Targeting Microglial Activation in Drug-Resistant Epilepsy: Emerging Therapeutic Strategies

Neuroinflammation has emerged as a central mechanism in the pathogenesis of epilepsy, particularly in drug-resistant epilepsy (DRE), where conventional antiseizure medications fail to achieve adequate control. Accumulating evidence indicates that inflammatory processes within the central nervous system contribute not only to seizure initiation but also to their perpetuation and pharmacoresistance. Among the key cellular mediators that play a pivotal role in neuroinflammation is microglia, which are the resident immune cells of the brain. In response to neuronal injury, infection, or recurrent seizures, microglia undergo activation and adopt diverse phenotypes ranging from pro-inflammatory to neuroprotective states. However, sustained or dysregulated microglial activation promotes the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species, thereby exacerbating neuronal hyperexcitability, disrupting synaptic function, and facilitating epileptogenesis. Recent researches have increasingly focused on targeting microglial activation as a therapeutic strategy in DRE. Preclinical and clinical studies have explored a range of anti-inflammatory interventions, including cytokine inhibitors, modulators of microglial signaling pathways such as Toll-like receptor and NF-κB pathways, and repurposed agents like minocycline and corticosteroids. Additionally, emerging therapies aimed at selectively modulating microglial phenotypes, shifting from pro-inflammatory to neuroprotective states, offer promising avenues for intervention. Despite these advances, challenges remain in translating these strategies into routine clinical practice, including issues of specificity, timing of intervention, and potential systemic side effects. Therapeutically, targeting microglial activation holds significant promise for addressing the unmet needs in DRE by not only reducing seizure frequency but also potentially modifying disease progression. A deeper understanding of microglial biology and its interaction with neuronal networks may facilitate the development of precision therapies tailored to inflammatory profiles in epilepsy. This review highlights the evolving landscape of microglia-targeted therapies and underscores their potential as a novel and complementary approach in the management of drug-resistant epilepsy.