The present study was aimed to characterize the anticonvulsant effects of piperine in combination with well established antiepileptic drug (AED) phenytoin, in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of phenytoin with piperine at the fixed-ratio of 1:1 from the MES test with respect to long-term memory and skeletal muscular strength were evaluated along with free plasma concentration of piperine and phenytoin. Parameters of oxidative stress (glutathione, malondialdehyde), brain serotonin and serum calcium levels were also determined to probe the mechanism involved in the interaction. Test of parallelism revealed that 2 drugs were associated with non-parallel dose response effects, hence only one fixed ratio combination (1:1) was evaluated which displayed additive interaction between the 2 drugs with a slight tendency towards superadditivity. Free plasma concentrations of piperine and phenytoin revealed no significant changes in their concentrations when the drugs were combined at the fixed-ratio of 1:1. In combination, neither long-term memory nor skeletal muscular strength was impaired. Analysis of biochemical parameters showed that the piperine alone or in combination with phenytoin successfully reversed the parameters of oxidative stress and increased brain serotonin levels as compared to MES group. However, no significant alteration in the serum calcium levels was observed by any treatment. In conclusion, the combination displayed additive interaction and slight tendency towards synergistic potential with protection towards side effects associated with AED therapy and is worthy of consideration for further investigations.
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