Journal of Pain and Relief: Professor Rita Levi-Montalcini on Nerve Growth Factor, Mast Cells and Palmitoylethanolamide, an Endogenous Anti-Inflammatory and Analgesic Compound

In the Journal of Pain and Relief a recent (2013) an article on PEA and the discovery of its mechanism of action, as well as the link with NGF related to Prof. Rita Levi- Montalcini’s work.
In the paper the author summerizes the relevance of PEA:

PEA has been explored in a variety of indications such as sciatic pain, diabetic pain, neuropathic pain, pain due to arthritis and pain in multiple sclerosis in the period 1992-2010 and around 20 clinical trials have documented its safety and efficacy in these chronic pain states [2,42]. In the period 1970-1980 its safety and efficacy was already documented in a series of double blind clinical trials in flu and respiratory infections. PEA is therefore most probably the best-documented nutraceutical around, with pharmacological profile described in more than 300 scientific papers

In the paper a discussion of the work of Levi-Montalcini in the early 50s of last century, and of her neurobiological work, which lead to the Nobel prize in 1986. That all is widely known, and many papers were- and still are published related to this tremendously important milestone for molecular biology and pharmacology [1]. 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 antiinflammatory and analgesic properties of the endogenous fatty amide palmitoylethanolamide. Palmitoylethanolamide (PEA) is a food component known already for more than 50 years and since 2008 used in the clinic [2]. In the period 1957-beginning of the 80s of last century, slowly PEA started to be recognized as a molecule with tissue-protective and anti-inflammatory activities, widely present in invertebrates, vertebrates and man [37]. In the period 1957, since the first description and synthesis of PEA, until 1980 many papers were published on pharmacology and the clinical effects of this simple fatty amide. However, its mechanism of action was not understood and thus scientific and clinical interest weaned. Rita Levi-Montalcini and her group discovered in 1993 that PEA acts as a natural modulator of hyperactive mast cells, counteracting the proinflammatory actions of NGF [8]. Since that hallmark paper, interest in PEA soared and many hundreds of publications emerged on PEA, its pharmacological profile, its mechanism of action and its value for treating many different chronic inflammation and pain states [2]. In this review we will discuss Levi-Montalcini’s discovery of PEA’s mechanisms of action and we will review the clinical relevance of PEA. PEA as a Nutraceutical Palmitoylethanolamide is synthesized and metabolized in animal cells via a number of enzymes and it exerts a multitude of physiological functions, related to metabolic homeostasis. PEA is available for human use since 2007 [2]. PEA was introduced in 2007 as a nutraceutical in Italy and Spain under the brand name een PEA-houdend product. The Italian company een Italiaans bedrijf produces it in Italy. een PEA-houdend product contains palmitoylethanolamide and a number of excipients, including sorbitol in one specific formulation. PEA is also under evaluation as special diettreatment for Inflammatory Bowel Syndrome by CM&D Pharma Ltd and Nestlé in the USA. Since 2012 PEA is also internationally available as a nutraceutical under the brand name PeaPure, produced in the Netherlands by the company Russell Science Ltd. PeaPure contains palmitoylethanolamide only, without any exipients or sorbitol. Birth of PEA The history of PEA started in a chemical, non-medical environment in 1952, when chemists synthesized a number of acyl-ethanolamides, among which PEA, without understanding its biological properties and its value [9]. Some years later the anti-inflammatory properties of egg yolk were discovered and dried egg yolk preparations were introduced as a kind of ‘pre-historical’ nutraceutical. Egg yolk and peanut oil were found to possessed anti-inflammatory activities, and PEA was discovered to be the carrier of these properties in 1957 [1012]. The story of the emergence of insights in the biological roles and value of PEA after its identification in 1952 and the contributions of Rita Levi-Montalcini is worth telling, because it shows that plausible explanations of the mechanism of action of drugs are required before a treatment concept will be explored in more detail in science and in the clinic. Without a satisfactory explanation, even in the presence of clinical efficacy, as was the case for PEA, a new therapeutic concept will not be embraced by the scientific community. PEA research sunk into oblivion after the first surges of interest between 1960 and the mid 80s of last century, due to the fact that no mechanism of action was convincingly demonstrated. 