Deciphering the interaction between N-palmitoyl-D-glucosamine and the endocannabinoidome.

Area of Science:

• Biochemistry
• Pharmacology
• Cell Biology

Background:

• N-palmitoyl-D-glucosamine (PGA) is an ALIA-amide, related to N-palmitoyl-ethanolamine (PEA), a mediator in the expanded endocannabinoid system (endocannabinoidome).
• ALIA-amides modulate hyperactivity in mast cells and central nervous system non-neuronal cells.

Purpose of the Study:

• To investigate if PGA induces an "entourage" effect similar to PEA.
• To determine if PGA elevates endogenous levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), and PEA.

Main Methods:

• HaCaT cells were treated with PGA (10 µM) for 40 minutes and 6 hours.
• Cellular concentrations of AEA, 2-AG, and PEA were measured.
• The effect of the serine hydrolase inhibitor MAFP was assessed.
• mRNA expression of anabolic and catabolic enzymes of the endocannabinoid system was analyzed.
• siRNA against ABHD4 was used to investigate its role.

Main Results:

• PGA treatment significantly increased cellular concentrations of AEA, 2-AG, and PEA at both time points.
• MAFP inhibited the PGA-induced increase in these mediators.
• PGA treatment reduced the mRNA expression of GDE1, DAGLB, FAAH, MAGL, and NAAA after 6 hours.
• siRNA-mediated knockdown of ABHD4, combined with PGA treatment, further increased endogenous AEA, 2-AG, and PEA levels.

Conclusions:

• PGA increases endogenous levels of PEA and key endocannabinoids (AEA, 2-AG).
• PGA's action is mediated, in part, by influencing the expression of enzymes involved in endocannabinoid synthesis and degradation.
• This study demonstrates for the first time that PGA enhances endocannabinoidome signaling.