Lovastatin Modulates Cortical Excitability, E/I Balance, and Antioxidant Markers in Drug-Resistant Epilepsy: A Proof-of-Concept Study

Background Drug-resistant epilepsy (DRE) is a major clinical challenge, with neuroinflammation and excitatory/inhibitory (E/I) imbalance implicated in its pathophysiology. This proof-of-concept case series aimed to investigate the neurochemical and neurophysiological effects of a short course of lovastatin in individuals with DRE. Methods Five participants with drug-resistant temporal lobe epilepsy completed a double-blind, placebo-controlled, crossover protocol involving oral administration of lovastatin (60 mg/day) and placebo for three consecutive days. Post-intervention assessments included: 1) magnetic resonance spectroscopy (MRS) in the visual cortex to quantify GABA+, Glutamate (Glx), and Glutathione (GSH); 2) resting-state EEG to measure the frequency of interictal epileptiform discharges (IEDs); and 3) event-related potentials (ERPs) during a facial recognition task. Results Compared to placebo, lovastatin administration was associated with a significant reduction in the GABA+/Glx ratio (p = 0.041) and IED frequency (p = 0.04), alongside a significant increase in GSH concentration (p = 0.039). Lovastatin also modulated visual processing ERPs, significantly delaying the P100 latency (p = 0.04) and reducing the absolute N110 peak amplitude (p = 0.04). Conclusion This study demonstrates that a short course of lovastatin can modulate key in-vivo biomarkers of E/I balance, redox state, and cortical excitability in patients with DRE. These preliminary findings provide a mechanistic rationale for further, larger studies to explore the potential of statins as a novel strategy for modifying pathological brain activity.