Palmitoylethanolamide (Normast, PeaPure) as regulatory mechanism for the metabolism of mast cells

Levi-Montalcini on natural defence molculesIdentification of palmitoylethanolamide (PEA) as regulatory mechanism for the metabolism of mast cells by Nobel Price Laureate Rita Levi Montalcini in 1993, and it’s use as a analgesic and anti-inflammatory compound.

Searching for non psychoactive Cannabinoids our clinic identified in 2010 the small molecule palmitoylethanolamide (PEA) as a potent novel and promising analgesic and anti-inflammatory agent. This molecule has been developed based on the work and insights of Rita Levi Montalcini, as an off spin of her work with nerve growth factors.

As PEA (as PeaPure or Normast) is gaining more and more international recognition as a break through molecule in the treatment of chronic pain and inflammation, it is worth while to shortly analyze how the mast cell modulation concept, palmitoylethanolamide and the ALIA concepts came into existence.

Palmitoylethanolamide as a regulating molecule

Identification of palmitoylethanolamide (Normast) as regulatory mechanism fo the metabolism of mast cells was done by Rita Levi Montalcini in 1993, and it’s use as a analgesic and anti-inflammatory compound was pointed out by her in several papers around that period.

Searching for non psychoactive Cannabinoids our clinic identified in 2010 the small molecule palmitoylethanolamide (PEA) as a potent novel and promising analgesic and anti-inflammatory agent. We had never heard about it, neither had any of our colleagues. A great ommission of all of us (as anglo-saxon orientated/biased scientists), as palmitoylethanolamide quickly now becomes one of the major breakthrough steps in the treatment of chronic pain.

This molecule has been developed based on the work and insights of Rita Levi Montalcini, as a spin-off of her work and instight in the field of nerve growth factors. As PEA or, using the trade name Normast, is gaining more and more international recognition as a break through molecule in the treatment of chronic pain and inflammation, it is worth while to shortly analyze how the entire concept around this molecule came into existence.

Current situation of PEA

PEA has been used under the brandnames Normast and PeaPure by million patients all over the world.

We ouselves have been working with this compound in our clinic since 2010 and treated probably more than 1000 patients, most of them with good results, without noticing any dose limiting side effects, or any troublesome side effects or drug-interactions, and the product was also helpfull in elderly, our oldest patient is 90.

Under our patients we even find many King Charles spaniels suffering from severe central neuropathic pain due to syringomyelia, who respond very favourably on the treament with 150 mg PEA/day. The dog reacted even better on the supplement PeaPure, most probably due to the absence of excipients in PeaPure.

In our hands PEA has been useful in the treatment of neuropathic pain in diabetic neuropathy, sciatic pain, chronic joint pain, chemotherapy induced pain, CIAPCIDP, central neuropathic pain eg in MS, pudendal neuralgia, vulvodynia, pelvic pain and fibromyalgia.

PEA’s target is amongst others the nuclear PARR rerceptor, and, as it is increasingly recognized that non-neuronal cells such as immune cells and glial cells in the PNS and CNS play a critical role inneuropathic pain, targeting these cells adds a new dimension to our treatment regime.

PEA most probably is one of the most promising compounds focussed on these targets.

The beginning of the mast cell modulation concept and the ALIA mechanism of PEA

In 1993 in an article titled  ‘ A proposed autacoid mechanism controlling mastocyte behavior’, the Nobelprize laureate Levi-Montalcini presented evidence ‘ supporting the possibility that lipid amides of the N-acylethanolamine type are potential prototypes of naturally ocurring molecules capable of modulating mast cellactivation in vivo.’

Together with some of her co-workers she put forward the following elegant hypothesis:

‘Tissue accumulation of ….free N-acylethanolamines has been reported to occur in pathological degenerative conditions. As such conditions are known to be associated with inflammatory reactions, one attractive hypothesis is that the production of these lipid metabolites may play an autacoid role in controlling mast cell behavior in pathological conditions.’

In this paper she also introduced the term ‘ALIA’ to stipulate the physiological mechanism of action of PEA in various inflammatory and painful states.

ALIA and autocoid physiology of PEA

The acronym ‘ALIA’ stamds for ‘autacoid local inflammation antagonism‘ and is a term Montalchini et al proposed for the novel mast cell modulation mechanism, based on PEA.

An autocoid is a simple molecule synthesized locally in tissue were it also acts locally. We could find the use of this term ‘autocoid’ already in biological literature from before world war II, around 1935.

Examples of molecules acting as autocoids are NO and leukotriens. An autocoid controls metabolism locally, whereas a hormone is produced locally but acts globally and also influences metabolism.

In this case PEA is formed locally in tissue suffering from inflammation or, as Montalcini puts it, neurogenic pain, and increased PEA concentrations are the body-own mechanisms to cope with pain and inflammation.

From another perspective one could state that this molecule is our natural defense molecule, or self-healing molecule, in case of over-active mast cell behaviour, and activated glia cells, as present in may different painful and inflammatory disorders.

