Oral Adelmidrol Administration Up-Regulates Palmitoylethanolamide Production in Mice Colon and Duodenum through a PPAR-γ Independent Action

Abstract

Adelmidrol is a promising palmitoylethanolamide (PEA) analog which displayed up-and-coming anti-inflammatory properties in several inflammatory conditions. Recent studies demonstrated that Adelmidrol is an in vitro enhancer of PEA endogenous production, through the so called “entourage” effect. The present study investigated the ability of Adelmidrol (1 and 10 mg/Kg per os) to increase the endogenous level of PEA in the duodenum and colon of mice after 21-day oral administration in the presence and absence of PPAR-γ inhibitor (1 mg/kg). The level of PEA was analyzed by HPLC-MS. The expression of PEA-related enzymatic machinery was evaluated by western blot and RT-PCR analysis. Our findings demonstrated that Adelmidrol significantly increased PEA levels in the duodenum and colon in a dose/time-dependent manner. We also revealed that Adelmidrol up regulated the enzymatic machinery responsible for PEA metabolism and catabolism. Interestingly, the use of the selective irreversible PPAR-γ antagonist did not affect either PEA intestinal levels or expression/transcription of PEA metabolic enzymes following Adelmidrol administration. The “entourage effect” with Adelmidrol as an enhancer of PEA was thus PPAR-γ-independent. The findings suggest that Adelmidrol can maximize a PEA therapeutic-based approach in several intestinal morbidities.

Cyclo(Pro-Tyr) elicits conserved cellular damage in fungi by targeting the [H+]ATPase Pma1 in plasma membrane domains

“…The following chemical variations also support the increase in B. cinerea membrane rigidity: i) the significant reduction in monoolein, an unsaturated lipid that significantly increases the fluidity of the lipid bilayer 46 , and ii) a reduction in the ergosterol byproduct ergocalciferol, which is described to increase membrane fluidity 47 . We also observed a reduction in palmitamide, an endogenous fatty acid synthesized from phosphatidylethanolamine at the plasma membrane 48 , and described it as a lipid messenger involved in cyclooxygenase activation for ROS detoxification 49 . A similar response in C. elegans was reproduced upon treatment with cyclo(Pro-Tyr), which elicited plasma membrane remodeling and enhanced the detoxification of ROS [50][51][52] .…”

Palmitoylethanolamide and Related ALIAmides for Small Animal Health: State of the Art

“…Accordingly, the exogenous administration of PEA to effectively ‘top up’ the body’s own supply is regarded as a promising approach [ 54 ]. Interestingly, other ALIAmides, such as Adelmidrol and PGA, have recently been found to increase the endogenous levels of PEA [ 55 , 56 , 57 ].…”

“…Besides increasing PEA levels, as previously mentioned, these fatty acid amides are suggested to interact with different receptors. PGA, for example, is considered to exert its protective function through a toll-like receptor 4 antagonism [ 94 ], while the precise molecular targets of Adelmidrol are still debated [ 55 , 95 ].…”

Targeting Neuroinflammation in Osteoarthritis with Intra-Articular Adelmidrol

“…Adelmidrol is a synthetic derivate of azelaic acid which works as a palmitoylethanolamide (PEA) enhancer increasing endogenous PEA levels [ 59 ]. Recently, it has been demonstrated that Adelmidrol is able to significantly increase the endogenous PEA level in the duodenum and colon of healthy mice in a dose/time-dependent and PPAR-γ-independent manner [ 60 ]. As with PEA, Adelmidrol belongs to the family of Autacoid Local Injury Antagonist Amides (ALIAmides) and its amphiphilic and amphipathic characteristics make Adelmidrol particularly soluble and suitable for topical [ 61 , 62 ] and intra-articular administration.…”