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Rita Levi-Montalcini on the relation between NGF, the mast cell and palmitoylethanolamide (PEA)

An unique interview with Nobel Laureate professor Rita Levi-Montalcini on her work on NGF, leading to a breakthrough in the 90s and the development of insight in the therapeutic role of endogenous compounds able to modulate inflammatory and chronic pain processes, the autocoids, or ALIA-mides. Here she talks on this relationship and the foundations of the therapeutic use of palmitoylethanolamide. Palmitoylethanolamide is since 2007 available in Italy and Spain as Normast, and since 2012 in the Netherlands and via the internet as PeaPure. Rita Levi-Montalcini was the oldest living Nobel price laureate, and died in december 2012 on the age of 103. Her last scientific paper was from 2012: Nerve growth factor regulates axial rotation during early stages of chick embryo development.[1] Manca A, Capsoni S, Di Luzio A, Vignone D, Malerba F, Paoletti F, Brandi R, Arisi I, Cattaneo A, Levi-Montalcini R. In: Proc Natl Acad Sci U S A. 2012 Feb 7;109(6):2009-14. Summary of her talk in the next cartoons for the quick reading...

Rita Levi-Montalcini: a tribute

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Professor Rita Levi-Montalcini discovered Nerve Growth Factor (NGF) in 1954, and many papers are published
since, relating to this tremendously important milestone for the medical sciences. Much less is known about another
milestone in molecular and clinical neurology she and her co-workers achieved. In the period 1993-1996 her group
identified the mechanism of action of the anti-inflammatory and analgesic properties activity of the endogenous fatty
amide palmitoylethanolamide (PEA).

PEA is a molecule with tissue-protective and anti-inflammatory activities, widely present in plants, animals and
man. Rita Levi-Montalcini and her group discovered in 1993 PEA as a natural modulator of hyperactive mast cells,
counteracting the pro-inflammatory actions of NGF. PEA however, has not been registered as pharmaceutical drug,
due to the fact that patent protection of the pure and natural compound was impossible. Therefore, developed as a
nutraceutical, it did not catch the attention of the medical community, which we hope to prove is incorrect. Based on
Levi-Montalcini’s work in the 90s PEA is now available as a nutraceutical for indications related to chronic pain and
chronic inflammation.

In the period 1970-1980 its safety and efficacy has been explored and documented in 6 double
blind clinical trials in flu and respiratory infections in around 2000 patients. Triggered by the findings of Levi-Montalcini
PEA has been evaluated since 1993 in a variety of pain indications such as sciatic pain, low back pain, diabetic pain,
neuropathic pain, pain due to arthritis in a total of 2000 patients. PEA is therefore most probably the best-documented
nutraceutical around, and its pharmacological profile has been described in more than 350 scientific papers. In this
review we will discuss Levi-Montalcini’s discovery of PEA’s mechanisms of action and its clinical relevance.

PEA: From Discovery to Clarification of its Mechanism
of Action by Prof. Levi-Montalcini

If we study the timeline of events related to PEA, we could define
three periods: During the first period 1957-mid 80s. PEA was seen as
an aspecific immunity-enhancer with anti-inflammatory properties
[13-16]. Flu and respiratory infections were indications for the use
of PEA, introduced in the clinic under the brand name Impulsin in
Czechoslovakia by the pharmaceutical company Spofa. In this period
PEA’s safety and efficacy was evaluated in a number of clinical trials,
resulting in a dose-recommendation of PEA 600-1800 mg/day in flu,
common cold and respiratory infections [17,18]. Around 2000 adult
volunteers and 400 children were entered in these trials [18]. All these
clinical trials pointed in the same direction: PEA has clear treatment
effects in respiratory infections, can be used as flu-prophylaxis and
is safe in its use. Side effects were not reported, and Kahlich et al.
explicitly stated: “No side effects were registered after several years of
clinical testing of Impulsin in military and civilian communities” [18].
A second period, which we call the Silent Gap period, lasted
around a decade, from the early 80s until 1993. As no mechanism of
action could be detected, and PEA was seen as an unspecific immune
enhancer, the scientific community lost interest.
In 1993 the third period started: Prof. Levi-Montalcini et al.
clarified its mechanism of action in various papers. This clarification
was related to her insights in the biological actions of NGF [8].

Referentie

[1] Manca A1, Capsoni S, Di Luzio A, Vignone D, Malerba F, Paoletti F, Brandi R, Arisi I, Cattaneo A, Levi-Montalcini R. | Nerve growth factor regulates axial rotation during early stages of chick embryo development. | Proc Natl Acad Sci U S A. | 2012 Feb 7;109(6):2009-14. doi: 10.1073/pnas.1121138109. Epub 2012 Jan 25.