Longitudinal 1H NMR metabolomics of serum in a chronic temporal lobe epilepsy model reveals systemic metabolic remodeling

Introduction: Temporal lobe epilepsy is associated with systemic metabolic alterations that may evolve during disease progression and in response to pharmacological treatment. This study employed a longitudinal 1H NMR-based metabolomics approach to characterize the serum metabolic profile of a chronic pilocarpine-induced rat model of temporal lobe epilepsy.Methods: Serum samples were collected longitudinally to identify phase-specific metabolic signatures. Following phenobarbital administration, animals were classified as drug-sensitive or drug-resistant according to their treatment response. The resulting metabolic profiles were investigated using multivariate and univariate statistical analyses.Results: The analysis revealed progressive systemic metabolic remodeling characterized by extensive alterations in lipid-related signals and significant increases in the ketone bodies 3-hydroxybutyrate and acetoacetate, as well as in glutamine. Following phenobarbital treatment, OPLS-DA showed a strong metabolic similarity between the drug-sensitive and drug-resistant groups, which occupied nearly identical metabolic spaces. Nevertheless, after stratification, creatine emerged as the only significantly different metabolite between responders and non-responders (p = 0.001).Discussion: The convergence of the metabolic profiles of drug-sensitive and drug-resistant animals suggests that the systemic effects of chronic epilepsy and phenobarbital treatment dominate the serum metabolome, potentially masking subtle molecular signatures associated with drug resistance. Creatine represents a notable exception and warrants further investigation as a potential marker distinguishing responders from non-responders.