A New Palmitoylethanolamide Form Combined with Antioxidant Molecules to Improve Its Effectivess on Neuronal Aging

Abstract

Palmitoylethanolamide is a nutraceutical compound naturally produced in many plants and animal source foods, but the natural form is poorly water-soluble. It has demonstrated an anti-inflammatory role as a neuroprotective mediator, acting on several molecular targets of the central nervous system involved on brain aging process. In healthy adults, palmitoylethanolamide is an endogenous PPAR-α (peroxisome proliferator-activated receptor α) agonist through which it performs anti-inflammatory activity and provides its effects by activating the cannabinoid receptor. The different formulations of palmitoylethanolamide (micronized palmitoylethanolamide, FM-LipoMatrix® palmitoylethanolamide and FM-LipoMatrix® palmitoylethanolamide plus lipoic acid and vitamin D3) were analyzed starting from intestinal barrier, to verify their bioavailability, to in primary astrocytes in which cell viability, reactive oxygen species (ROS) and nitric oxide (NO) production, NFKB activity, MAPK, p53 and PPARα activities were investigated. Additionally, cannabinoid and estrogen receptors were analyzed using the western blot technique. The combination of palmitoylethanolamide in FM-LipoMatrix®, lipoic acid and vitamin D3 shows better absorption predicting an improvement on plasma concentration; this formulation also shows a reduction in ROS and NO production and the data show the interaction of palmitoylethanolamide with cannabinoids and estrogen receptors inhibiting neuroinflammatory markers. All these data support the hypothesis of a new potential strategy to restore brain function and slow down brain aging in humans.

Design, Characterization, and In Vitro Assays on Muscle Cells of Endocannabinoid-like Molecule Loaded Lipid Nanoparticles for a Therapeutic Anti-Inflammatory Approach to Sarcopenia

“…This finding may indicate, on one side, the non-toxic effect of PEA, and on the other, PEA ability to restore the cell susceptibility. This event, which also induces cell activation, was observed by other authors on neuronal cells and attributed to PEA antioxidant properties [ 63 ].…”

A Combination of α-Lipoic Acid (ALA) and Palmitoylethanolamide (PEA) Blocks Endotoxin-Induced Oxidative Stress and Cytokine Storm: A Possible Intervention for COVID-19

“…In the first set of experiments, on both HSAEC and THP-1 cells, the role of PEA and ALA under physiological condition was analyzed in a dose-dependent manner. In this step, cell viability test was performed with ALA (from 5 µM to 500 µM) (36) and PEA (from 1 µM to 10 µM) (28) to determine their optimal concentrations for 24 h, and these concentrations (ALA 50 µM and PEA 5 µM) were maintained in all successive experiments. The combination with ALA and PEA was investigated during 24 h to analyze cell viability without cytotoxicity on both cell types.…”

“…For this reason, it could be useful to combine traditional drugs with an adjuvant treatment consisting of natural bioactive compounds such as the afore mentioned ALA or another bioactive substance such as palmitoylethanolamide (PEA) with known anti-inflammatory properties. PEA is considered a food supplement with immunomodulatory, anti-inflammatory, neuroprotective and pain-relieving properties (28). The main ultra-micronized-PEA immunomodulatory effect seems to be related to mast cells (29) which are typically involved in respiratory infections caused by coronavirus and/or other influenza viruses (30).…”

The Endocannabinoids-Microbiota Partnership in Gut-Brain Axis Homeostasis: Implications for Autism Spectrum Disorders

“…In support of a functional interplay between eCB signaling and vitamin D metabolism, there are the disruptive effects induced by high-dose systemic Δ9-THC administration in tasks simulating schizophrenia-like aberrant processing that were boosted by developmental vitamin D deficiency (Burne et al, 2014). A recent study addressing on astrocytes specific markers of neuronal aging and the anti-inflammatory potential of PEA (e.g., against reactive oxygen species and nitric oxide production) reported greater neuroprotective effects through the use of an innovative drug formulation consisting in PEA, alpha lipoic acid and vitamin D combination (Morsanuto et al, 2020). Not only the PEA/alpha lipoic acid/vitamin D formulation showed better cell viability, anti-inflammatory and anti-oxidant effects but also higher potency in the activation of CB 2 receptors (Morsanuto et al, 2020), which have also been recently described to have a fundamental role in the preservation of social memory .…”

“…A recent study addressing on astrocytes specific markers of neuronal aging and the anti-inflammatory potential of PEA (e.g., against reactive oxygen species and nitric oxide production) reported greater neuroprotective effects through the use of an innovative drug formulation consisting in PEA, alpha lipoic acid and vitamin D combination (Morsanuto et al, 2020). Not only the PEA/alpha lipoic acid/vitamin D formulation showed better cell viability, anti-inflammatory and anti-oxidant effects but also higher potency in the activation of CB 2 receptors (Morsanuto et al, 2020), which have also been recently described to have a fundamental role in the preservation of social memory . Thus, to further support the importance of the endocannabinoids-microbiota reciprocal contamination for the understanding of ASD there are also the studies describing an association between vitamin D deficiency and risk of autism (Principi and Esposito, 2020) as well as the fact that PEA provided therapeutic beneficial in subjects with ASD (Khalaj et al, 2018) and the existence of a specific interaction between vitamin D metabolism, eCB signaling and changes in gut microbiota (Su et al, 2016;Guida et al, 2020;Morsanuto et al, 2020).…”