Definitions
PEA
(N-palmitoylethanolamide): An endogenous fatty acid amide synthesized and
metabolized by cells that binds to cell receptors. It influences a multitude of
physiological functions and has potent anti-inflammatory and pain-relieving
properties.
Endocannabinoid
System: A lipid communication network that has critical physiological functions
and serves a vital purpose for our health and well-being through signaling
processes, homeostasis and hormone regulation.
Lipids and the ECS
In 1929, scientists
George Oswald Burr and his wife, Mildred Burr, discovered that omega 6
fatty acids were essential for health. This kicked off science’s interest into
lipids, and by the 1960s a new age of lipid research had begun. Edward Dennis
of University of California at San Diego wrote:
“Lipids
are in many ways the most important of the biomolecules because they are the
ultimate controllers and regulators of our bodily processes; they are key to
signaling events in cells. Further, imbalances in lipids are implicated in many
illnesses, such as heart disease, stroke, arthritis, diabetes and Alzheimer
disease. If we are going to solve these diseases, we must know what the lipids
are and what they do.”
The
endocannabinoid system (ECS) is a lipid communication network with important
physiological functions in all animal life. The complex biochemical array of
pathways involved in the synthesis, release, transport, and degradation of
endocannabinoids by the body is also known as the endocannabinoidome. This
lipid signaling network is a key modulator of physiological functions in many
of the other networks and signaling systems including; the nervous system, the
endocrine network, the immune system, the gastrointestinal tract, and the
reproductive system, as well as others.
Endocannabinoids,
the products of the ECS, are directly released from membranes, which
distinguishes them from other transmitter molecules, such as dopamine or
hormones. Moreover, unlike the neurotransmitters or hormones, which are
synthesized in one place but act globally in the body, the endocannabinoids are
synthesized locally and act locally.
PEA – The Rising Star of the ECS
Classical
endocannabinoids include, anandamide (also termed AEA) and 2-acyl glycerol
(2-AG). But other endocannabinoids were later discovered, and one in particular
has been studied in considerable detail, N-palmitoylethanolamide or PEA. The
origins of PEA started in 1939 when clinician and researcher Coburn was looking
into how to prevent the incidence of rheumatic fever in poor children living in
New York. He stumbled upon egg yolk as a key ingredient that prevented and/or
reduced rheumatic fever. In 1957 scientists at Merck Sharp and Dome identified
PEA as the molecule that provided this protection against streptococcal
infection and rheumatic fever.
However,
it wasn’t until 1993 that the mechanism of action of PEA was determined through
the work of Rita Levi-Montalcini an Italian scientist who back in 1954 had discovered
the nerve growth factor (NGF).
Levi-Montalcini’s
discovery was that NGF activated specific immune cells called mast cells that further caused
inflammation and allergic reactions. Almost forty years later, she discovered
how a naturally produced fatty acid amide called PEA stopped the activation of
mast cells, thereby preventing inflammation and allergies. Furthermore,
Levi-Montalcini discovered that PEA was produced locally by cells under
threat from noxious and injurious external triggers, like UV-A, various toxins,
allergens, infectious agents as well as other inflammatory agents. The local
production of PEA thereby reduced their threat. PEA was not only produced
locally but also acted locally. It seemed like PEA was called into
action whenever there was demand, when the body needed protection not only
against outside triggers but also when the body was under threat from within,
for example against ageing or whenever the immune system was overactive as in
various autoimmune disorders, which occurs when the body stops recognizing
friend from foe, and starts acting against itself. Mast cells seem to be key
components of the inflammatory response.
Levi-Montalcini
succinctly pointed out the interaction between PEA 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-acylethanolamine like palmitoylethanolamide
(PEA), which accumulate in tissues following injury and which down modulate
mast cell activation, exert a local, and anti-injury function via mast
cells. Palmitoylethanolamide is orally active in reducing tissue inflammation
and mast cells.”
Once the
mechanism of action of PEA was identified, there was a flurry of research on
PEA, and new and interesting health benefits were soon discovered. As early as
1980, it was learned that PEA had a tendency to accumulate
in the damaged heart muscle due to ischemia or deprivation of oxygen, and this
might be of physiological importance because of its anti-inflammatory
properties. Researcher Denis Epps suggested that these fatty molecules played a
protective role, and that their presence, “may signify a response of myocardial
tissue to injury directed at minimizing damage and promoting survival”.
Recent
studies have confirmed what Epps and his colleagues postulated. It has been
shown in various animal disease models, and human tissue analysis that PEA
protects various tissues, including the colon, kidney and particularly the nervous
tissue. It shows potential benefits in spinal cord injury as well as other
conditions like shock, stroke, MS and Alzheimer’s.
Currently
there are number of animal and human studies on the application of PEA in the
following conditions:
- Endometriosis
- Benign prostatic
hyperplasia (BPH)
- Burning mouth syndrome
- Inflammatory bowel
disease and syndrome (IBD/IBS)
- Depression
- Autism
- Transient brain injury
- Arthritis
- Pain originating from various
types
- Coronary heart disease
- Chronic kidney disease
- Atopic dermatitis and
eczema
- Vulvodynia
- Cannabis dependence
- Migraine
- Infectious diseases
In
conclusion, PEA is an endogenously, and locally produced anti-injury molecule, the sole function of which is to offer
immediate protection through down modulating disease processes and acting against
noxious stimuli in various systems of the body. The medical potential of this
fascinating and undervalued molecule that comes to the body’s rescue when the
need arises is worthy of wider attention in the context of ongoing research
into the endocannabinoid system.
References:
- Kuehl FA, Jacob TA, Ganley OH, Ormond
RE, Meisinger MAP (1957) The identification of N-2-hydroxyethyl-palmitamide as
a natural occurring anti-inflammatory agent. J Am Chem Soc 79: 5577-5578.
- Epps DE, Natarajan V, Schmid PC, Schmid
HO (1980) Accumulation of N-acylethanolamine glycerophospholipids in infarcted
myocardium. Biochim Biophys Acta 618: 420-430.
- Esposito E, Paterniti I, Mazzon E, Genovese T,
Di Paola R, et al. (2011) Effects of
palmitoylethanolamide on release of mast cell peptidases and neurotrophic
factors after spinal cord injury. Brain Behav Immun 25: 1099-1112.
- Keppel Hesselink JM, Hekker TA (2012)
Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic
pain associated with various pathological conditions: a case series. J Pain Res
5: 437-442.
- Petrosino S, Iuvone T, Di Marzo V (2010)
N-palmitoyl-ethanolamine: Biochemistry and new therapeutic opportunities.
Biochimie 92: 724-727.
- Gatti A, Lazzari M, Gianfelice V, Di Paolo A, Sabato E,
et al. (2012) Palmitoylethanolamide in the treatment of
chronic pain caused by different etiopathogenesis. Pain Med 13: 1121-1130.
- Keppel Hesselink, J (2013) Professor
Rita Levi-Montalcini on Nerve Growth Factor, Mast Cells and
Palmitoylethanolamide, an Endogenous Anti-Inflammatory and Analgesic . Compound
Pain Relief 2013, 2:1-5