Urolithin A pretreatment protects against seizures through IGF-1R Tyr1166/1167 phosphorylation inhibition and enhances the antiseizure effect of valproic acid

Abstract Urolithin A (UA), a metabolite derived from gut microbiota that originates from ellagitannins found in pomegranate, berries, and walnuts, has emerged as a promising postbiotic exhibiting mitophagy-inducing and neuroprotective properties. This study examined the antiseizure effects of UA pretreatment and its potential to enhance the efficacy of valproic acid (VPA), a first-line antiseizure medication, using a pilocarpine-induced status epilepticus (SE) rat model. UA significantly reduced seizure stage, prolonged latency, shortened duration, and decreased incidence of seizures, while alleviating SE-induced behavioral and cognitive impairments. Network pharmacology revealed insulin-like growth factor 1 receptor (IGF-1R) as a critical target of UA. Subsequent experiments demonstrated that UA exerts its therapeutic effects by inhibiting the phosphorylation of IGF-1R. Importantly, the combination of UA and VPA yielded enhanced antiseizure effects compared to either treatment alone in mitigating seizures and behavioral comorbidities. These findings suggest that UA may serve as a valuable adjuvant to conventional antiseizure therapy. Additionally, this study elucidates the antiseizure potential of UA as a pomegranate-derived postbiotic, providing experimental evidence from an animal model to support a UA-VPA combination strategy aimed at improving the efficacy of epilepsy treatment.