NAT: N-acyltransferase (Ca2+-dependent)
Produces NAPE from phospholipids.
iNAT: N-acyltransferase (Ca2+-independent)
Produces NAPE from phospholipids. Low abundant in brain.
NAPE-PLD: N-acyl-phosphatidylethanolamine (NAPE)-hydrolyzing phospholipase D
Produces Anandamide from NAPE
ABDH4: α/β-hydrolase 4
Lyso-PLD: lyso-phospholipase D
GDE1: glycerophosphodiester phosphodiesterase 1
PTPN22: protein tyrosine phosphatase, non-receptor type 22
FAAH-1: fatty acid amide hydrolase-1
FAAH-2: fatty acid amide hydrolase-2
NAAA: N-acylethanolamine-hydrolyzing acid amidase
In a mouse model of depression, chronic unpredictable mild stress causes depression-like behavior, atrophy of hippocampus and frontal cortex and increases corticosterone levels. Oral application of OEA (1.5 – 6 mg/kg) reverted these effects suggesting therapeutic potential for OEA in the treatment of depression (Jin et al., 2015).
Functional Gastro-Intestinal Disorders
In patients with diarrhea-type IBS higher levels of 2AG and lower levels of OEA and PEA were found. In contrast, patients with constipation-type IBS had higher levels of OEA and lower levels of FAAH. Also, PEA levels were inversely correlated with abdominal pain suggesting substantial involvement of the endocannabinoid system in the pathophysiology of IBS (Fichna et al., 2013).
In a model of maternal separation, sleep reduction has been related to the endocannabinoid system through the expression of CB1 in the prefrontal cortex and hypothalamus while oleamide improved sleep in adult rats (Reyes Prieto et al., 2012).
endocannabinoids such as OEA bind to GPR119 to increase cAMP (signals high energy/glucose content to a cell), stimulate insulin secretion and cause fat deposition (Overton et al., 2006). OEA reduced food intake and weight gain in rodents via PPARα and TRPV1 (Overton et al., 2006).
In a mouse model of Parkinson’s, OEA (at 5mg/kg) protected dopaminergic neurons from degeneration in a PPARα-dependent way (Gonzalez-Aparicio et al., 2014). Similarly, systemic application of OEA, and to a lesser extent PEA, was found to inhibit pro-inflammatory cytokines and thus to protect against neurodegeneration (Sayd et al., 2014). In another study, OEA reduced L-dopa-induced-dyskinesia in a TRPV1-dependent way (González-Aparicio and Moratalla, 2014).
England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358.
Fezza, F., Bari, M., Florio, R., Talamonti, E., Feole, M., & Maccarrone, M. (2014). endocannabinoids, related compounds and their metabolic routes. Molecules (Basel, Switzerland), 19(11), 17078-17106. https://doi.org/10.3390/molecules191117078
Fichna, J., Sałaga, M., Stuart, J., Saur, D., Sobczak, M., Zatorski, H., Timmermans, J.-P., Bradshaw, H.B., Ahn, K., and Storr, M.A. (2014). Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 26, 470–481.
González-Aparicio, R., and Moratalla, R. (2014). Oleoylethanolamide reduces L-DOPA-induced dyskinesia via TRPV1 receptor in a mouse model of Parkinson´s disease. Neurobiol. Dis. 62, 416–425.
Gonzalez-Aparicio, R., Blanco, E., Serrano, A., Pavon, F.J., Parsons, L.H., Maldonado, R., Robledo, P., Fernandez-Espejo, E., and de Fonseca, F.R. (2014). The systemic administration of oleoylethanolamide exerts neuroprotection of the nigrostriatal system in experimental Parkinsonism. Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. CINP 17, 455–468
Jin, P., Yu, H.-L., Tian-Lan, null, Zhang, F., and Quan, Z.-S. (2015). Antidepressant-like effects of oleoylethanolamide in a mouse model of chronic unpredictable mild stress. Pharmacol. Biochem. Behav. 133, 146–154.
Lara-Celador, I., Goñi-de-Cerio, F., Alvarez, A., and Hilario, E. (2013). Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury. Neural Regen. Res. 8, 731–744.
Overton, H.A., Babbs, A.J., Doel, S.M., Fyfe, M.C.T., Gardner, L.S., Griffin, G., Jackson, H.C., Procter, M.J., Rasamison, C.M., Tang-Christensen, M., et al. (2006). Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 3, 167–175.
Reyes Prieto, N.M., Romano López, A., Pérez Morales, M., Pech, O., Méndez-Díaz, M., Ruiz Contreras, A.E., and Prospéro-García, O. (2012). Oleamide restores sleep in adult rats that were subjected to maternal separation. Pharmacol. Biochem. Behav. 103, 308–312.
Sayd, A., Antón, M., Alén, F., Caso, J.R., Pavón, J., Leza, J.C., Rodríguez de Fonseca, F., García-Bueno, B., and Orio, L. (2014). Systemic administration of oleoylethanolamide protects from neuroinflammation and anhedonia induced by LPS in rats. Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. CINP 18.
Several clinical trials have tested the therapeutic potential of cannabinoids after Stroke. Meta-analysis revealed that both endocannabinoids like AEA, OEA or PEA and plant cannabinoids like THC or CBD can significantly reduce neuronal degeneration after Stroke (England et al., 2015). Specifically activating CB1 and/or CB2 receptors had the strongest protective effect but other receptors such as 5-TH1a and PPARα are also likely to be involved.
England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental Stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358.