Oleamide

Results from in vitro and ex vivo skin aging models assessing the antiglycation and anti-elastase MMP-12 potential of glycylglycine oleamide.[Pubmed:27382322]

Clin Cosmet Investig Dermatol. 2016 Jun 22;9:143-50.

BACKGROUND: Glycation is an aging reaction of naturally occurring sugars with dermal proteins. Type I collagen and elastin are most affected by glycation during intrinsic chronological aging. AIM: To study the in vitro and ex vivo assays in human skin cells and explants and the antiaging effects of glycylglycine Oleamide (GGO). MATERIALS AND METHODS: The antiglycation effect of GGO was assessed in a noncellular in vitro study on collagen and, ex vivo, by immunohistochemical staining on human skin explants (elastin network glycation). The ability of GGO to contract fibroblasts was assessed in a functional assay, and its anti-elastase (MMP-12) activity was compared to that of oleic acid alone, glycylglycine (GG) alone, and oleic acid associated with GG. RESULTS: In vitro, GGO reduced the glycation of type I collagen. Ex vivo, GGO restored the expression of fibrillin-1 inhibited by glycation. Furthermore, GGO induced a tissue retraction of almost 30%. Moreover, the MMP-12 activity was inhibited by up to 60%. CONCLUSION: Under the present in vitro and ex vivo conditions, GGO prevents glycation of the major structural proteins of the dermis, helping to reduce the risk of rigidification. By maintaining the elastic function of the skin, GGO may be a promising sparring partner for other topical antiaging agents.

Antiallergic Activity of Ethanol Extracts of Arctium lappa L. Undried Roots and Its Active Compound, Oleamide, in Regulating FcepsilonRI-Mediated and MAPK Signaling in RBL-2H3 Cells.[Pubmed:27087645]

J Agric Food Chem. 2016 May 11;64(18):3564-73.

The antiallergic potential of Arctium lappa L. was investigated in Sprague-Dawley rats, ICR mice, and RBL-2H3 cells. Ethanol extract (90%) of A. lappa (ALE, 100 mug/mL) inhibited the degranulation rate by 52.9%, determined by the level of beta-hexosaminidase. ALE suppressed passive cutaneous anaphylaxis (PCA) in rats and attenuated anaphylaxis and histamine release in mice. To identify the active compound of ALE, we subsequently fractionated and determined the level of beta-hexosaminidase in all subfractions. Oleamide was identified as an active compound of ALE, which attenuated the secretion of histamine and the production of tumor necrosis factor (TNF)-alpha and interleukin-4 (IL-4) in cells treated with compound 48/80 or A23187/phorbol myristate acetate (PMA). Oleamide suppressed FcepsilonRI-tyrosine kinase Lyn-mediated pathway, c-Jun N-terminal kinases (JNK/SAPK), and p38 mitogen-activated protein kinases (p38-MAPKs). These results showed that ALE and Oleamide attenuated allergic reactions and should serve as a platform to search for compounds with antiallergic activity.

A new dermocosmetic containing retinaldehyde, delta-tocopherol glucoside and glycylglycine oleamide for managing naturally aged skin: results from in vitro to clinical studies.[Pubmed:28203099]

Clin Cosmet Investig Dermatol. 2017 Feb 2;10:35-42.

INTRODUCTION: Natural aging of skin tissues, the addition of the cumulative action of the time and radiation exposure result in skin atrophy, wrinkles and degeneration of the extracellular matrix (ECM). The aim of the study was to investigate the beneficial effect of a combination containing retinaldehyde (RAL), delta-tocopherol glucoside (delta-TC) and glycylglycine ole-amide (GGO) and of a dermocosmetic containing the combination. MATERIALS AND METHODS: The protective effect of the combination was assessed through in vitro gene expression of ultraviolet (UV)-irradiated fibroblasts. A skin aging assay using UV light on ex vivo skin samples and a clinical study conducted in 36 women aged from 35 to 55 years with a minimum of level 4 to a maximum of level 6 on the crow's feet photoscale assessed the antiaging effect of the dermocosmetic. RESULTS: When added to UV-irradiated fibroblasts, the combination substantially improved the ECM in activating the elastin fiber production (fibrillin 2, fibulin 1 and 5 and lysyl oxidase-like 2) as well as that of proteins involved in the cellular ECM interactions (integrin b1, paxillin and actin a2). An ex vivo photodamaged human skin model showed that the dermocosmetic formulation containing the combination of the active ingredients protected the elastic network against UV-induced alterations including both elastin and fibrillin-rich fibers in the dermis. A daily application of the dermocosmetic for 2 months on naturally aged skin resulted in a statistically significant improvement (p<0.05) of visible signs of aging comprising crow's feet, wrinkles and periocular fine lines. Finally, the formulation was well tolerated. CONCLUSION: The dermocosmetic containing RAL, delta-TC and GGO provides a substantial benefit in the daily care of naturally aged skin in women aged 35-55 years.

