Imperatorin interacts additively with novel antiseizure medications in the mouse maximal electroshock-induced seizure model: an isobolographic transformation

TL;DR

This study shows that imperatorin, a natural compound, works additively with new seizure medications in mice without affecting drug levels in the brain.

Contribution

The novel contribution is identifying additive interactions between imperatorin and four novel antiseizure medications in a mouse seizure model.

Findings

Imperatorin at 50 mg/kg significantly enhanced the anticonvulsant effects of LCM, OXC, PGB, and TPM.

Interactions between imperatorin and ASMs were classified as additive via isobolographic analysis.

Imperatorin did not alter the brain concentrations of the tested antiseizure medications.

Abstract

Anticonvulsant effects of imperatorin (IMP) have been experimentally confirmed earlier, but no information is available on the interaction profiles of this naturally occurring coumarin when combined with novel antiseizure medication (ASMs). This study aimed to determine the effects of IMP on the anticonvulsant effects of lacosamide (LCM), oxcarbazepine (OXC), pregabalin (PGB), and topiramate (TPM) in the maximal electroshock-induced seizure (MES) model in mice.

The anticonvulsant effects exerted by novel ASMs (LCM, OXC, PGB, and TPM) when combined with constant doses of IMP (25 and 50 mg/kg) underwent isobolographic transformation to precisely classify the observed interactions in the mouse MES model. Total brain concentrations of ASMs were measured with high-pressure liquid chromatography to exclude the pharmacokinetic nature of interactions among IMP and the tested ASMs.

IMP (50 mg/kg) significantly enhanced (p < 0.01) the anticonvulsant potency of LCM, OXC, PGB, and TPM in the mouse MES model. IMP (25 mg/kg) mildly potentiated the anticonvulsant action of LCM, OXC, PGB, and TPM, but no statistical significance was reported for these combinations. The isobolographic transformation of data from the MES test revealed that the interactions of novel ASMs with IMP were additive. Moreover, IMP (50 mg/kg) did not affect the total brain content of any of the novel ASMs in experimental mice.

The additive interactions of IMP with LCM, OXC, PGB, and TPM in the mouse MES model accompanied by no pharmacokinetic changes in the total brain content of ASMs are worthy of recommendation for further studies.

The online version contains supplementary material available at 10.1007/s43440-023-00555-4.

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