Glucocorticoid-regulated crosstalk between arachidonic acid and endocannabinoid biochemical pathways coordinates cognitive-, neuroimmune-, and energy homeostasis-related adaptations to stress.

Arachidonic acid and its derivatives constitute the major group of signaling molecules involved in the innate immune response and its communication with all cellular and systemic aspects involved on homeostasis maintenance. Glucocorticoids spread throughout the organism their influences over key enzymatic steps of the arachidonic acid biochemical pathways, leading, in the central nervous system, to a shift favoring the synthesis of anti-inflammatory endocannabinoids over proinflammatory metabolites, such as prostaglandins. This shift modifies local immune-inflammatory response and neuronal activity to ultimately coordinate cognitive, behavioral, neuroendocrine, neuroimmune, physiological, and metabolic adjustments to basal and stress conditions. In the hypothalamus, a reciprocal feedback between glucocorticoids and arachidonate-containing molecules provides a mechanism for homeostatic control. This neurochemical switch is susceptible to fine-tuning by neuropeptides, cytokines, and hormones, such as leptin and interleukin-1beta, assuring functional integration between energy homeostasis control and the immune/stress response.

17beta-oestradiol and progesterone regulate anandamide synthesis in the rat uterus.

Anandamide is an endocannabinoid known to participate in reproductive processes. This study observed that 17beta-oestradiol and progesterone modulated the production of anandamide and its metabolizing enzymes in the rat uterus. Anandamide production was highest at the oestrous stage and 17beta-oestradiol and progesterone stimulated its synthesis in ovariectomized rats. During early pregnancy, anandamide production remained constant on days 1-5 of gestation and diminished towards day 6. On day 6, implantation sites showed lower synthesis compared with interimplantation sites. In the delayed implantation model, 17beta-oestradiol inhibited anandamide synthesis compared with progesterone. During pseudopregnancy, anandamide production did not decrease towards day 6 as occurred during normal gestation. The administration of 17beta-oestradiol augmented anandamide production in rats on day 5 of pseudopregnancy; the treatment with mifepristone did not produce any change in anandamide synthesis. Anandamide-metabolizing enzymes were regulated by progesterone and 17beta-oestradiol. The effect of ovarian hormones on the synthesis of anandamide depends on different physiological conditions, oestrous cycle and early pregnancy, and on the presence of the activated blastocyst. Thus, ovarian hormones, as signals that emanate from the mother, operate in conjunction with the blastocyst intrinsic programme, regulating the synthesis of anandamide in a specific manner during crucial reproductive events that may compromise pregnancy outcome.

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

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 acid-containing endocannabinoids 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.