Interaction of pregabalin with carbamazepine in the mouse maximal electroshock-induced seizure model: a type I isobolographic analysis for non-parallel dose-response relationship curves

To characterize the anticonvulsant effects of pregabalin (PGB - a third-generation antiepileptic drug) in combination with carbamazepine (CBZ - a classical antiepileptic drug) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs).

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. Potential adverse-effect profiles of interaction of PGB with CBZ at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory, skeletal muscular strength and antinociceptive activity were measured along with total brain CBZ concentrations.

In the mouse MES model, PGB administered singly had its DRRC non-parallel to that for CBZ. With type I isobolographic analysis for non-parallel DRRCs, the combination of PGB with CBZ at the fixed-ratio of 1:1 exerted additive interaction. In the combination, neither motor coordination, long-term memory nor muscular strength were affected. PGB administered alone and in combination with CBZ exerted antinociceptive effects, whereas CBZ administered alone produced no antinociceptive activity in mice subjected to the acute thermal pain model. Pharmacokinetic estimation of total brain antiepileptic drug concentrations revealed that PGB had no impact on total brain concentrations of CBZ in experimental animals.

In conclusion, the additive interaction between PGB and CBZ is worthy of consideration while extrapolating the results from this study to clinical settings.