Broad lipidomic and transcriptional changes of prophylactic PEA administration in adult mice

Abstract

Beside diverse therapeutic properties of palmitoylethanolamide (PEA) including: neuroprotection neuroprotection, inflammation and pain alleviation, prophylactic effects have also been reported in animal animal models of infections, inflammation, neurological diseases, etc. The availability of PEA as (ultra)micronized nutraceutical formulations with reportedly no side effects, renders it accordingly accordingly an appealing candidate in human preventive care, such as in population at high risk of disease disease development or for healthy aging. PEA’s mode of action is multi-faceted. Consensus exists that that PEA’s effects are primarily modulated by the peroxime proliferator-activated receptor alpha (PPARα) and that PEA-activated PPARα has a pleiotropic effect on lipid metabolism, inflammation gene gene networks, host defense mechanisms, etc. Yet, an exhaustive view of how the prophylactic PEA administration administration changes the lipid signaling in brain and periphery so as to elicit a beneficial response response to various negative stimuli remains still elusive. We therefore, undertook a broad lipidomic lipidomic and transcriptomic study in brain and spleen of control mice to unravel the positive molecular molecular phenotype rendered by prophylactic PEA. We applied a tissue lipidomic and transcriptomic approach approach based on simultaneous extraction and subsequent targeted liquid chromatography multiple reaction reaction monitoring (LC-MRM) and mRNA analysis by qPCR, respectively. We targeted lipids of COX-2 and LOX-pathways, membrane phospholipids, lipid products of cPLA2, and free fatty acids, along with various various genes involved in their biosynthesis and function. Additionally, plasma lipidomics was applied applied to reveal circulatory consequences and/or reflection of PEA’s action. We found broad, distinct distinct, and several previously unknown tissue transcriptional regulation of inflammatory pathways pathways. In hippocampus also transcriptional regulation by PEA of neuronal activity and excitability excitability was evidenced. A massive downregulation of membrane lipid levels in the splenic tissue of of the immune system with a consequent shift toward pro-resolving lipid environment was also detected detected. Plasma lipid pattern reflected to a large extent the hippocampal and splenic lipidome changes changes, highlighting the value of plasma lipidomics to monitor effects of nutraceutical PEA administration administration. Altogether, these findings contribute new insights into PEA’s molecular mechanism and helps answering the question: how PEA prepares the body for insults and what are the “good lipids lipids” that underlie this action?