Abstract
BACKGROUND: The ketogenic diet (KD) has been shown to effectively reduce seizures. Ketogenic medium-chain triglycerides (MCTs) enhance brain energy metabolism in adults with neurological disorders, but their effect on peripheral metabolites in children with epilepsy is unclear. The function and mechanisms of MCTs in pediatric epilepsy remain poorly understood. METHODS: We performed untargeted LC-MS metabolomics on blood samples from children with epilepsy (n = 14) and healthy controls (n = 20), identifying octanoic acid (OA) as significantly elevated. To explore its potential role, OA was administered in a PTZ-induced seizure model in juvenile mice. Behavioral analysis, Nissl staining, and immunofluorescence demonstrated that OA modulated seizure susceptibility and activated GPR40, a receptor expressed in neurons. RESULTS: (1) A total of 518 metabolites were examined in plasma samples, with the top 20 metabolites selected, of which 14 were upregulated and 6 were downregulated. (2) In the PTZ-induced epilepsy model, OA significantly prolonged seizure latency by 59.86 ± 7.032 s (P < 0.0001), without affecting seizure grade or duration. Mechanistically, OA enhanced GPR40 activation and inhibited astrocyte activation in the hippocampus. CONCLUSION: This study identified and validated peripheral blood metabolites in children with epilepsy. OA was found to exert a protective effect via GPR40 activation, enhancing neuroprotection. These findings suggest that OA may play a critical role in neuroprotection and could serve as a potential therapeutic target for pediatric epilepsy.