Potencjał terapeutyczny formonunetyny w opornej na leki epilepsji: badania na modelu myszy z rotenon-PTZ-lamotrygyną

Drug-resistant epilepsy (DRE) affects nearly one-third of individuals with epilepsy and remains a major therapeutic challenge despite the availability of multiple antiseizure medications. Mitochondrial dysfunction and chronic neuroinflammation, particularly NLRP3 inflammasome activation, are increasingly recognized as key contributors to pharmacoresistance. Formononetin, a plant-derived isoflavone, has shown anticonvulsant and neuroprotective effects in pentylenetetrazol (PTZ) kindled mice by restoring glutamate-GABA balance and attenuating neuroinflammatory signaling. The present study explored the therapeutic potential of formononetin in a rotenone-PTZ-lamotrigine mouse model of DRE. Mice were subjected to rotenone-adjuvant PTZ kindling in the presence of lamotrigine to induce a refractory seizure phenotype and were subsequently treated with formononetin. Seizure severity was quantified using the Racine scale, and GABA and glutamate levels were measured in whole-brain tissue. Oxidative and inflammasome-related changes were assessed by estimating NAD(P)H: quinone oxidoreductase-1 (NQO1), IL-1β, and caspase-1 in hippocampal and cortical regions using ELISA. We also evaluated astroglial and microglial activation by GFAP and Iba1 expression in the hippocampus and cortex. Formononetin treatment reduced seizure severity, improved the excitatory-inhibitory neurotransmitter balance, enhanced NQO1 levels, and attenuated IL-1β levels and caspase-1 activation, accompanied by a marked reduction in GFAP and Iba1-positive glial reactivity. These findings suggest that formononetin confers anticonvulsant and neuroprotective effects in a mitochondrial dysfunction-linked, lamotrigine-resistant epilepsy model, likely via coordinated modulation of oxidative defense, NLRP3-caspase-1 signaling, and glial activation. Formononetin thus emerges as a promising adjunctive candidate for managing drug-resistant epilepsy, warranting further mechanistic and translational investigation.