Tetracosahexaenoylethanolamide, a novel n-acylethanolamide, is elevated in ischemia and increases neuronal output

Lin Lin, Adam H Metherel, Mathieu Di Miceli, Zhen Liu, Cigdem Sahin, Xavier Fioramonti, Carolyn L. Cummins, Sophie Layé, Richard P. Bazinet
J. Lipid Res.. 2020-08-21; : jlr.RA120001024
DOI: 10.1194/jlr.ra120001024

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N-acylethanolamines (NAEs) are endogenous lipid-signaling molecules derived from fatty acids that regulate numerous biological functions, including in the brain. Interestingly, NAEs are elevated in the absence of fatty acid amide hydrolase (FAAH) and following CO2-induced ischemia/hypercapnia, suggesting a neuroprotective response. Tetracosahexaenoic acid (THA) is a product and precursor to docosahexaenoic acid (DHA), however, the NAE product – tetracosahexaenoylethanolamide (THEA) – has never been reported. Presently, THEA was chemically synthesized as an authentic standard to confirm THEA presence in biological tissues. Whole brains were collected and analyzed for unesterified THA, total THA and THEA in wild-type and FAAH-KO mice that were euthanized by either head-focused microwave fixation, CO2 + microwave or CO2 only. PPAR activity by transient transfection assay and ex vivo neuronal output in medium spiny neurons (MSN) of the nucleus accumbens by patch clamp electrophysiology were determined following THEA exposure. THEA in the wild-type mice was nearly doubled (p<0.05) following ischemia/hypercapnia (CO2 euthanization) and up to 12-times higher (p<0.001) in the FAAH-KO compared to wild-type. THEA did not increase (p>0.05) transcriptional activity of PPARs relative to control, but 100nM THEA increased (p<0.001) neuronal output in MSN of the nucleus accumbens. Here were identify a novel NAE, THEA, in the brain that is elevated upon ischemia/hypercapnia and by knockout of the FAAH enzyme. While THEA did not activate PPAR, it augmented the excitability of MSN in the nucleus accumbens. Overall, our results suggest THEA is a novel NAE that is produced in the brain upon ischemia/hypercapnia and regulates neuronal excitation.

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