α-asaronol alleviates seizures, neuroinflammation and cognitive deficits in a mice model of lithium-pilocarpine-induced seizures.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Temporal lobe epilepsy (TLE) is often drug-resistant and accompanied by cognitive deficits and anxiety, which are inadequately addressed by current anti-seizure medications. Acorus tatarinowii Schott, a traditional remedy for convulsions and neurological disorders, contains bioactive components - α-asarone, α-asaronol and β-asarone -capable of crossing the blood-brain barrier, yet their comparative efficacy and mechanisms in epilepsy remain unclear. AIM OF THE STUDY: This study systematically compared the anti-epileptic effects of α-asarone, α-asaronol, and β-asarone from A. tatarinowii Schott, and investigated the mechanism of the most active compound. MATERIALS AND METHODS: Anticonvulsant activity was evaluated using maximal electroshock seizure (MES) test and pentylenetetrazol (PTZ)-induced acute seizure models. The most promising component was further studied in a chronic lithium-pilocarpine (LIP)-induced TLE model. Mechanisms were explored via integrated multi-omics analysis, including network pharmacology, proteomics, metabolomics, and molecular dynamics simulations. RESULTS: α-Asaronol demonstrated superior and earlier-onset seizure protection compared to α-asarone, and β-asarone. In chronic TLE, it dose-dependently reduced seizure frequency and duration, while alleviating cognitive impairment and anxiety. α-Asaronol also attenuated hippocampal neuronal loss, glial activation, and shifted microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype, suppressing TNF-α, IL-1β, and IL-6 release. Mechanistically, it targeted PPARγ, modulated PPAR-related signaling, and restored epilepsy-associated disruptions in taurine/hypotaurine and pyrimidine metabolism. CONCLUSION: α-Asaronol from A. tatarinowii Schott exerts multi-faceted anti-epileptic effects, not only suppressing seizures but also improving comorbidities, likely through PPARγ-mediated anti-inflammatory and metabolic modulation. It represents a promising candidate for the treatment of drug-resistant TLE and its co-occurring neuropsychiatric symptoms.