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

Abstract

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.