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  • Review article / Medicine and Health Sciences

    Role of Palmitoylethanolamide as Adjuvant Treatment for Respiratory Infection

    Role of Palmitoylethanolamide as Adjuvant Treatment for Respiratory Infection

    Authors: José Javier Hernández Martínez

    Coauthors: José Antonio Cánovas Ivorra, Esteban Salas Rezola

    Keywords: Palmitoylethanolamida. Infección respiratoria. COVID-19

    Keywords: Palmitoylethanolamide. Respiratory infection. COVID-19

    Abstract: Palmitoylethanolamide (PEA) can help in early recovery from respiratory infections and in minimizing the damage through its effect on PPARs, which causes a decrease in TNF-α and IL-1β that, in turn, reduces COX-2 and iNOS levels and thus minimizes the vascular endothelial damage. Therefore, it would seem logical to assert that it can constitute an adjuvant treatment for COVID-19-type respiratory infections. However, randomized studies are required to verify the above hypothesis.


    Citation: José Javier Hernández Martínez, José Antonio Cánovas Ivorra, Esteban Salas Rezola. Role of Palmitoylethanolamide as Adjuvant Treatment for Respiratory Infection. https://:doi.org/10.24175/sbd.2020.000017
    Received: October 09, 2020  Accepted: October 15, 2020  Published: October 26, 2020
    Copyright: © 2020 Hernández Martínez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC), which allows, distribution, reproduction in any medium, provided the original author and source are credited and non-commercial use.
    Funding: I certify that no funding has been received for the conduct of this study and/or preparation of this manuscript.
    Conflicts of Interest: I have no conflicts of interest to declare

    

    Role of Palmitoylethanolamide as Adjuvant Treatment for Respiratory Infection

    José Javier Hernández Martínez1, José Antonio Cánovas Ivorra2 y Esteban Salas Rezola3

    1Head of Neurology, Hospital Clínica Benidorm HCB (Benidorm Clinical Hospital), Medical Director, Hospital Daño Cerebral Casaverde Alicante (Casaverde Alicante Hospital of Cerebral Damage); 2Medical Specialist in Urology and Andrology, Hospital Clínica Benidorm HCB (Benidorm Clinical Hospital); 3Medical Specialist in Anesthesiology. Hospital General de Alicante (Alicante General Hospital).

    Keywords: Palmitoylethanolamide. Respiratory Infection. Covid-19

    ABSTRACT

    Palmitoylethanolamide (PEA) can help in early recovery from respiratory infections and in minimizing the damage through its effect on PPARs, which causes a decrease in TNF-α and IL-1β that, in turn, reduces COX-2 and iNOS levels and thus minimizes the vascular endothelial damage. Therefore, it would seem logical to assert that it can constitute an adjuvant treatment for COVID-19-type respiratory infections. However, randomized studies are required to verify the above hypothesis.

    Introduction

    Due to the current situation of concern related to the respiratory infection caused by COVID-19, first of all, we should consider whether Palmitoylethanolamide (PEA) (Figure1) can help in early recovery or in improvement of lesions from pneumonia. For these purposes, we have chosen this molecule currently available on the market. It is used as an antioxidant and an agent improving other pathologies caused by inflammation due to its antioxidant mechanism.

    Figure 1. The molecular structure of palmitoylethanolamide.

    The principal objective of the meta-analysis is to verify the role of the said molecule in respiratory infections, and for these purposes, two independent searches were conducted in the Medical Subject Headings (MESH) of the National Library of Medicine (PEA pneumonia and PEA respiratory infection).

    A total of seven articles have been retrieved during the search at the National Library of Medicine covering the following period: the oldest article is dated March 1998, and the most recent article is dated April 2020. With all this information, we intend to comprehend the knowledge acquired about the respiratory infection in relation to this molecule.

    Before we start the analysis, we shall present the development of knowledge about the physiology of PEA in order to have a base of knowledge a priori accepted as valid in our study.

    Molecular physiology of PEA.

    PEA is an endogenous fatty acid amide belonging to the class of nuclear factor agonists. It is used in basic research and in clinical medicine due to its neuroprotective, antineuroinflammatory, and analgesic properties1-6.