The broadening of the ALIA concept and the role of palmitoylethanolamide in central nervous disorders

In 1995 Levi Montalcini reported the results of the work of her coworkers related to the protective effects of palmitoylethanolamide in central nervous damage. That was in a paper published in the Proceedings of the National Academy of Science.

She pointed out that activated NMDA receptors have been implicated in a variety of pathological states in the CNS leading to neuronal injury. She also pointed out that little is known about endogenous molecules and mechanisms capable of modulating the NMDA induced excitotoxic neuronal death.

In such CNS pathology the body prepares its own defense mechanism via Saturated N-acylethanolamides like palmitoylethanolamide.

These compounds accumulate in ischemic tissues and are synthesized by neurons upon excitatory amino acid receptor activation.

She summarized the research findings pointing out that N-acylethanolamides, like palmitoylethanolamide, and N-acylphosphatidylethanolamides accumulate in conditions involving degenerative changes to tissues, as in CNS and cardiac ischemia.

In addition to this excitatory amino acids   stimulate the synthesis of N-acylethanolamides and N-acylphosphatidylethanolamides in cultured central neurons. In a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons, palmitoylethanolamide could beshown to be an endogenous protective agent in case of NMDA induced neuron death.

Levi Montalcini extrapolated these findings and came to the conclusion that by providing the neuron with exogenous palmitoylethanolamide, one might be making available quantities of its physiological modulator sufficient to restore cellular homeostasis in the face of an excitotoxic challenge.

As the cannabinoid palmitoylethanolamide was already shown by her group to stabilize mast cell hyperactivity in inflammation, she coined the concept ALIA, autacoid local inflammation antagonism.

In the 1996 paper on the protective effects of PEA in central neuron death, she broadened the concept:

“Palmitoylethanolamide, in reality, appears to exert a more broad local autacoid antiinjury function, thus the acronym autacoid local injury antagonism for ALIA.”

In the same period of time Montalcini pointed out the importance of the nerve growth factor as a inflammatory mediator in neuropathic pain states, as well as in diseases as multiple sclerosis.

Mast cell as important players

She stressed the importance of mast cell activity in activated plaques in MS patients, and the pathological cascade of events triggered by these activated mast cells. In the same period she proved that mast cells can be sources of the synthesis of nerve growth factor, the base of the pathological immune system-CNS crosstalk.

In an authoritative review article on nerve growth factors, in TINS 1996, Montalcini already asked attention for the therapeutic potential of palmitoylethanolamide
in neuropathic pain and multiple sclerosis.

In that famous article Levi Montalcini wrote about palmitoylethanolamide and the mast cell:

…unregulated mast-cell activation constitutes a considerable risk to the health of the organism, and it is not unreasonable to expect that nature should have devised a means for the host to defend itself against such damage.

It has recently been proposed that saturated N-acylethanolamides like palmitoylethanolamide, which accumulate in tissues following injury and which downmodulate mast-cell activation in vitro, exert a local, autacoid, anti-injury function via mast cells.

Palmitoylethanolamide is orally active in reducing tissue inflammation and mast-cell degranulation in vivo, in decreasing hyperalgesia that accompanies peripheral nerve compression, and in limiting the neurological deficits of experimental allergic encephalomyelitis.

Moreover, palmitoylethanolamide appears to project against excitotoxic neuronal death in vitro and to be produced by cultured CNS neurones upon excitatory amino acid receptor activation.

The mechanism of this action of N-acylethanolamides has been termed autacoid local injury antagonism (ALIA).

The observed pharmacological effects of palmitoylethanolamide appear to reflect the consequences of supplying the tissue with a sufficient quantity of its physiological regulator of cellular homeostasis.

And concluding, and how right she was:

Conceivably, palmitoylethanolamide and its congeners (‘ALIAmides’) might play a role in modulating cellular defence mechanisms by acting at non-CB1 cannabinoid receptors. The activation of such receptors might down-modulate deleterious cellular processes following pathological events or noxious stimuli in both the immune and nervous systems…..

She is a visionary scientist!

Literature, presented by Rita Levi-Montalcini

L. FACCI, R. DALToso, S. ROMANELLO, A. BURIANI, S. D. SKAPER, ANDA.
LEON. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc. Natl. Acad. Sci. USA Vol. 92, pp. 3376-3380, April 1995

S. D. SKAPER, A. BURIANI, R. DAL TOSO, L. PETRELLI, S. ROMANELLO, L.
FACCI, AND A. LEON The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proc. Natl. Acad. Sci. USA Vol. 93, pp. 3984-3989, April 1996

Montalcini nerve growth factor TINS 1996 [1]; [1]: Levi-Montalcini R, Skaper SD, Dal Toso R, Petrelli L, Leon A. | Nerve growth factor: from neurotrophin to neurokine. |Trends Neurosci. | 1996 Nov;19(11):514-20.

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