PEA and related lipid molecules are ubiquitous messenger molecules that participate in intracellular signaling, function in communication from cell to cell, and serve as neurotransmitters. Our knowledge about these molecules intensified since 1993, after the work of the Nobel price laureate Rita Levi-Montalcini on palmitoylethanolamide and its inhibiting effects on inflammation, much happened. It seems that all Montalcini said in 1993 about inflammation, the role of the mastcell and the modulation of the mastcell by the endogenous modulator palmitoylethanolamide has been substantiated by new research.
Over the past ten years, she has published a steady stream of papers with her colleague Luigi Alao and others on the wider role of NGF. They have shown that mast cells are able to bind NGF and recently they described how these cells are also able to synthesise, store, and release this factor (Proc Natl Acad Sci USA 1994; 91: 3739-43).
Prof Levi-Montalcini around 1990 was associated with Researchlife, a small company based in Castelfranco Veneto in Northern Italy. In that period the company’s researchers reported that a cannabinoid receptor (CB2) was expressed on mast cells; this was later proven to be incorrect, but it was at that time an important contribution, because it explained why the sensitivity of CB2 to palmitoylethanolamide differed from that to anandamide, which antagonises the central CB 1 receptor. The findings of Montalcini suggested in 1993 that palmitoylethanolamide might be able to antagonise local autacoid inflammation, thus offering a new approach to anti-inflammatory therapy that does not involve inhibition of prostaglandin synthetase and is free from the side-effects associated with non-steroidal anti-inflammatory drugs. (Rita Levi-Montalcini. By: Jack, David B., Lancet, 00995355, 6/10/1995, Vol. 345, Issue 8963).
Since the discovery of EGF and NGF, several other growth factors have been discovered. Levi-Montalcini and her fellow scientist, Cohen, the Nobel committee noted in 1986, “have created a scientific school with an increasing number of followers.”
Recently, a number of pharmacologists reviewed the literature and found new experimental data supporting the role of the mastcell in our central nervous system. They state that their experimental data strongly suggest the participation of mastcells in the processes which eventually lead to autoimmune demyelination, a kind of neuroinflammation, which is of relevance for e.g. multiple sclerosis.
They reviewed the data around the mastcell and highlighted the functional relation between mastcells and nerve fibres. This relation clearly demonstrates how important mastcells can be in the pathogenesis of chronic pain and neuro-inflammation.
This all highlights the therapeutic use of palmitoylethanolamide (PEA) in modulation of the mastcell, as Montalcini correctly pointed out in 1993. PEA can be administered as Normast or PeaPure, as supplements, supporting the natural healing capacity of our body in situations of chronic pain and neuro-inflammation. PeaPure consists of palmitoylethanolamide alone, pure without pharmaceutical excipients; in Normast palmitoylethanolamide is formulated together with chemical and pharmaceutical excipients; in a 600 mg tablet 2883 mg consists of these additives.
The case presented here on the anti-neuro-inflammatory action of PEA in CRPS further adds data to the chapter in neuro-immunology.
Their review of this relationship follows:
Mast cells (MC) prefer to locate around vessels and nerve fibers (Selye, 1965) and some of them are in a close approximation to nerves in connective tissues of various organs (Stead et al., 1989).
MC are also present in the central nervous system (CNS) of both humans and mice (Maślińska et al., 1999) and are increased in number in certain diseases (Epari et al., 2006).
In mouse, most MC are localized in the thalamus and appear to be mainly degranulated in the experimental model of multiple sclerosis (MS) (Brenner et al., 1994).
These anatomical findings are suggestive of functional communication between nerve and MC. Molecular evidence supports this hypothesis:
(1) nerves in contact with MC often contain neuropeptides and release them on stimulation (Stead et al., 1987; Keller and Marfurt, 1991);
(2) MC express receptors for many neuropeptides (Cooke et al., 1998; Suzuki et al., 1999; van der Kleij et al., 2003; De Jonge et al., 2004);
(3) MC can be also stimulated by nerve growth factor (NGF) and can in turn release it triggering a positive feed-back loop (Kawamoto et al., 2002).
The nerve-MC communication induces a mutual functional response. If on the one hand, electrical stimulation of nerve fibers results in mast cell activation (i.e., degranulation or secretion of mediators) (Dimitria-dou et al., 1991), on the other, MC synthesize and release a variety of molecules which, in turn influence neuronal activity (Frieling et al., 1993).
Modulation the detrimental effects of mastcells in neuro-inflammatory diseases as multiple sclerosis, and more specifically treating spasms and pain in MS clearly is supported by much pharmacological research. Recently clinical trials proved the relevance of PEA in the treatment of spams and pain in stroke and MS. Both symptoms are based on neuro-desctruction due to neuro-inflammation.
