Asarone

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.

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.

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.

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.

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.

Dravet syndrome (DS), a rare and severe developmental encephalopathy in children classified as a refractory epilepsy syndrome, presents significant challenges in therapeutic development with urgent unmet needs. α-Asaronol (α-AOL), a terminal hydroxylated metabolite of α-asarone (α-A) and an active constituent of Acorus plants, has demonstrated potent anti-seizure effects in mouse and zebrafish models based on preliminary studies. However, its therapeutic potential for DS remains unexplored. Given the pediatric focus of this research, parallel investigation of its primary metabolites (α-OA and α-TMCA) is imperative to ensure safety. This study aims to (1) validate the general anti-seizure activities of α-OA and α-TMCA, (2) evaluate their comparative efficacy against DS alongside α-AOL, and (3) elucidate underlying mechanisms. We systematically assessed anti-seizure activities using pentylenetetrazol-induced seizure models in zebrafish and mice, followed by rigorous evaluation in a zebrafish DS model (scn1Lab^-/- mutants). Mechanistic pathways were investigated through GABA_A receptor modulation, energy metabolism regulation, and molecular docking analyses. Results revealed dose-dependent anti-seizure efficacy across all models, with potency ranking α-AOL > α-A > α-OA ≫ α-TMCA. Notably, α-AOL exhibited superior efficacy in scn1Lab^-/- mutants compared to α-asarone and reference drugs stiripentol and cannabidiol. Mechanistic studies identified dual pathways for α-AOL: potentiation of GABA_A receptor currents (EC₅₀ = 34.0 μmol/L) and inhibition of neuronal lactate dehydrogenase activity. These findings establish terminal oxidation of α-asarone as a critical metabolic pathway enhancing anti-seizure efficacy while reducing toxicity, positioning α-AOL as a promising lead compound for DS therapeutics.