Neuroprotective Effects of Piper methysticum against Phenytoin-Induced Cognitive Impairment in Mice

Abstract

Cognitive impairments are a common comorbidity in epileptic patients, resulting from both the underlying neurological disorder and antiepileptic medication. Phenytoin, a widely prescribed anticonvulsant, has been shown to negatively impact cognitive function. This investigation aims to assess the efficacy of methanol root extract of Piper methysticum (MREPM) in mitigating phenytoin-induced cognitive impairments in a pentylenetetrazole (PTZ) kindled mouse model. The MREPM extract was evaluated in vivo, where kindled mice received post-treatment with phenytoin (40 mg/kg, p.o.) alone or in combination with MREPM extract at doses of 100, 200, and 400 mg/kg (p.o.) for 14 days. Seizure severity score and cognitive functions were accessed using (a) PTZ kindling induction and (b) passive-avoidance (PA) task.  Treatment with phenytoin per se and along with MREPM showed significant reduction in seizure severity score as compared to vehicle control. Administration of phenytoin (40 mg/kg, p.o.) for 14 days significantly impaired cognitive performance in the passive avoidance (PA) task. Co-administration of MREPM extract (100 mg/kg for 7 days) with phenytoin during the second week of treatment significantly mitigated Phenytoin (PHT)-induced cognitive impairment (1.92±0.03 and .48±0.05) compare with control (5.34±0.12 and 4.81±0.21) at 7th and 14th week, respectively.  The results demonstrated that MREPM improved memory acquisition and retention, while preserving the anticonvulsant activity of phenytoin. The results of this study indicate that the combination of MREPM with phenytoin leads to a decrease in seizure severity and an improvement in cognitive function in mice kindled with PTZ, indicating a potential therapeutic benefit of MREPM in mitigating PHT-associated cognitive impairment.