Targeting Oxidative Stress With Combination Treatment of Alpha-Lipoic Acid and Antiseizure Drugs in Rodent Model: A Systematic Review

Abstract

Epilepsy is a chronic neurological disease marked by repeated seizures due to excessive neuronal activity, frequently linked to oxidative stress. Treatment in epilepsy involves chronic use of antiseizure drugs (ASDs) which further exacerbates oxidative stress. Given its role in epilepsy, oxidative stress has been a target for therapeutic intervention, with antioxidants being explored as potential agents to mitigate oxidative damage. This systematic review investigates studies which have used alpha lipoic acid (ALA) in conjunction with ASDs in rodents, and focuses on its antioxidant properties on oxidative stress, biochemical activity, molecular activity and behavioral outcomes. Following PRISMA guidelines, a comprehensive literature search across Google Scholar, ScienceDirect, Springer Link, and PubMed databases from 2020 to 2025 yielded 4622 studies, of which seven met the inclusion criteria. The results reveal that ALA, either alone or in combination with ASD, significantly mitigates oxidative stress by reducing malondialdehyde levels and enhancing the role of key antioxidants such as catalase, glutathione, superoxide-dismutase, etc. Additionally, ALA alleviates behavioral deficits and exhibits neuroprotective, hepato-protective, and anti-inflammatory effects. Furthermore, ALA modulates molecular markers by upregulating Nrf-2 and SIRT1 pathways while downregulating TNF-α and caspase 3, thereby reducing apoptosis and inflammation. Although promising, the findings are constrained by limited sample sizes, brief study periods, and a lack of comprehensive investigations on dose–response relationships and systemic effects. Most of the studies focus on limited biochemical and molecular markers, overlooking comprehensive evaluations of systemic and behavioral outcomes. This review highlights the potential of ALA as an adjunct therapy for epilepsy and emphasizes the need for more robust preclinical studies to confirm its efficacy and to fill the lacunas for advancing the therapeutic potential of ALA in epilepsy management.