Stearoylethanolamide

Stearoylethanolamide interferes with retrograde endocannabinoid signalling and supports the blood-brain barrier integrity under acute systemic inflammation

Neuroinflammation plays a prominent role in the onset of demyelinating diseases, major depressive disorder and delayed neurodegeneration. An open question remains whether pharmacological suppression of inflammation can effectively reduce the progression of these states. Bioactive lipid mediators such as N-acylethanolamines (NAEs) have an anti-inflammatory activity and are of pharmacological interest due to their endogenous on-demand production and the existence of distinct biological targets in humans and animals. Here we demonstrate for the first time, that treatment with stearoylethanolamide (SEA), a prevailing endogenously formed NAE, is neuroprotective against LPS-induced neuroinflammation in C57BL/6 male mice. SEA restricted the spreading of peripheral inflammation to the brain, and averted the activation of resident microglia and leukocyte trafficking to the brain parenchyma. Treatment with SEA per se increased the neuronal expression of cannabinoid receptors CB1/2 and brain levels of the most potent endogenous CB1/2 agonist 2-arachidonoylglycerol in vivo. SEA enhanced the amplitude of synaptic vesicle release, supported the balanced signal-to-noise ratio in glutamate- and GABAergic neurotransmission and decreased the excitotoxic risk associated with higher extracellular glutamate levels under neuroinflammation. The interference of SEA with the endocannabinoid system and presynaptic neurotransmitter release may represent an intrinsic neuroprotective mechanism that is triggered by inflammation and glutamate excitotoxicity. Thus, our data allows to consider SEA for the preventive therapy of acute and late-onset neuroinflammation-associated synaptic dysfunction and neurodegeneration.

Stearoylethanolamide exerts anorexic effects in mice via down-regulation of liver stearoyl-coenzyme A desaturase-1 mRNA expression

Given the recent demonstration that oleoylethanolamide (OEA), a cannabinoid receptor-inactive N-acylethanolamine, decreases food intake by activating the nuclear receptor PPARalpha (peroxisome proliferator-activated receptor alpha) in the periphery, we here evaluated the effects of both saturated and unsaturated C18 N-acylethanolamides (C18:0; C18:1; C18:2) in mice feeding behavior after overnight starvation. Our results show stearoylethanolamide (SEA, C18:0) exerts, unlike other unsaturated C18 homologs, a marked dose-dependent anorexic effect evident already at 2 h after its intraperitoneal administration. In addition, oral administration of SEA (25 mg/kg) was also effective in reducing food consumption, an effect ascribed to the molecule itself and not to its catabolites. Moreover, although the anorexic response to oral administered SEA was not associated with changes in the levels of various hematochemical parameters (e.g., glucose, cholesterol, triglycerides, leptin) nor in liver mRNA expression of peroxisome proliferator-activated receptors (PPARs) including PPARalpha, the anorexic effect of SEA was interestingly accompanied by a reduction in liver stearoyl-CoA desaturase-1 (SCD-1) mRNA expression. As SCD-1 has been recently proposed as a molecular target for the treatment of obesity, the novel observation provided here that SEA reduces food intake in mice in a structurally selective manner, in turn, correlated with downregulation of liver SCD-1 mRNA expression, has the potential of providing new insights on a class of lipid mediators with suitable properties for the pharmacological treatment of over-eating dysfunctions.

Satiety Factors Oleoylethanolamide, Stearoylethanolamide, and Palmitoylethanolamide in Mother's Milk Are Strongly Associated with Infant Weight at Four Months of Age-Data from the Odense Child Cohort