    It was identified as a natural food ingredient with medicinal properties in 1943 in an epidemiological study focused on pediatric rheumatic fever7. It was isolated for the first time from purified lipid fractions of soybean, egg yolk, and peanut flour8,9 and later was found in a wide variety of food sources10-13, cells14-19, tissues20-26 and fluids of the body10,27-30 of humans and various species of animals.

    In animals, biosynthesis of PEA occurs by way of hydrolysis of its direct phospholipid precursor, N-palmitoyl phosphatidylethanolamine, by the action of selective N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD)31. The degradation of PEA into palmitic acid and ethanolamine occurs due to the action of two different hydrolytic enzymes, fatty acid amide hydrolase (FAAH)32 and, more specifically, N-acylethanolamine acid amidase (NAAA)33.

    PEA appears to act on different receptors (PPAR-α and GPR55), where it seems to act directly, and on CB1, CB2, and TRPV1 receptors, where the action can be indirect.

    PPAR-α is a nuclear receptor protein that belongs to the PPAR family and acts as a transcription factor that regulates expression of different genes34. An immunological action has been established for the PPAR family35,36, and it seems to be involved in inflammatory processes36,37; it is probable that it does so through heterodimerization with the retinoic acid receptor (RXR) and reduction of pro-inflammatory gene transcription38.

    The GPR55 receptor belongs to a large GPCR family. It can be activated by cannabinoid derivatives, and recent studies suggest that this is a possible way to treat inflammation39. The CB1 and CB2 receptors are not direct targets of PEA but they can be indirectly activated by PEA through the mechanisms of the entourage effect6,19,40,41. The CB1 receptor does not appear to be involved in inflammation, and the CB2 receptor has a very low expression in the brain but is related to activated astrocytes and microglia cells, and these appear to have control over inflammation and nociception42-44.

    Methods

    In order to make the knowledge of the PEA role in respiratory infection complete, a MESH search has been conducted at the National Library of Medicine for the terms of PEA pneumonia and PEA respiratory infection. Seven research articles have been retrieved and analyzed thoroughly to identify conclusive data on the PEA role in a respiratory infection. As it is logical for knowledge accumulated over time, the documentation has been analyzed in chronological order.

    The first article analyzed dated 1998 describes a pulmonary challenge in Balb/c mice with aerosol of 100 μg/ml endotoxin (lipopolysaccharide isolated from E. coli) (LPS, Sigma, St Louis, MO, USA) diluted in saline solution (NaCl, 0.9%). PEA at a dose of 750 nmol.kg/L was shown to decrease the level of tumor necrosis factor alpha (TNF-α) in bronchoalveolar lavage fluid by 31.5% but had no effect on neutrophil recruitment. Based on the conclusions drawn in this article, we can assume that there is a distinctive affinity of the compounds for the cannabinoid receptors of murine macrophages45.

    In order to understand what constitutes a decrease in TNF-α, we provide a short summary about this protein. It belongs to the group of cytokines, and these proteins are released into the blood flow mainly by the cells of the immune system. They seem to be involved in a wide variety of processes, such as inflammation, apoptosis, and rheumatoid joint destruction. These processes are related to white blood cells, macrophages, vascular endothelium and can be detected in other tissues in the face of an external aggression, such as infections.

    Release of TNF-α in the vascular endothelium causes release of nitric oxide (NO), which triggers vasodilation, and, as a consequence, vascular permeability increases, which brings about the final activation of T- and B-lymphocytes46.

    Between 2002 and 2004, there was a discussion about possible activation of the proliferative peroxisome-activated nuclear receptor (PPAR) by PEA47,48. To test this possibility, Verme et al. evaluated the effects of PEA administration on mRNA levels of PPAR, which are known to be regulated by PPAR agonists. The results suggest that PEA activates the PPAR selectively.

    Later, in a study performed in 2005 by Verme, it was demonstrated that PEA activated the nuclear PPAR with the potency comparable to that of the synthetic agonist Wy-14643. However, it was concluded that an unambiguous demonstration of this would require further experimentation in the future49.

