Jamal Muhammad, Azam Muhammad, Simjee Shabana Usman
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
Drug Chem Toxicol. 2024 May;47(3):287-295. doi: 10.1080/01480545.2023.2168689. Epub 2023 Jan 17.
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.
丙戊酸（VPA）是治疗癫痫最常用的药物之一。长期使用VPA不仅会导致肝毒性，还会损害认知功能。据报道，二甲双胍可预防癫痫发生并增强记忆力。为了对抗VPA引起的不良事件，有人提出将亚治疗剂量的VPA与二甲双胍联合使用，可能会减轻治疗剂量VPA所产生的毒性。采用戊四氮（PTZ）诱导的小鼠癫痫点燃模型，评估亚治疗剂量的VPA（100mg/kg）和二甲双胍（200mg/kg）的联合作用。通过被动回避试验分析记忆表现，同时采用碱性彗星试验测定遗传毒性。进行组织病理学检查和血清生化分析以确定肝毒性。结果表明，VPA与二甲双胍联合用药可降低癫痫发作评分。单独给予VPA（300mg/kg）不会加重PTZ引起的记忆损害，然而，亚治疗剂量的VPA与二甲双胍联合使用可增强记忆功能。此外，在碱性彗星试验中，联合治疗与300mg/kg VPA相比，遗传毒性降低。肝脏组织病理学检查和血清肝酶分析显示，联合治疗（VPA+二甲双胍）可逆转PTZ或VPA（300mg/kg）治疗动物（未给予其他治疗）所出现的毒性。根据研究数据得出结论，亚治疗剂量的VPA与二甲双胍联合使用可能用于癫痫发作。与单独使用VPA治疗相比，这将预防肝毒性并增强记忆功能。