Regulation of appetite and food intake is partly regulated by N-acylethanolamine lipids oleoylethanolamide (OEA), stearoylethanolamide (SEA), and palmitoylethanolamide (PEA), which induce satiety through endogenous formation in the small intestine upon feeding, but also when orally or systemic administered. OEA, SEA, and PEA are present in human milk, and we hypothesized that the content of OEA, SEA, and PEA in mother's milk differed for infants being heavy (high weight-for-age Z-score (WAZ)) or light (low WAZ) at time of milk sample collection. Ultra-high performance liquid chromatography-mass spectrometry was used to determine the concentration of OEA, SEA, and PEA in milk samples collected four months postpartum from mothers to high (n = 50) or low (n = 50) WAZ infants. Associations between OEA, SEA, and PEA concentration and infant anthropometry at four months of age as well as growth from birth were investigated using linear and logistic regression analyses, adjusted for birth weight, early infant formula supplementation, and maternal pre-pregnancy body mass index. Mean OEA, SEA, and PEA concentrations were lower in the high compared to the low WAZ group (all p < 0.02), and a higher concentration of SEA was associated with lower anthropometric measures, e.g., triceps skinfold thickness (mm) (β = -2.235, 95% CI = -4.04, -0.43, p = 0.016), and weight gain per day since birth (g) (β = -8.169, 95% CI = -15.26, -1.08, p = 0.024). This raises the possibility, that the content of satiety factors OEA, SEA, and PEA in human milk may affect infant growth.

Binding, degradation and apoptotic activity of stearoylethanolamide in rat C6 glioma cells

Stearoylethanolamide (SEA) is present in human, rat and mouse brain in amounts comparable with those of the endocannabinoid anandamide (arachidonoylethanolamide; AEA). Yet, the biological activity of SEA has never been investigated. We synthesized unlabelled and radiolabelled SEA to investigate its binding, degradation and biological activity in rat C6 glioma cells. We report that SEA binds to a specific site distinct from known cannabinoid or vanilloid receptors, and that AEA and capsazepine partly (approx. 50%) antagonized this binding. Treatment of C6 cells with SEA inhibits cellular nitric oxide synthase and does not affect adenylate cyclase, whereas treatment with cannabinoid type 1 agonist 2-arachidonoylglycerol activates the former enzyme and inhibits the latter. C6 cells also have a specific SEA membrane transporter, which is inhibited by NO, and a fatty acid amide hydrolase capable of cleaving SEA. In these cells, SEA shows pro-apoptotic activity, due to elevation of intracellular calcium, activation of the arachidonate cascade and mitochondrial uncoupling. NO further enhances SEA-induced apoptosis. Moreover, the cannabinoid type 1 receptor-mediated decrease in cAMP induced by AEA in C6 cells is potentiated by SEA, suggesting that this compound also has an 'entourage' effect. Taken together, this study shows that SEA is an endocannabinoid-like compound which binds to and is transported by new components of the endocannabinoid system. It seems noteworthy that degradation and pro-apoptotic activity of SEA are regulated by NO in a way opposite to that reported for AEA.

Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity

Chronic widespread pain (CWP) is a complex condition characterized by central hyperexcitability and altered descending control of nociception. However, nociceptive input from deep tissues is suggested to be an important drive. N-Acylethanolamines (NAEs) are endogenous lipid mediators involved in regulation of inflammation and pain. Previously we have reported elevated levels of the 2 NAEs, the peroxisome proliferator-activated receptor type-α ligand N-palmitoylethanolamine (PEA) and N-stearoylethanolamine (SEA) in chronic neck/shoulder pain (CNSP). In the present study, the levels of PEA and SEA in women with CWP (n=18), CNSP (n=34) and healthy controls (CON, n=24) were investigated. All subjects went through clinical examination, pressure pain threshold measurements and induction of experimental pain in the tibialis anterior muscle. Microdialysis dialysate of the trapezius was collected before and after subjects performed a repetitive low-force exercise and analyzed by mass spectrometry. The levels of PEA and SEA in CNSP were significantly higher post exercise compared with CWP, and both pre and post exercise compared with CON. Levels of both NAEs decreased significantly pre to post exercise in CWP. Intercorrelations existed between aspects of pain intensity and sensitivity and the level of the 2 NAEs in CWP and CNSP. This is the first study demonstrating that CNSP and CWP differ in levels of NAEs in response to a low-force exercise which induces pain. Increases in pain intensity as a consequence of low-force exercise were associated with low levels of PEA and SEA in CNSP and CWP. These results indicate that PEA and SEA have antinociceptive roles in humans.