV (1:20,000), and PB with LEV (1:20) were supra-additive (synergistic) in suppressing seizures. In contrast, VPA and ETS with LEV (1:1, 2:1, and 4:1), CZP with LEV (1:1000, 1:5000, and 1:10,000), and PB with LEV (1:1, 1:5, and 1:10) were additive. No adverse effects were observed. ETS significantly reduced brain LEV concentrations but no other pharmacokinetic changes were observed. The combinations of CZP with LEV (1:20,000); VPA and ETS with LEV (1:2); and PB with LEV (1:20) appear to be favorable combinations exerting supra-additive interactions in suppressing PTZ-induced seizures.

Design, synthesis, and anticonvulsant activity of new hybrid compounds derived from 2-(2,5-dioxopyrrolidin-1-yl)propanamides and 2-(2,5-dioxopyrrolidin-1-yl)butanamides.

The library of 27 new 1-(4-phenylpiperazin-1-yl)- or 1-(morpholin-4-yl)-(2,5-dioxopyrrolidin-1-yl)propanamides and (2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5, 10, 11, and 24 displayed the broad spectra of activity across the preclinical seizure models, namely, the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-hertz (6 Hz) model of pharmacoresistant limbic seizures. The highest protection was demonstrated by 11 (ED50 MES = 88.4 mg/kg, ED50 scPTZ = 59.9 mg/kg, ED50 6 Hz = 21.0 mg/kg). This molecule did not impair the motor coordination of animals in the chimney test even at high doses (TD50 > 1500 mg/kg), yielding superb protective indexes (PI MES > 16.97, PI PTZ > 25.04, PI 6 Hz > 71.43). As a result, 11 displayed distinctly better safety profile than clinically relevant AEDs ethosuximide, lacosamide, or valproic acid.

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.

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

BACKGROUND The 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. METHODS Electroconvulsionswere produced inmice by means of a current (sine-wave, 50Hz, maximum 500 V, strength from 3-10 mA, ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). RESULTS Ivabradine administered intraperitoneally (ip), 60 min before the MEST test, at doses of 5 and 10 mg/kg, did not alter the threshold for maximal electroconvulsions in mice. In contrast, ivabradine at doses of 15 and 20 mg/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 18.29 mg/kg, respectively. CONCLUSIONS Based 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.