Effect of acute and chronic exposure to lovastatin on the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

• Published in: European journal of pharmacology 2021-09, Vol.907, p.174290, Article 174290
• Main Authors: Tomaszewski, Michał, Zolkowska, Dorota, Plewa, Zbigniew, Czuczwar, Stanisław J., Łuszczki, Jarogniew J.
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - administration & dosage; Anticonvulsants - pharmacokinetics; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Antiepileptic drugs; Brain - drug effects; Brain - metabolism; Disease Models, Animal; Electroshock - adverse effects; Lovastatin; Lovastatin - administration & dosage; Lovastatin - pharmacokinetics; Lovastatin - pharmacology; Lovastatin - therapeutic use; Male; Maximal electroshock-induced seizures; Mice; Pharmacokinetic/pharmacodynamic interaction; Seizures - drug therapy; Valproic Acid - administration & dosage; Valproic Acid - pharmacokinetics; Valproic Acid - pharmacology; Valproic Acid - therapeutic use
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174290

Numerous studies indicate neuroprotective activity of statins, commonly used cholesterol lowering drugs in epilepsy and several other neurological diseases. Promising anti-convulsant and neuroprotective effects of statins, attributed to their anti-excitotoxic and anti-inflammatory action were reported in several animals’ seizure models. To determine the effects of acute (single) and chronic (once daily for 7 consecutive days) administration of lovastatin on the protective activity of four classical antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin and valproate in the mouse maximal electroshock seizure model. Seizure activity (maximal electroconvulsions) in mice were generated by alternating current delivered via ear-clip electrodes. Adverse-effect profile of lovastatin combinations with the tested antiepileptic drugs was assessed in the chimney test (motor performance). Total brain concentrations of antiepileptic drugs were evaluated with the fluorescence polarization immunoassay technique as a measure of the pharmacokinetic interaction between drugs. Lovastatin administered acutely or chronically (5–20 mg/kg) did not significantly affect the threshold for electroconvulsions in mice. Acute lovastatin (10 mg/kg) significantly enhanced the anticonvulsant effect of valproate, which was accompanied with a 34% significant increase in total brain concentration of valproate. Acute lovastatin in combination with phenytoin impaired motor performance by notably decreasing the TD50 value of phenytoin. Chronic lovastatin (10 mg/kg) markedly enhanced the anticonvulsant potential of phenytoin. Acute lovastatin increased anticonvulsant action of valproate but also significantly raised level of valproate in brain after combined administration suggesting pharmacokinetic nature of interaction. The combinations of chronic lovastatin combined with phenytoin can potentially enhance the anticonvulsant potency of phenytoin. •Lovastatin given acutely enhances the anticonvulsant action of valproate in the MES-induced seizures in mice.•Lovastatin given acutely increases total brain content of valproate in mice.•Lovastatin given chronically potentiates the antiseizure properties of phenytoin in the MES test in mice.•Chronic lovastatin has no impact on total brain level of phenytoin in mice.