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Isobolographic characterisation of interactions among selected newer antiepileptic drugs in the mouse pentylenetetrazole-induced seizure model

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Abstract

The aim of this study was to characterise the types of interactions between gabapentin (GBP), tiagabine (TGB) and three second-generation antiepileptic drugs (AEDs) with different mechanisms of action (felbamate [FBM], loreclezole [LCZ], and oxcarbazepine [OXC]) by isobolographic analysis. Anticonvulsant and acute neurotoxic adverse effect profiles of combinations of GBP and TGB with other AEDs at fixed ratios of 1:3, 1:1 and 3:1 were investigated in pentylenetetrazole (PTZ)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated for each combination in order to properly classify the investigated interactions. Isobolographic analysis revealed that only the combination of GBP with OXC at the fixed ratio of 1:1 exerted supra-additive (synergistic) interaction (P<0.05) against PTZ-induced seizures. The other combinations tested between GBP and OXC (1:3 and 3:1), as well as all combinations of GBP with FBM or LCZ (1:3, 1:1 and 3:1) were additive in the PTZ test. Similarly, all combinations of TGB with FBM LCZ, and OXC (at the fixed ratios of 1:3, 1:1 and 3:1) were associated with additive interactions against PTZ-induced seizures in mice. In the chimney test, the isobolographic analysis revealed that the combinations of GBP and OXC (at the fixed ratios of 1:3 and 1:1), GBP and LCZ (at 1:1), as well as TGB and OXC (at 1:3 and 1:1) were sub-additive (antagonistic; P<0.05 and P<0.01). In contrast, only one combination tested (TGB and LCZ at the fixed ratio of 1:1) was supra-additive (synergistic; P<0.05) in the chimney test, whereas the other combinations of GBP and TGB with OXC, FBM, and LCZ displayed barely additivity. Based upon the current preclinical data, GBP and OXC appear to be a particularly favourable combination. Also, the combinations of GBP with FBM, GBP with LCZ, and TGB with OXC are beneficial. In contrast, during the combining of TGB with FBM, or TGB with LCZ, the utmost caution is advised because of their unfavourable profiles in this preclinical study.

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Abbreviations

AED:

Antiepileptic drug

BI:

Benefit index

CNS:

Central nervous system

ED50:

Median effective dose

FBM:

Felbamate

GABA:

γ-Aminobutyric acid

GBP:

Gabapentin

LCZ:

Loreclezole

OXC:

Oxcarbazepine

PI:

Protective (therapeutic) index

PTZ:

Pentylenetetrazole

TD50:

Median toxic dose

TGB:

Tiagabine

VGB:

Vigabatrin

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Acknowledgements

This study was supported by a grant from the Medical University of Lublin. The authors express their thanks to Miss K. Darocha and Miss J. Depa for their excellent technical assistance. Dr. J.J. Luszczki is a recipient of the Fellowship for Young Researchers from the Foundation for Polish Science.

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Authors and Affiliations

  1. Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland

    Jarogniew J. Luszczki & Stanislaw J. Czuczwar

  2. Department of Physiopathology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950, Lublin, Poland

    Stanislaw J. Czuczwar

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  1. Jarogniew J. Luszczki
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  2. Stanislaw J. Czuczwar
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Correspondence to Jarogniew J. Luszczki.

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Luszczki, J.J., Czuczwar, S.J. Isobolographic characterisation of interactions among selected newer antiepileptic drugs in the mouse pentylenetetrazole-induced seizure model. Naunyn Schmied Arch Pharmacol 372, 41–54 (2005). https://doi.org/10.1007/s00210-005-1088-9

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