Inhibitory action of linoleamide and oleamide toward sarco/endoplasmic reticulum Ca(2+)-ATPase.[Pubmed:27595606]

Biochim Biophys Acta Gen Subj. 2017 Jan;1861(1 Pt A):3399-3405.

BACKGROUND: SERCA maintains intracellular Ca(2+) homeostasis by sequestering cytosolic Ca(2+) into SR/ER stores. Two primary fatty acid amides (PFAAs), Oleamide (18:1(9-cis)) and linOleamide (18:2(9,12-cis)), induce an increase in intracellular Ca(2+) levels, which might be caused by their inhibition of SERCA. METHODS: Three major SERCA isoforms, rSERCA1a, hSERCA2b, and hSERCA3a, were individually overexpressed in COS-1 cells, and the inhibitory action of PFAAs on Ca(2+)-ATPase activity of SERCA was examined. RESULTS: The Ca(2+)-ATPase activity of each SERCA was inhibited in a concentration-dependent manner strongly by linOleamide (IC50 15-53muM) and partially by Oleamide (IC50 8.3-34muM). Inhibition by other PFAAs, such as stearamide (18:0) and elaidamide (18:1(9-trans)), was hardly or slightly observed. With increasing dose, linOleamide decreased the apparent affinity for Ca(2+) and the apparent maximum velocity of Ca(2+)-ATPase activity of all SERCAs tested. Oleamide also lowered these values for hSERCA3a. Meanwhile, Oleamide uniquely reduced the apparent Ca(2+) affinity of rSERCA1a and hSERCA2b: the reduction was considerably attenuated above certain concentrations of Oleamide. The dissociation constants for SERCA interaction varied from 6 to 45muM in linOleamide and from 1.6 to 55muM in Oleamide depending on the isoform. CONCLUSIONS: LinOleamide and Oleamide inhibit SERCA activity in the micromolar concentration range, and in a different manner. Both amides mainly suppress SERCA activity by lowering the Ca(2+) affinity of the enzyme. GENERAL SIGNIFICANCE: Our findings imply a novel role of these PFAAs as modulators of intracellular Ca(2+) homeostasis via regulation of SERCA activity.

Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors.[Pubmed:14707029]

Br J Pharmacol. 2004 Jan;141(2):253-62.

1. The ability of the endogenous fatty acid amide, cis-Oleamide (ODA), to bind to and activate cannabinoid CB(1) and CB(2) receptors was investigated. 2. ODA competitively inhibited binding of the nonselective cannabinoid agonist [(3)H]CP55,940 and the selective CB(1) antagonist [(3)H]SR141716A to rat whole-brain membranes with K(i) values of 1.14 microm (0.52-2.53 microm, Hill slope=0.80, n=6) and 2.63 microm (0.62-11.20 microm, Hill slope=0.92, n=4), respectively. AEA inhibited [(3)H]CP55,940 binding in rat whole-brain membranes with a K(i) of 428 nm (346-510 nm, Hill slope=-1.33, n=3). 3. ODA competitively inhibited [(3)H]CP55,940 binding in human CB(1) (hCB(1)) cell membranes with a K(i) value of 8.13 microm (4.97-13.32 microm, n=2). In human CB(2) transfected (hCB(2)) HEK-293T cell membranes, 100 microm ODA produced only a partial (42.5+/-7%) inhibition of [(3)H]CP55,940 binding. 4. ODA stimulated [(35)S]GTPgammaS binding in a concentration-dependent manner (EC(50)=1.64 microm (0.29-9.32 microm), R(2)=0.99, n=4-9), with maximal stimulation of 188+/-9% of basal at 100 microm. AEA stimulated [(35)S]GTPgammaS binding with an EC(50) of 10.43 microm (4.45-24.42 microm, R(2)=1.00, n=3, 195+/-4% of basal at 300 microm). Trans-Oleamide (trans-ODA) failed to significantly stimulate [(35)S]GTPgammaS binding at concentrations up to 100 microm. 5. ODA (10 microm)-stimulated [(35)S]GTPgammaS binding was reversed by the selective CB(1) antagonist SR141716A (IC(50)=2.11 nm (0.32-13.77 nm), R(2)=1.00, n=6). 6. The anatomical distribution of ODA-stimulated [(35)S]GTPgammaS binding in rat brain sections was indistinguishable from that of HU210. Increases of similar magnitude were observed due to both agonists in the striatum, cortex, hippocampus and cerebellum. 7. ODA (10 microm) significantly inhibited forskolin-stimulated cyclic AMP (cAMP) accumulation in mouse neuroblastoma N1E 115 cells (P=0.02, n=11). ODA-mediated inhibition was completely reversed by 1 microm SR141716A (P<0.001, n=11) and was also reversed by pretreatment with 300 ng ml(-1) pertussis toxin (P<0.001, n=6). 8. These data demonstrate that ODA is a full cannabinoid CB(1) receptor agonist. Therefore, in addition to allosteric modulation of other receptors and possible entourage effects due to fatty acid amide hydrolase inhibition, the effects of ODA may be mediated directly via the CB(1) receptor.