1993 was the year of resurrection for PEA, due to Levi-Montalcini’s paper [8]. 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 [1316]. 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]. Discovery of PEA as an Anti-inflammatory Compound The first real milestone was in 1957 when MSD scientists identified PEA as anti-inflammatory food-compound [11]. Kuehl et al. [11] isolated the anti-inflammatory factor in crystalline form in 1957 from soybean lecithin as well as from a phospholipid fraction of egg yolk and hexane extracted peanut meal. That product was tested using a local passive joint anaphylaxis assay in the guinea pig and was identified as N-palmitoylethanolamide, i.e. N- (2-hydroxyethyl)- palmitamide. They also synthesized the compound, as well as various analogues, and attributed the anti-inflammatory activity to the ethanolamine moiety of the series of molecules they synthesized. On 20 October of 1957 Kuehl and 4 colleagues reported: “We have succeeded in isolating a crystalline anti-inflammatory factor from soybean lecithin and identifying it as N- (2-hydroxyethyl)- palmitamide. The compound also was isolated from a phospholipid fraction of egg yolk and from hexane-extracted peanut meal.” This was the first description of PEA and its biological activity as an anti-inflammatory agent. The identification was clear after hydrolysis of the compound yielded palmitic acid and ethanolamine. Furthermore, PEA could be synthesized by refluxing ethanoladine with palmitic acid. This all permitted the identification of the inflammatory fatty compound as the known N- (2-hydroxyethyl)-palmitamide. Bachur et al. [3] analyzed various tissues for the presence of fatty amides and found PEA present in several tissues of the rat and guinea pig and consistently in brain, liver, and muscle. However, they pointed out that PEA’s mechanism of action remained a mystery: “The role of the fatty acid amides in metabolism is unexplained as yet” [3]. In 1967 and 1972 it was found that oral administration of PEA to mice decreased mortality caused by Shigella dysenteriae toxin, streptolysin O, or live group A Streptococcus, as well as the mortality rate resulting from traumatic shock [14]. The authors clearly pointed out that PEA could play a modifying role in the course of development of certain immunological processes, and stated that its mechanism of action has not been clarified and that further analytical studies were needed. In 1975 the first supportive effects of PEA in cancer as a modulator of toxicity of chemotherapy was reported, based on an animal model [19]. In 2011, the research group of Professor Gruccu in Rome demonstrated the supportive effects of PEA in neuropathic pains and nerve damage after chemotherapy, totally in line with these early findings [20]. In 1975 also for the first time the results of a small pilot trial in rheumatic pain were published, supporting the analgesic properties of PEA [21]. In 1980 Dennis Epps, from the university of Minnesota, reported the accumulation of PEA in the infarcted myocardium, and stated this might be of physiological importance because of its anti-inflammatory properties. It was Epps who first suggested that these fatty molecules played a protective role during ischemia, and that its presence:” may signify a response of myocardial tissue to injury directed at minimizing damage and promoting survival” [22]. Meanwhile, more recent pharmacological studies all confirmed that the hypothesis of Epps et al. [22] was correct. PEA protects nervous tissue in various lesion-models related to spinal cord injury as well as in shock, stroke, MS and Alzheimer [2328]. That the scientific activities focused on the physiological effects of PEA was clearly related to the absence of the pharmacological understanding of the receptor for this endogenous compound at that time. In the period 1957-1993 there were no clear mechanism of action studies that gave insight into how PEA could exert its physiological actions.

In 1993 this all changed, due to the work of Rita Levi-Montalcini and her co-workers [8]. Levi-Montalcini earned her Nobel Prize due to her work in the field of the nerve growth factor, NGF [1]. She pointed out the role of NGF during inflammation and its activating role on mast cells. The positive feedback of NGF on mast cell behavior could be modulated and inhibited by PEA and this was the first explanation of how PEA could inhibit inflammation. Hand in hand with this very relevant finding, she also was one of the first neurobiologist who pointed out that the mast cells are no Cinderella cells (her own words), but, and she quoted Galli, mast cells are rather ‘master cells’ [29].

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