Glucocorticoids shift arachidonic acid metabolism toward endocannabinoid synthesis: A non-genomic anti-inflammatory switch

Abstract

Glucocorticoids are capable of exerting both genomic and non-genomic actions in target cells of multiple tissues, including the brain, which trigger an array of electrophysiological, metabolic, secretory and inflammatory regulatory responses. Here, we have attempted to show how glucocorticoids may generate a rapid anti-inflammatory response by promoting arachidonic acidderived endocannabinoid biosynthesis. According to our hypothesized model, non-genomic action of glucocorticoids results in the global shift of membrane lipid metabolism, subverting metabolic pathways toward the synthesis of the anti-inflammatory endocannabinoids, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), and away from arachidonic acid production. Post-transcriptional inhibition of cyclooxygenase-2 (COX 2 ) synthesis by glucocorticoids assists this mechanism by suppressing the synthesis of pro-inflammatory prostaglandins as well as endocannabinoid-derived prostanoids. In the central nervous system (CNS) this may represent a major neuroprotective system, which may cross-talk with leptin signaling in the hypothalamus allowing for the coordination between energy homeostasis and the inflammatory response.

A quantitiative LC-MS/MS method for the measurement of arachidonic acid, prostanoids, endocannabinoids, N-acylethanolamines and steroids in human plasma

“…Furthermore, N-acylethanolamines other than AEA, which exhibit distinct saturated or unsaturated fatty acids and show no (or little) direct effect on CB receptors (i.e., linoleoyl ethanolamide (LEA), palmitoyl ethanolamide (PEA), oleoyl ethanolamide (OEA), stearoyl ethanolamide (SEA)), have been shown to act as ECs entourage molecules, possibly acting in concert with ECs [15][16][17][18]. Yet another important class of signaling lipids involves the steroids, which appear to functionally interlink the different AA lipid signaling networks, including the endocannabinoid system [19,20]. Steroids (glucocorticoids and mineralocorticoids) are involved in numerous physiological processes, including immunomodulation [21].…”

Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

“…In parallel, interactions between endocannabinoids and the HPA axis are reciprocal. Studies have shown that glucocorticoids can activate the release of endocannabinoids, AEA and 2-AG [152]. Conversely, endocannabinoids act efficiently to regulate stress response, partly by modulating the glucocorticoid system [150,153].…”

Cannabinoid receptor expression and phosphorylation are differentially regulated between male and female cerebellum and brain stem after repeated stress: Implication for PTSD and drug abuse

“…It is known that females have higher basal corticosteroid levels and greater stress-induced corticosteroid secretion but slower corticosteroid clearance from circulation [8,9]. Chronic exposure to corticosterone, CB 1 agonists and cannabinoids has been shown to downregulate CB 1 receptor density, CB 1 receptor binding and CB 1 mRNA expression in brain regions such as cerebellum and hippocampus [15,22,26,37,41].…”