Allosteric regulation by oleamide of the binding properties of 5-hydroxytryptamine7 receptors.[Pubmed:10571256]

Biochem Pharmacol. 1999 Dec 1;58(11):1807-13.

Oleamide belongs to a family of amidated lipids with diverse biological activities, including sleep induction and signaling modulation of several 5-hydroxytryptamine (5-HT) receptor subtypes, including 5-HT1A, 5-HT2A/2C, and 5-HT7. The 5-HT7 receptor, predominantly localized in the hypothalamus, hippocampus, and frontal cortex, stimulates cyclic AMP formation and is thought to be involved in the regulation of sleep-wake cycles. Recently, it was proposed that Oleamide acts at an allosteric site on the 5-HT7 receptor to regulate cyclic AMP formation. We have further investigated the interaction between Oleamide and 5-HT7 receptors by performing radioligand binding assays with HeLa cells transfected with the 5-HT7 receptor. Methiothepin, clozapine, and 5-HT all displaced specific [3H]5-HT (100 nM) binding, with pK(D) values of 7.55, 7.85, and 8.39, respectively. Oleamide also displaced [3H]5-HT binding, but the maximum inhibition was only 40% of the binding. Taking allosteric (see below) cooperativity into account, a K(D) of 2.69 nM was calculated for Oleamide. In saturation binding experiments, Oleamide caused a 3-fold decrease in the affinity of [3H]5-HT for the 5-HT7 receptor, without affecting the number of binding sites. A Schild analysis showed that the induced shift in affinity of [3H]5-HT reached a plateau, unlike that of a competitive inhibitor, illustrating the allosteric nature of the interaction between Oleamide and the 5-HT7 receptor. Oleic acid, the product of Oleamide hydrolysis, had a similar effect on [3H]5-HT binding, whereas structural analogs of Oleamide, trans-9,10-octadecenamide, cis-8,9-octadecenamide, and erucamide, did not alter [3H]5-HT binding significantly. The findings support the hypothesis that Oleamide acts via an allosteric site on the 5-HT7 receptor regulating receptor affinity.

Brain lipids that induce sleep are novel modulators of 5-hydroxytrypamine receptors.[Pubmed:8755606]

Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):8078-82.

Amide derivatives of fatty acids were recently isolated from cerebrospinal fluid of sleep-deprived animals and found to induce sleep in rats. To determine which brain receptors might be sensitive to these novel neuromodulators, we tested them on a range of receptors expressed in Xenopus oocytes. cis-9,10-Octadecenamide (ODA) markedly potentiated the action of 5-hydroxytryptamine (5-HT) on 5-HT2A and 5-HT2C receptors, but this action was not shared by related compounds such as oleic acid and trans-9,10-octacenamide. ODA was active at concentrations as low as 1 nM. The saturated analog, octadecanamide, inhibited rather than potentiated 5-HT2C responses. ODA had either no effect or only weak effects on other receptors, including muscarinic cholinergic, metabotropic glutamate, GABA(A), N-methyl-D-asparate, or alpha-amino-3-hydroxy-5-methyl-4-isoxozolepropionic acid receptors. Modulation of 5-HT2 receptors by ODA and related lipids may represent a novel mechanism for regulation of receptors that activate G proteins and thereby play a role in alertness, sleep, and mood as well as disturbances of these states.

Chemical characterization of a family of brain lipids that induce sleep.[Pubmed:7770779]

Science. 1995 Jun 9;268(5216):1506-9.

A molecule isolated from the cerebrospinal fluid of sleep-deprived cats has been chemically characterized and identified as cis-9,10-octadecenoamide. Other fatty acid primary amides in addition to cis-9,10-octadecenoamide were identified as natural constituents of the cerebrospinal fluid of cat, rat, and human, indicating that these compounds compose a distinct family of brain lipids. Synthetic cis-9,10-octadecenoamide induced physiological sleep when injected into rats. Together, these results suggest that fatty acid primary amides may represent a previously unrecognized class of biological signaling molecules.

Oleamide is an endogenous fatty acid amide which can be synthesized de novo in the mammalian nervous system, and has been detected in human plasma.

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