Therapeutic potential of N-acetylcysteine in epilepsy: A systematic review

Abstract

Background: Epilepsy is a long-term neurological disorder that is defined by repeated seizures, often resistant to standard anti-seizure medications. Oxidative stress, mitochondrial impairment, and neuroinflammation are central to epileptogenesis. N-acetylcysteine (NAC), an antioxidant and glutathione precursor, was shown to possess potential neuroprotective properties in model systems, and therefore systematic assessment was indicated.

Methods: This systematic review was conducted in accordance with PRISMA 2020. The databases accessed were PubMed, Scopus, Web of Science, EMBASE, ScienceDirect, and the Cochrane Library up to December 2024. The inclusion criteria were controlled experimental animal studies reporting the measurement of NAC in epilepsy models. Extraction of data on seizure frequency reduction, oxidative stress modulation, mitochondrial integrity, behavioral scoring, and histopathological changes was emphasized. Bias was assessed with the SYRCLE tool.

Results: Eight studies were identified to be included. NAC doses ranged from 0.1 mg/L (immersion in water) to 600 mg/kg (intraperitoneal) with treatment durations from a single acute administration to 40-day chronic treatment. Statistically significant reduction of frequency and severity of seizures was noted in 75% of studies with a reduction in percentages of EEG spikes in a dose-dependent manner and an increase in latency of seizures up to 135% being obtained. MDA levels decreased and SOD activity increased in all described models. Chronic treatment increased mitochondrial membrane potential and controlled mTOR and Drp1 expression. Aggravation of seizures was noted at doses higher than 500 mg/kg/day in absence epilepsy models with weight loss and motor impairment at higher chronic doses.

Conclusion: NAC exerted anticonvulsant, antioxidant, and neuroprotective actions in preclinical models of epilepsy in a dose- and duration-dependent manner. Although encouraging, the side effects occurred at high dose levels, stressing dose optimization and additional translational studies to delineate therapeutic windows.