Ewa Wojda

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.

Isobolographic characterization of interactions of levetiracetam with the various antiepileptic drugs in the mouse 6 Hz psychomotor seizure model.

The aim of this study was to characterize the anticonvulsant effects of levetiracetam (LEV) in combination with the various antiepileptic drugs (clonazepam [CZP], oxcarbazepine [OXC], phenobarbital [PB], tiagabine [TGB], and valproate [VPA]), in the mouse 6 Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3s stimulus duration) delivered via ocular electrodes and isobolographic analysis for parallel and non-parallel dose-response effects was used to characterize the consequent anticonvulsant interactions between the various drug combinations. Potential concurrent adverse-effect profiles of interactions between LEV and CZP, OXC, PB, TGB, and VPA at the fixed-ratio of 1:1 were evaluated in the chimney (motor performance), passive avoidance (long-term memory), and grip-strength (muscular strength) tests. LEV administered singly was associated with a dose-response relationship curve (DRRC) that was parallel to that for CZP and non-parallel to that for OXC, PB, TGB and VPA. With isobolography for parallel DRRCs, the combination of LEV with CZP at three fixed-ratios of 1:3, 1:1 and 3:1 was additive in nature. With isobolography for non-parallel DRRCs the combinations of LEV with OXC, TGB and VPA at the fixed-ratio of 1:1 were also additive. In contrast, the isobolography for non-parallel DRRCs revealed that the interaction for the combination of LEV with PB at the fixed-ratio of 1:1 was supra-additive (synergistic). None of the combinations were associated with any concurrent adverse effects with regards to motor coordination, long-term memory or muscular strength. LEV is associated with favorable anticonvulsant synergism with PB and is additive with regards to CZP, OXC, TGB and VPA in the mouse 6 Hz psychomotor seizure model.

Synergistic interaction of gabapentin with tiagabine in the hot-plate test in mice: an isobolographic analysis

This study was aimed at determining the analgesic effect of gabapentin and tiagabine, two antiepileptic drugs that were administered alone and in combination at a fixed ratio of 1:1, in the acute thermal pain model (hot-plate test) in mice. Linear regression analysis was used to evaluate the dose-response relationships between logarithms of antiepileptic drug doses and their resultant maximum possible antinociceptive effects in the mouse hot-plate test. From linear equations, we calculated doses that increased the antinociceptive effect by 50% (ED(50) values) for gabapentin, tiagabine and their combination. The type of interaction between gabapentin and tiagabine was assessed using the isobolographic analysis. Results indicated that both antiepileptic drugs produced the definite antinociceptive effect, and the experimentally derived ED(50) values for gabapentin and tiagabine, when applied alone, were 504.4 mg/kg and 5.67 mg/kg, respectively. With isobolography, the experimentally derived ED(50 mix) value for the fixed ratio combination of 1:1 was 139.31 mg/kg and significantly differed from the theoretically calculated ED(50 add) value, which was 255.04 mg/kg (p < 0.05), indicating the synergistic interaction between gabapentin and tiagabine in the hot-plate test in mice. In conclusion, the combination of tiagabine with gabapentin at a fixed ratio of 1:1 exerted a synergistic interaction in the mouse model of nociceptive pain. If the results from this study could be extrapolated to clinical settings, the combination of tiagabine with gabapentin might be beneficial for pain relief in humans.

Characterization of acute adverse-effect profiles of selected antiepileptic drugs in the grip-strength test in mice

The aim of this study was to assess the acute adverse effects (neurotoxic) of several antiepileptic drugs (clonazepam, lamotrigine, oxcarbazepine, phenytoin, phenobarbital and topiramate) by measuring skeletal muscular strength in mice using the grip-strength test. Linear regression analysis of grip-strength in relation to drug dose-response allowed us to determine D(50) values, the dosages of antiepileptic drugs that reduced grip-strength in mice by 50% compared to control animals. Each of the antiepileptic drugs studied reduced skeletal muscular strength in mice in a dose-dependent manner. The D(50) for clonazepam was 31.7 mg/kg, lamotrigine -47.7 mg/kg, oxcarbazepine -87.3 mg/kg, phenobarbital -128.7 mg/kg, phenytoin -69.7 mg/kg, and topiramate -509.5 mg/kg. In conclusion, the grip-strength test can aid in evaluating acute adverse effects of drugs with respect to their influence on muscular strength in experimental animals.