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Integrated proteomics and lipidomics analysis of hippocampus to reveal the metabolic landscape of epilepsy

ABSTRACT: Epilepsy is a group of chronic brain disorders characterized by recurrent, abnormal neuronal firing that causes temporary CNS dysfunction. Hippocampal sclerosis (HS) is identified as the predominant pathological alteration in epilepsy, particularly in temporal lobe epilepsy. This study investigates the metabolic profiles of epileptic hippocampal tissues using proteomics and lipidomics techniques. An epilepsy model was established in SD rats via intraperitoneal injection of PTZ, with hippocampal tissue samples subsequently extracted for histopathological examination. Proteomics analysis was conducted using iTRAQ combined with LC-MS/MS, while lipidomics analysis employed UHPLC Q-TOF/MS. Proteomic analysis revealed 144 differentially expressed proteins in acute epileptic hippocampus and 83 in chronic epileptic hippocampus. Key proteins, including Nefh, Vim, Gsn, Sirt2, Cnp, Mef2d, and Ctsd, were pivotal in epileptic hippocampal tissue injury and validated through PRM. Concurrently, lipid metabolomics revealed 83 differentially expressed metabolites in acute epileptic hippocampus and 142 in chronic epileptic hippocampus. Bioinformatics analysis indicated that glycerophospholipid, sphingolipid, and glyceride metabolism pathways were crucial in epileptic hippocampal tissue injury. Integrated proteomics and lipidomics analysis revealed significant correlations between Gsn, Ctsd, and Nefh with four metabolic pathways. These findings provide deeper insights into the pathophysiological mechanisms of epileptic hippocampal tissue damage, potentially unveiling novel therapeutic avenues for clinicians.

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Peng Zhang

PROVIDER: PXD056630 | iProX | Wed Oct 09 00:00:00 BST 2024

REPOSITORIES: iProX

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Project description:<h4><strong>INTRODUCTION: </strong>Approximately 1% of the world's population is impacted by epilepsy, a chronic neurological disorder characterized by seizures. One-third of epileptic patients are resistant to AEDs, or have medically refractory epilepsy (MRE). One non-invasive treatment that exists for MRE includes the ketogenic diet, a high-fat, low-carbohydrate diet. Despite the KD's success in seizure attenuation, it has a few risks and its mechanisms remain poorly understood. The KD has been shown to improve metabolism and mitochondrial function in epileptic phenotypes. Potassium channels have implications in epileptic conditions as they have dual roles as metabolic sensors and control neuronal excitation.</h4><h4><strong>OBJECTIVES: </strong>The goal of this study was to explore changes in the lipidome in hippocampal and cortical tissue from Kv1.1-KO model of epilepsy.</h4><h4><strong>METHODS: </strong>FT-ICR/MS analysis was utilized to examine nonpolar metabolome of cortical and hippocampal tissue isolated from a Kv1.1 channel knockout mouse model of epilepsy (n = 5) and wild-type mice (n = 5).</h4><h4><strong>RESULTS: </strong>Distinct metabolic profiles were observed, significant (p < 0.05) features in hippocampus often being upregulated (FC ≥ 2) and the cortex being downregulated (FC ≤ 0.5). Pathway enrichment analysis shows lipid biosynthesis was affected. Partition ratio analysis revealed that the ratio of most metabolites tended to be increased in Kv1.1-/-. Metabolites in hippocampal tissue were commonly upregulated, suggesting seizure initiation in the hippocampus. Aberrant mitochondrial function is implicated by the upregulation of cardiolipin, a common component in the mitochondrial membrane.</h4><h4><strong>CONCLUSION: </strong>Generally, our study finds that the lipidome is changed in the hippocampus and cortex in response to Kv1.1-KO indicating changes in membrane structural integrity and synaptic transmission.</h4>

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Integrated proteomics and lipidomics analysis of hippocampus to reveal the metabolic landscape of epilepsy

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