Anandamide

Anandamide, an endocannabinoid derived from arachidonic acid-containing membrane lipids, exerts its actions by binding and activating CB1 and CB2 receptors (cannabinoid receptors 1 and 2) and the vanilloid transient receptor potential vanilloid 1 (TRPV1) receptor^[1-2]. Anandamide is involved in the regulation of pain, mood, and cognition^[3].

In vitro, primary microglial cultures were pretreated with 1μM Anandamide for 30min, stimulated with 100ng/mL Lipopolysaccharide (LPS) for 24h, and assayed for nitric oxide; LPS alone markedly increased nitric oxide (NO) release, whereas Anandamide reduced it by ~30%^[4]. Pretreating human vascular smooth muscle cells (hVSMC) with 100nM Anandamide for 1h (protein assays) or 2.5h (immunofluorescence and PLA) suppressed the cytokine-induced expression of 21 inflammatory genes, including the key chemokine CCL2, by elevating H3K27me3 and reducing H3K27ac at the CCL2 promoter, thereby compacting chromatin^[5].

In vivo, after intraperitoneal administration of Anandamide (10mg/kg) to mice, hyperglycemia after oral glucose loading was improved, whereas glucose clearance and insulin sensitivity were impaired, without altering transporter-mediated glucose absorption^[6]. Following two bilateral intracerebroventricular injections (2μL; 1μL/min; 100ng) of Anandamide to male Wistar rats, Anandamide prevented streptozotocin (STZ)-induced deficits in recognition and non-associative emotional memory without affecting tone fear conditioning, blocked STZ-elicited enlargement of the cerebral ventricles, and, like STZ, decreased Bcl2-associated athanogene (BAG2) levels^[7].

References:
[1] Goodfellow CE, Glass M. Anandamide receptor signal transduction. Vitam Horm. 2009;81:79-110.
[2] Biringer RG. The rise and fall of anandamide: processes that control synthesis, degradation, and storage. Mol Cell Biochem. 2021;476(7):2753-2775.
[3] Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2(3):e94. Published 2012 Mar 20.
[4] Malek N, Popiolek-Barczyk K, Mika J, et al. Anandamide, Acting via CB2 Receptors, Alleviates LPS-Induced Neuroinflammation in Rat Primary Microglial Cultures. Neural Plast. 2015;2015:130639.
[5] Pflüger-Müller B, Oo JA, Heering J, et al. The endocannabinoid anandamide has an anti-inflammatory effect on CCL2 expression in vascular smooth muscle cells. Basic Res Cardiol. 2020;115(3):34.
[6] Troy-Fioramonti S, Demizieux L, Gresti J, et al. Acute activation of cannabinoid receptors by anandamide reduces gastrointestinal motility and improves postprandial glycemia in mice. Diabetes. 2015;64(3):808-818.
[7] Moreira-Silva D, Carrettiero DC, Oliveira ASA, et al. Anandamide Effects in a Streptozotocin-Induced Alzheimer's Disease-Like Sporadic Dementia in Rats. Front Neurosci. 2018;12:653.