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Mechanism of Action

Pictured: Mast cell releasing histamine

Palmitoylethanolamide (PEA) is a biologically active, endogenous lipid that is widely distributed throughout the body's tissues and is produced on demand. It was first isolated from egg yolks in 1957 as an anti-inflammatory component and has been studied extensively in recent years.*

PEA plays a key role in maintaining homeostasis by regulating many physiological reactions associated with pain and inflammation.* Some chronic conditions can result in a hyper-immune response involving microglia, mast cells and astrocytes. Excessive activation of these satellite, non-neuronal cells has been shown to maintain pain, inflammation and result in neurodegeneration. PEA appears to act as a protective endogenous mediator that is produced “on demand” during inflammatory and neurodegenerative conditions to counter inflammation, pain, and neuronal damage.* Multiple studies have demonstrated that endogenous PEA increases in the brain and spinal cord following neuropathic pain induction, injury and other related conditions.* Microglia, astrocytes and mast cells are the most recognized cellular targets of PEA. PEA has been shown to down-modulate these cells and reduce neuropathic pain in a number of experimental models.*


Pictured: Microglial cell

On a molecular level, PEA reduces the activity of the pro-inflammatory enzyme COX, as well as NOS (nitric oxide synthase). Cannabinoid receptors type 1 and 2 (CB1 and CB2), cannabinoid-like G-coupled receptors GPR55 and GPR119, Transient Receptor Potential Vanilloid Receptor type 1 (TRPV1) channels and nuclear Peroxisome Proliferator Activated Receptor-alpha (PPAR-α) are the PEA molecular targets studied most. Activation of the PPAR-alpha nuclear receptor aids in the restoration of metabolic balance within cells and plays an important role in analgesia.*





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6. D'Amico, Ramona et al. “ALIAmides Update: Palmitoylethanolamide and Its Formulations on Management of...” International journal of molecular sciences vol. 21,15 5330. 27 Jul. 2020, doi:10.3390/ijms21155330
7. Cordaro, Marika et al. “An Update of Palmitoylethanolamide and Luteolin Effects in Preclinical and Clinical Studies of Neuroinflammatory Events.” Antioxidants (Basel, Switzerland) vol. 9,3 216. 5 Mar. 2020, doi:10.3390/antiox9030216








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