Recent anecdotal data in literature, by an Italian rehab clinic, supporting the role of PEA in amyotrophic lateral sclerosis, which also is a neuro-immunological disorder, further supports the above approach.
Let us now qoute the important part on mast cells from:
Mast Cells Synthesize, Store, and Release Nerve Growth Factor
by A. Leon, A. Buriani, R. Dal Toso, M. Fabris, S. Romanello, L. Aloe and R. LeviMontalcini in: Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 9 (Apr. 26, 1994), pp. 3739-3743
“Mast cell progenitors migrate from the bloodstream to
those tissues where they undergo terminal phenotypic dif-
ferentiation, proposing that these cells represent potential
mobile quanta for replenishment of tissue NGF. NGF itself
can increase tissue mast cell number in vivo (15, 46) and affect
mast cell survival, differentiation, and mediator release in
vitro (47-50). RPMCs express the functional NGF receptor
tyrosine kinase (51), indicating possible autocrine and para-
crine actions of NGF on mast cells. Given that NGF can
affect not only neurons but also hematopoietic cells, mast
cells may, through the release of NGF, convey information
to the nervous system as well as modulate their own behavior
and the reactivity of tissue-infiltrating cells.
The capacity of at least connective tissue-type mast cells to
produce NGF points to their having a pathophysiological
potential far beyond that currently recognized. The ability of
mast cells to synthesize and release NGF may represent a
well-integrated tissue defense mechanism for maintaining
and/or restoring homeostatic functions after noxious pertur-
bations (16). On the other hand, mast cell hyerplasia and
nerve remodeling are found in some chronic inflammatory
states (18, 52-54). Such tissue modifications may be triggered
and/or sustained by mast cell-derived NGF and lead to
long-lasting changes in tissue reactivity and behavioral re-
sponses toward persistent or recurrent inflammatory stimuli.
Accordingly, alterations in mast cell properties-e.g., in the
entity and duration of their activation-could play a critical
role in the progression and/or secondary complications of
inflammatory tissue responses. A more complete under-
standing of their local stimulatory and inhibitory regulation
(55) might open avenues to the management of inflammatory
disease states, including those of autoimmune origin.”
Literature on the mastcell and its role in CNS pathology
Bebo Jr., B.F., Vandenbark, A.A., Offner, H., 1996. Male SJL mice do not relapse after induction of EAE with PLP 139–151. J. Neurosci. Res. 45, 680–689. Berridge, M.J., 1993. Inositol trisphosphate and calcium signalling. Nature 361, 315–325. Boccaccio, G.L., Carminatti, H., Colman, D.R., 1999. Subcellular fractionation and association with the cytoskeleton of messengers encoding myelin proteins. J. Neurosci. Res. 58, 480–491. Boggs, J.M., 2006. Myelin basic protein: a multifunctional protein. Cell. Mol. Life Sci. 63, 1945–1961. Boggs, J.M., Rangaraj, G., Hill, C.M., Bates, I.R., Heng, Y.M., Harauz, G., 2005. Effect of arginine loss in myelin basic protein, as occurs in its deiminated charge isoform, on mediation of actin polymerization and actin binding to a lipid membrane in vitro. Biochemistry 44, 3524–3534. Brenner, T., Soffer, D., Shalit, M., Levi-Schaffer, F., 1994. Mast cells in experimental allergic encephalomyelitis: characterization, distribution in the CNS and in vitro activation by myelin basic protein and neuropeptides. J. Neurol. Sci. 122, 210–213. Brown, M.A., Tanzola, M.B., Robbie-Ryan, M., 2002. Mechanisms underlying mast cell influence on EAE disease course. Mol. Immunol. 38, 1373–1378. Cooke, H.J., Fox, P., Alferes, L., Fox, C.C., Wolfe Jr., S.A., 1998. Presence of NK1 receptors on a mucosal-like mast cell line, RBL-2H3 cells. Can. J. Physiol. Pharmacol. 