    To understand this article well, we must delve a little more into PPARs. These receptors are ligand-activated transcription factors which belong to the nuclear receptor superfamily. Three isoforms of this receptor are known: PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3). PPARα is involved in oxidation of fatty acids, and it is expressed most greatly in metabolically active tissues, such as liver, kidney, and skeletal muscle, but it has also been found in heart, monocytes, vascular endothelium, and smooth muscle cells. PPARγ is involved in adipocyte differentiation and insulin sensitivity, and it has two isoforms: PPARγ1 that is expressed at a high level in adipose tissues, and PPARγ2 that is expressed in various tissues. PPARγ is also expressed in vascular smooth muscle cells and in the heart, although very scarcely in the latter. PPARβ/α is most widely distributed in the body, and its level of expression depends on the degree of differentiation50.

    In 2012, based on previous studies by Loverme that showed the anti-inflammatory and analgesic effects mediated by binding and activation of the peroxisome proliferator-activated receptor (PPAR)α, Redlich found that the stimulation of microglial cells by PEA led to a significant increase in phagocytosis of pathogens. This suggests that PEA enhances inherent cellular immunity by increasing phagocytosis of invading bacteria, and thus acts as an endogenous protective factor in the brain. Stimulation of bacterial phagocytosis by microglial cells through PEA could increase resistance of the brain to infection and decrease permanent neuronal damage51.

    In 2014, Nau reconsidered the possibility that PEA could prevent infections due to the effect caused by its action on TNF-α52. And in 2016, Di Paola's team induced idiopathic pulmonary fibrosis in mice by way of intratracheal administration of saline with bleomycin sulfate (1 mg/kg BW) in a volume of 100 μL. PEA was injected intraperitoneally at three different dose levels (1, 3, or 10 mg/kg) 1 h after instillation of bleomycin, and subsequently such dose level was administered daily.

    The experimental animals were sacrificed on Days 7 and 21 with an overdose of pentobarbitone. In the cohort of mice that were sacrificed after seven days of administration of bleomycin, bronchoalveolar lavage and determination of the myeloperoxidase activity were performed, pulmonary edema was evaluated, and histopathological characteristics of the lesions were examined. In the cohort of mice that were sacrificed on Day 21, mortality was assessed on a daily basis, and the surviving mice were subsequently sacrificed.

    An immunohistochemical study was conducted to measure CD8, tumor necrosis factor alpha, CD4, interleukin-1 beta, transforming growth factor beta, nitric oxide, and fibroblast growth factor levels. Compared to the mice treated with bleomycin without administering PEA, animals that also received PEA at dose levels of 3 or 10 mg/kg had a significantly decreased level of weight loss, mortality, inflammation, lung damage (as assessed histologically), and pulmonary fibrosis both in the mice sacrificed on Day 7 and in those sacrificed on Day 21.

    PEA did not inhibit significantly the inflammatory response or pulmonary fibrosis at a dose level of 1 mg/kg. This study demonstrates that PEA at dose levels of 3 and 10 mg/kg reduces the extent of lung inflammation in a mouse model of idiopathic pulmonary fibrosis.

    Therefore, administration of PEA at dose levels of 3 or 10 mg/kg 1 h after instillation of bleomycin and daily thereafter inhibits bleomycin-induced airway leukocyte infiltration by 46% at a dose level of 3 mg/kg and by 60% at a dose level of 10 mg/kg, respectively. On the other hand, the activity of myeloperoxidase at doses of 3 and 10 mg/kg did not show any significant inhibition other than inhibition of a number of macrophages, eosinophils, neutrophils, and lymphocytes. The administration, however, did significantly inhibit the increase in lung collagen content caused by the administration of bleomycin by 10% at a dose of 1 mg/kg, by 32% at a dose of 3 mg/kg and up to 60% at a dose of 10 mg/kg.

    Bleomycin showed a substantial increase in lung staining for TNF-α and IL-1β, and after PEA administration at dose levels of 3 or 10 mg/kg, it was seen that the said increase was extinguished both for TNF-α and IL-1β53.

