Anti-epileptic effect of saikosaponin a by inhibiting ferroptosis via the IL-17/Akt/ERK signaling pathway in the temporal lobe epilepsy model.

Abstract

Saikosaponin A (SSa), a triterpenoid saponin isolated from Astragalus membranaceus, possesses multiple pharmacological properties, including anticonvulsant, antiepileptic, and anti-inflammatory activities. This study aimed to elucidate the molecular mechanisms by which SSa exerts therapeutic effects in temporal lobe epilepsy (TLE), with a particular focus on the involvement of ferroptosis pathways. In a kainic acid-induced TLE mouse model, electroencephalography (EEG) was used to monitor seizure frequency. Behavioral tests were employed to evaluate cognitive, learning, and memory functions. Additionally, molecular biology techniques were used to investigate the neuroprotective mechanisms of SSa. EEG recordings showed that SSa treatment significantly reduced seizure frequency and severity. Behavioral assessments indicated improvements in cognition, learning, and memory. Histological analysis revealed decreased neuronal death in the hippocampus. Transmission electron microscopy and Golgi-Cox staining demonstrated a marked increase in hippocampal neuron density following SSa treatment. At the cellular level, SSa significantly downregulated the expression of IL-17, phosphorylated Akt (p-Akt), and phosphorylated ERK (p-ERK) in Erastin-induced ferroptotic hippocampal neurons. Notably, the inhibitory effect of SSa on ferroptosis was reversed by IL-17 agonist treatment, suggesting that IL-17 plays a pivotal role in this pathway. In conclusion, SSa alleviates seizures and improves cognitive function in TLE by inhibiting IL-17/Akt/ERK-mediated ferroptosis in hippocampal neurons.