Alterations in the Endocannabinoid System as a Link Between Unbalanced Energy Homeostasis, Neuroinflammation, and Neurological and Neuropsychiatric Disorders

Profiling Rat Brain Monoacylglycerol Lipase Activity Using an Ammonia- Adduct Enhanced Selected Ion Monitoring Liquid-Chromatography Positive Electrospray Ionization Mass Spectrometry Assay

“…The endocannabinoid system (ECS) has involvement in the signaling network of physiological processes in both the central nervous system (CNS) and peripheral tissues and thus, plays an important role in disorders of the CNS [1], in the immune system [2,3], in energy homeostasis [4], in inflammatory pain [5] and in the cardiovascular system of mammals [6]. The ECS consists of the endocannabinoids, type-1 and type-2 G protein-coupled cannabinoid receptors (i.e., CB 1 and CB 2 ), transporters, and enzymes that tightly regulate biosynthesis and degradation of endocannabinoids ( Figure 1) [3,7,8].…”

“…The balance between AEA and 2-AG biosynthesis and inactivation determines their accumulation in tissues and thus, their biological activity. Therefore, for the past decade, the modulation of AEA and 2-AG levels in biological fluids and tissues through the binding of small molecule inhibitors to FAAH and MAGL enzymes has been a therapeutic strategy for a number of diseases including pain, schizophrenia, stroke, obesity, Alzheimer's disease, multiple sclerosis, and cancer, to name just a few [1][2][3][4][5][6][23][24][25]. Several small molecule reversible and irreversible inhibitors for FAAH and MAGL have been discovered with the numbers of selective FAAH inhibitors exceeding those of MAGL inhibitors [26][27][28][29].…”

“…Adding low levels of metal salts, such as, sodium acetate (0.01%) in the mobile phase has been reported to improve the sensitivity for quantitation of non-nitrogen containing endocannabinoids utilizing SIM LC / MS techniques by providing a controlled source of Na + cations [44]; however, the introduction of nonvolatile salts in the mobile phase over a relatively short periods of time will typically cause metal ion accumulation in the ESI source and reduce the overall sensitivity of the assay. Since the ECS is an active area of research [1][2][3][4][5][6][23][24][25][26][27][28][29][30] and LC / MS instrumentation is extremely common in many analytical laboratories, having a reliable LC / MS method that is also sensitive and specific to measure the concentration of 2-AG and its congeners in brain tissues, would be beneficial in efforts to develop MAGL inhibitors for potential therapeutic utilities.…”