    Later in 2017, Saturnino's work group presented a study that substantiated the anti-inflammatory and antioxidant effects of PEA along with the biological evaluation of N-palmitoyl-ethanolamine, a molecule characterized by an added acid (such as palmitoyl amides or hexadecyl esters) useful for decreasing its hydrolysis rate in vitro and prolonging its biological activity. Two of these compounds, phenyl-carbamic acid and 2-methyl-pentadecanoic acid (4-nitro-phenyl)-amide, have been shown to have good anti-inflammatory and antioxidant properties, to the same extent as PEA54.

    With the emerging infection of COVID-19, Antonio Gigante suggests that PEA inhibits the release of preformed mast cells, and thus reduces histamine and TNF-α, thereby lowering the secretion of hyperactive mediators that are dose-dependent. This lowering occurs through the reduction of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) that play a key role in the regulation of the immune response to the infection55.

    Discussion:

    Based on the studies presented recently, it seems logical to conclude that PEA acts by stimulating the nuclear PPARs, of which three isoforms are available. The PPARα isoform is the one that is involved in oxidation of fatty acids and is expressed more greatly in metabolically active tissues, such as liver, kidney, and skeletal muscle, but which, in its turn, has also been found in heart, monocytes, vascular endothelium, and smooth muscle cells. As a consequence of this activation, there is a decrease in TNF-α and IL-1β levels, and following the decrease in TNF-α less nitric oxide is released into the blood flow, and therefore vascular permeability is decreased; as a consequence, there is a reduced recruitment of inflammatory cells, immunoglobulins and the complement system, ultimately causing a reduction in activation of T- and B-lymphocytes. As it is also involved in platelet activation and adhesion, this decrease will lead to a decreased activation of the coagulation cascade, and it is still to be determined what will be less likely to cause clot formation. This decrease in TNF-α reduces the activation of this cascade proportionally, which has been evidenced in a mouse model of idiopathic pulmonary fibrosis where it has been shown that the leukocyte infiltrate and the collagen content on the damaged fibers are also decreased. On the other hand, it has been proven that the activation of PPARα increases pathogen phagocytosis and improves the progress of neuronal infections as well as decreases cyclooxygenase 2 (COX-2) activation (Figure 2).

    Preliminary data on COVID-19 indicate that the respiratory infection has been accompanied in many cases by secondary thrombosis at the cardiovascular, cerebrovascular, and extremity levels, which has led to heart attacks, strokes, and amputations during the pandemic. A possibility is considered that the adjuvant administration of PEA in patients with the COVID-19-induced infection may improve these parameters during the acute phase of the infection.

    Figure 2. Graphic representation of the data obtained and the biochemical cascade caused by the action of PEA.

    Conclusions:

    It seems logical to conclude that the action of PEA on the nuclear PPARs in the context of a respiratory infection, induced either by coronavirus or by any other viral or bacterial infection, can cause a decrease in TNF-α and IL-1β, and thus reduce the vascular endothelial damage that occurs during these infections, as well as reduce the leukocyte infiltrate and the pulmonary damage caused by collagen accumulation. We consider the possibility that it can also minimize the risk of acute myocardial infarction, stroke, and thrombosis caused by the action of TNF-α on the vascular endothelium.

    However, controlled, prospective, and correctly randomized clinical trials are required to verify this scientific hypothesis, but a priori in basic medicine it meets the criteria for considering a study in humans, since this molecule meets the safety standards that are required for its marketing as a dietary supplement.

    Conflict of interest

    There is no conflict of interest.

    Description of the authors' roles

    This paper has been written by a team of specialists in neurology, urology, and anesthesiology who have debated and analyzed different articles in order to shape this new pathway that can improve outcome of lung infections by reducing the damage caused by excessive activation of the immune system.

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About The Author/s
José Javier Hernández Martínez
firefritz@gmail.com
Head of Neurology, Hospital Clínica Benidorm HCB, Medical Director, Hospital Daño Cerebral Casaverde, Alicante


José Antonio Cánovas Ivorra
Medical Specialist in Urology and Andrology, Hospital Clínica Benidorm HCB


Esteban Salas Rezola
Medical Specialist in Anesthesiology. Hospital General de Alicante


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DOI: 10.24175/sbd.2020.000017

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