Investigating Properties of Palmitoylethanolamide in Physiology and Disease: Far Beyond an Anti-Inflammatory Shield

Palmitoylethanolamide (PEA) among N-acylethanolamides displays a noteworthy impact on different inflammatory conditions and promises to become a valuable anti-inflammatory tool that does not interfere with the cyclooxygenase pathway. Mounting evidence confirms the multi-dimensional PEA-mediated crosstalk between microglia and mast cells, which would open new therapeutic opportunities targeting a neuroimmune axis and influencing both health and disease. In particular, PEA acts as a preserver of cellular homeostasis by regulating microglia cell activity and inhibiting mast cell activation in the central nervous system. The improved bioavailability and efficacy of ultramicronized formulations of PEA reflect its ultimate usefulness for different clinical applications, including significantly relieving inflammation but also reducing the pro-inflammatory burden of complex patients with either neuropathies or non-neurologic afflictions. This review aims to comprehensively delineate the therapeutic potential of PEA beyond its mere indication for acute inflammation and to highlight PEA activity as a broad-spectrum pan-tissue protective agent through the results of different preclinical and also some clinical studies. Much more remains to be learned about further PEA mechanisms of action that regulate neuroinflammation, and additional studies will have to investigate the exact role of microglia and mast cells in inflammatory diseases.