Palmitoylethanolamide: a lipid transmitter

In the first part of palmitoylethanolamide’s story, between 1957 and 1993 it became clear that PEA had significant biological effects such as analgesia and anti-inflammation. In 1993 Montalcini unraveled the first mechanism of action of PEA: the modulation of the mast cell and the inhibition of the inflammatory effects of compounds such as histamine and Nerve Growth Factor (NGF).

In the period 1993 and 2000 most scientists though palmitoylethanolamide was an endocannabinoid, but little by little one started to understand palmitoylethanolamide is NOT an endocannabinoid, but a lipid neurotransmitter of its own. Or better, a lipid signaling molecule.

Lipids Signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses.

The groups of lipid signaling molecules consists of:

Endogenous Cannabinoids
Palmitoylethanolamide and other N-acyl-ethanolamides
PI3 Kinase (PI3K)
Phosphatidylinositol bisphosphate (PIP2) Second Messenger Systems
Phosphoinositide 3-Kinase (PI3K)

Ceramides for instance are lipids composed of sphingosine and a fatty acid and derive from the hydrolisis of sphingolipids. Sphingolipids have an important structural role in cell membrane but, when hydrolized by sphingomyelinase (wiki), they release ceramides in the cytosol that can act as second messengers, promoting differentiation, proliferation and apoptosis.

Exactly the same mechanism holds true for PEA: it is a fatty acid amine derived from a lipid fraction of the membranes, NAPE and is synthesized by NAPE hydrolyzing enzymes, the released PEA shuttles into the cytosol via protein carriers and travels to its target, for instance the PPAR receptor.

Lipid signaling plays a role in a great many disorders:

Signalling lipids such as eicosanoids, phosphoinositides, sphingolipids and fatty acids control important cellular processes, including cell proliferation, apoptosis, metabolism and migration. Extracellular signals from cytokines, growth factors and nutrients control the activity of a key set of lipid-modifying enzymes: phospholipases, prostaglandin synthase, 5-lipoxygenase, phosphoinositide 3-kinase, sphingosine kinase and sphingomyelinase. These enzymes and their downstream targets constitute a complex lipid signalling network with multiple nodes of interaction and cross-regulation. Imbalances in this network contribute to the pathogenesis of human disease. Although the function of a particular signalling lipid is traditionally studied in isolation, this review attempts a more integrated overview of the key role of these signalling lipids in inflammation, cancer and metabolic disease, and discusses emerging strategies for therapeutic intervention.

A recent symposium (april 2013) carries the title:
Unveiling the Significance of Lipid Signaling in Neurodegeneration and Neuroprotection…
We know lipid signaling is a hot topic and palmitoylethanolamide is one of those lipid mediators which has been available for the clinic since 5 years now. PEA has been tested in around 4000 patients for its analgesic and anti-inflammatory effects and currently is available world wide as the supplement PeaPure.

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