Combination of metformin and sub-therapeutic dose of valproic acid prevent valproic acid-induced toxicity in animal model of epilepsy

Abstract

Valproic acid (VPA) is one of the most prescribed drugs for epilepsy. Extended use of VPA not only induces hepatotoxicity but also impairs the cognitive functions. Metformin has been reported to prevent epileptogenesis and enhance memory. To counter the VPA-induced adverse events, it is hypothesized that combination of sub-therapeutic dose of VPA with metformin may attenuate the toxicity stemming from the therapeutic dose of VPA. Pentylenetetrazole (PTZ)-induced kindling model of epilepsy in mice was used to assess the combined effects of sub-therapeutic dose of VPA (100 mg/kg) and metformin (200 mg/kg). The memory performance was analyzed by passive avoidance test, while alkaline comet assay was used to determine genotoxicity. Histopathological examination and serum biochemical analysis was performed to determine hepatotoxicity. Results showed that combination dose of VPA with metformin reduced seizure scores. VPA (300 mg/kg) administered as a single agent did not enhance memory impairment caused by PTZ, however, combination of sub-therapeutic dose of VPA with metformin enhanced memory function. Furthermore, in alkaline comet assay, combination therapy demonstrated reduced genotoxicity compared to the VPA 300 mg/kg. Histopathological examination of liver and analysis of serum hepatic enzymes revealed that combination therapy (VPA + metformin) reversed the toxicity as seen in case of PTZ or VPA (300 mg/kg) treated animals with no other treatment given. Based on the study data, it is concluded that the combination of sub-therapeutic dose of VPA with metformin might be used for epileptic seizures. This will prevent the hepatotoxicity and enhanced memory functions as compared to the VPA given as a single agent therapy.

Keywords:

• Epilepsy
• metformin
• Valproic acid
• hepatotoxicity
• memory impairment

Acknowledgement

We acknowledge the organizers of ISN-APSN 2022 Meeting, to publish the abstract of this article in the conference abstract book in the Journal of Neurochemistry, Volume 162, issue S1, Abstract No. WTH 10–02.

Ethical approval

This research was approved by the Animal Research Ethics Committee of the ICCBS, University of Karachi (license number 2019–006). Procedures involving animals and their care were carried out in conformity with international guidelines for the use of laboratory animals (NIH Guide for the Care and Use of Laboratory Animals, NIH Publications No. 85–23, 1985).

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The final content of this paper was read and approved by all authors for publication.

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