Targeting brain and peripheral plasticity of the lipidome in acute kainic acid-induced epileptic seizures in mice via quantitative mass spectrometry

• Changes of the phospholipid, endocannabinoid, endocannabinoid-like molecule, arachidonic acid and eicosanoid levels, respectively, occur in brain and periphery of mice with kainic acid induced acute epileptic seizures.
• Hippocampus, hypothalamus, cerebellum, striatum, cortex and thalamus of acute epileptic seizure mice exhibit distinct and specific lipid changes.
• Lipid alteration occurs, distinctly, in lungs and hearts of mice with kainic acid induced epileptic seizures.
• Lipid signatures of kainic acid induced acute epileptic seizure in mouse plasma reflect dysregulation of the endocannabinoid system, inflammatory processes and phospholipid metabolism.

Epilepsy is a highly common chronic neurological disorder, manifested in many different types, affecting ~ 1% of the worldwide human population. The molecular mechanisms of epileptogenesis have not yet been clarified, and pharmacoresistance exhibited by 30–40% of epilepsy patients remains a major obstacle in medical care. Growing evidence indicates a role of lipid signalling pathways in epileptogenesis, thus lipid signals emerge as potential biomarkers for the onset and evolving course of the epileptic disorder, as well as potential therapeutic agents and targets. For this purpose, we applied a lipidomic strategy to unravel lipid alterations in brain regions, periphery tissues and plasma that are specific for acute epileptic seizures in mice at 1 h after seizure induction by systemic kainic acid injection as compared to vehicle controls. Specifically, levels of (i) selected phospholipids and sphingomyelins, (ii) the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), and the endocannabinoid-related compounds oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), (iii) arachidonic acid (AA), (iv) selected eicosanoids, and (v) fatty acyl content of lipidome were determined in pulverized tissues from six brain regions of kainic acid induced epileptic seizure models and vehicle controls: hypothalamus, hippocampus, thalamus, striatum, cerebellum and cerebral cortex, and from peripheral organs, such as heart and lungs, and in plasma. Alterations in lipid levels after acute epileptic seizures as compared to non-seizure controls were found to be brain region- and periphery tissue-specific, including specific plasma lipid correlates, highlighting their value as marker candidates in translational research studies, and/or drug discovery and response monitoring.

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