Professor Salvatore Cuzzocrea and his research group published in 2013 an interesting paper on Palmitoylethanolamide (PEA) as an endogenous fatty acid amide displaying anti-inflammatory and analgesic actions and its mechanism of actions. (in their paper: Molecular evidence for the involvement of PPAR-delta and PPAR-gamma in anti-inflammatory and neuroprotective activities of palmitoylethanolamide after spinal cord trauma Journal of Neuroinflammation 2013, 10:20 doi:10.1186/1742-2094-10-20)
Their focus was on one of the targets of palmitoyethanolamide, the nuclear receptors; ligand-dependent transcription factors whose activation affects genes controlling vital processes.
The peroxisome proliferator-activated receptors (PPARs) have emerged as links between lipids, metabolic diseases, and innate immunity.
PPAR-a is mostly distributed in several peripheral organs and metabolically active tissues (i.e. liver, heart, intestine and skeletal muscle) controlling fatty acid catabolism and inflammatory processes.
PPAR-alpha for instance is activated by PEA which also signal through membrane receptors, thereby creating a lipid signaling network between the cell surface and the nucleus.There are three known isoforms of PPARs, PPAR-α, PPAR-γ, and PPAR-β/δ, each with different tissue specificity and physiological function. All three PPARs bind a variety of natural and synthetic ligands, none of which completely fills the ligand binding pocket, and PPAR ligands can adopt different binding modes. The authors pointed out that several studies clearly demonstrated that PPAR-α and PPAR-γ agonists exert beneficial effects in several experimental models of CNS injury and disease, such as amyotrophic lateral sclerosis, Parkinson’s disease, cerebral ischemia or hemorrhage, and experimental autoimmune encephalomyelitis.
Recently, the presence of PPAR-α and PPAR-γ in discrete areas of the brain and spinal cord has been suggested.
In vivo administration of PEA,reduces inflammation and tissue injury associated with spinal cord injury (SCI) and promotes the initiation of neurotrophic substance after SCI.
The authors investigated whether the protective and anti-inflammatory effects of PEA observed in a compression model of SCI are partially mediated by other PPAR isotypes, in addition to PPAR-α.
Their animal experiments confirmed that PPAR-α is involved in protective effects of PEA in spinal cord trauma. Moreover, the anti-inflammatory effect elicited by PEA could be antagonized by the administration of the antagonists for PPAR-γ, and PPAR-δ receptors, highlighting the involvement of such receptors in PEA-induced protective effects of spinal cord trauma. PPARs are constitutively expressed in the lumbar and thoracic spinal cord of healthy animals.
We conclude with their discussion on PEA’s mechanisms of action:
PEA has been shown to be effective in several experimental models of inflammation, both of immunogenic and neurogenic origin.Despite its various described pharmacological properties, the cellular/receptor mechanism responsible for the actions of PEA is still debated. The first hypothesis on the mechanism of action of PEA was formulated when Aloe and colleagues, introducing the ALIA acronym (Autacoid Local Inflammation Antagonism), indicated that some endogenous N-acylethanolamines, such as PEA, exerted a local antagonism on inflammation.
Moreover, various studies have hypothesized that PEA may act via
indirect interaction with CB2 receptors. In fact, it has been shown that the use of
SR144528, a CB2 specific receptor antagonist, eliminated the antinociceptive effects of PEA.
PEA was then found able to potentiate the effect of anandamide on CB or vanilloid receptor (VR1), the so-called entourage effect . Considering the known changes of endocannabinoid system in the lesioned spinal cord (increase in 2-AG and CB2, decrease in CB1 levels), PEA may indirectly regulate CB receptors expression through the increase in endocannabinoid tone or the modulation of proinflammatory cytokines.
Indeed, CB2 receptors would play a crucial role in limiting the spreading of this neuroinflammatory process. In the present study we show that the absence of PPAR-α, in PPAR-αKO mice, as well as the use of PPAR-δ and PPAR-γ antagonist, results in a reduced anti-inflammatory action of PEA in an experimental model of SCI. Part of our results are in agreement with previous observations indicating that PPAR-αKO mice are more susceptible to induction of SCI, possibly due to a less efficient anti-inflammatory control exerted by endogenous PPAR-α ligand. But in this paper we show that also PPAR-δ and PPAR-γ can be involved in the neuroprotective and anti-inflammatory effects of PEA.
Source Molecular evidence for the involvement of PPAR-delta and PPAR-gamma in anti-inflammatory and neuroprotective activities of palmitoylethanolamide after spinal cord trauma Journal of Neuroinflammation 2013, 10:20 doi:10.1186/1742-2094-10-20