Neuroinflammation, Oxidative Stress and Mitochondrial Dysfunction in Epilepsy: An Integrated Critical Review of Molecular Mechanisms and Therapeutic Opportunities
TL;DR
The integrated pathway is biologically credible and therapeutically attractive, but its clinical value will depend on identifying the patients, disease stages and molecular states in which each node is causal rather than merely reactive.
Abstract
Epilepsy is a heterogeneous brain disorder in which recurrent seizures arise from diverse genetic, structural, metabolic, immune and unknown causes. Neuroinflammation, oxidative stress and mitochondrial dysfunction have each been implicated in seizure generation and epileptogenesis, but their importance depends on whether they are initiating mechanisms, amplifiers of an established epileptic network, consequences of seizures, or markers of tissue injury. This critical narrative review integrates molecular, animal and human evidence to evaluate the bidirectional neuroimmune-redox-mitochondrial network and its therapeutic relevance. Literature from 1990 to 28 June 2026 was selected through live scholarly searching, citation tracing and bibliographic verification, with emphasis on peer-reviewed mechanistic studies, human biomarker or tissue investigations, clinical trials, consensus statements and high-quality reviews. The strongest causal evidence comes from experimental models in which interleukin-1 signalling, high-mobility group box 1-Toll-like receptor 4 signalling, blood-brain barrier transforming growth factor-beta pathways, reactive oxygen species generation, impaired antioxidant defences and mitochondrial respiratory defects can alter seizure threshold, neuronal injury or epileptogenesis. Human evidence confirms activation of several corresponding pathways, including glial and cytokine responses, translocator protein positron-emission tomography signals and mitochondrial respiratory abnormalities, but is often cross-sectional and vulnerable to confounding by recent seizures, antiseizure medicines and end-stage surgical tissue. Mitochondria appear to be a mechanistic convergence point because energetic failure and calcium dysregulation increase reactive oxygen species, while mitochondrial damage can release danger signals that recruit innate immunity. Recent experimental evidence linking mitochondrial DNA leakage to cyclic GMP-AMP synthase-stimulator of interferon genes signalling further sharpens this connection, although clinical validation is lacking. Therapeutically, ketogenic dietary therapies have established antiseizure efficacy, whereas anti-inflammatory and redox-directed approaches range from phenotype-specific clinical experience to predominantly preclinical disease-modification evidence. Future progress depends on mechanistic endotyping, longitudinal biomarkers, target-engagement measures and trials that separate acute seizure suppression from durable modification of epileptogenesis and comorbidity. The integrated pathway is therefore biologically credible and therapeutically attractive, but its clinical value will depend on identifying the patients, disease stages and molecular states in which each node is causal rather than merely reactive.