76, 188–193. Cohen, G., Makranz, C., Spira, M., Kodama, T., Reichert, F., Rotshenker, S., 2006. Non-PKC DAG/phorbol-ester receptor(s) inhibit complement receptor-3 and nPKC inhibit scavenger receptor-AI/II-mediated myelin phagocytosis but cPKC, PI3k, and PLCgamma activate myelin phagocytosis by both. Glia 53, 538–550. De Jonge, F., De Laet, A., Van Nassauw, L., Brown, J.K., Miller, H.R., van Bogaert, P.P., 2004. In vitro activation of murine DRG neurons by CGRP-mediated mucosal mast cell degranulation. Am. J. Physiol.: Gasterointest. Liver Physiol. 287, G178–G191. Dietsch, G.N., Hinrichs, D.J., 1991. Mast cell proteases liberate stable encephalitogenic fragments from intact myelin. Cell. Immunol. 135, 541–548. Dimitriadou, V., Buzzi, M.G., Moskowitz, M.A., Theoharides, T.C., 1991. Trigeminal sensory fiber stimulation induces morphological changes reflecting secretion in rat dura mater mast cells. Neuroscience 44, 97–112. Dines, K.C., Powell, H.C., 1997. Mast cell interactions with the nervous system: relationship to mechanisms of disease. J. Neuropathol. Exp. Neurol. 56, 627–640. Epari, S., Sharma, M.C., Sarkar, C., Garg, A., Gupta, A., Mehta, V.S., 2006. Chordoid meningioma, an uncommon variant of meningioma: a clinicopathologic study of 12 cases. J. Neurooncol. 78, 263–269. Estève, M.A., Carré, M., Braguer, D., 2007. Microtubules in apoptosis induction: are they necessary? Curr. Cancer Drug Targets 8, 713–729. Franklin-Tong, V.E., Gourlay, C.W., 2008. A role for actin in regulating apoptosis/ programmed cell death: evidence spanning yeast, plants and animals. Biochem. J. 413, 389–404. Frieling, T., Cooke, H.J., Wood, J.D., 1993. Histamine receptors on submucous neurons in guinea pig colon. Am. J. Physiol. 264, G74–G80. Furuno, T., Ito, A., Koma, Y., Watabe, K., Yokozaki, H., Bienenstock, J., Nakanishi, M., Kitamura, Y., 2005. The spermatogenic Ig superfamily/synaptic cell adhesion molecule mast-cell adhesion molecule promotes interaction with nerves. J. Immunol. 174, 6934–6942. Gaietta, G.M., Yoder, E.J., Deerinck, T., Kinder, K., Hanono, A., Han, A., Wu, C., Ellisman, M.H. J., 2003. HT2a receptors in rat sciatic nerves and Schwann cell cultures. Neurocytology 32, 373–380. Greenberg, G., Burnstock, G., 1983. A novel cell-to-cell interaction between mast cells and other cell types. Exp. Cell Res. 147, 1–13. Gregory, G.D., Robbie-Ryan, M., Secor, V.H., Sabatino Jr., J.J., Brown, M.A., 2005. Mast cells are required for optimal autoreactive T cell responses in a murine model of multiple sclerosis. Eur. J. Immunol. 35, 3478–3486. Ibrahim, M.Z., Reder, A.T., Lawand, R., Takash, W., Sallouh-Khatib, S., 1996. The mast cells of the multiple sclerosis brain. J. Neuroimmunol. 70, 131–138. Kawamoto, K., Aoki, J., Tanaka, A., Itakura, A., Hosono, H., Arai, H., Kiso, Y., Matsuda, H., 2002. Nerve growth factor activates mast cells through the collaborative interaction with lysophosphatidylserine expressed on the membrane surface of activated platelets. J. Immunol. 168, 6412–6419. Keller, J.T., Marfurt, C.F., 1991. Peptidergic and serotoninergic innervation of the rat dura mater. J. Comp. Neurol. 309, 515–534. Lange, J., Schlieps, K., Lange, K., Knoll-Köhler, E., 1997. Activation of calcium signaling in isolated rat hepatocytes is accompanied by shape changes of microvilli. Exp. Cell Res. 234, 486–497. Letourneau, R., Rozniecki, J.J., Dimitriadou, V., Theoharides, T.C., 2003. Ultrastructural evidence of brain mast cell activation without degranulation in monkey experimental allergic encephalomyelitis. J. Neuroimmunol. 145, 18–26. Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., Langer-Gould, A., Strober, S., Cannella, B., Allard, J., Klonowski, P., Austin, A., Lad, N., Kaminski, N., Galli, J.S., Oksenberg, R.J., Raine, S.C., Heller, R., Steinman, L., 2002. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508. Malaviya, R., Twesten, N.J., Ross, E.A., Abraham, S.N., Pfeifer, J.D., 1996. Mast cells process bacterial Ags through a phagocytic route for class I MHC presentation to T cells. J. Immunol. 156, 1490–1496. Maślińska, D., Woźniak, R., Kaliszek, A., Schmidt-Sidor, B., Lipska, A., Woolley, D.E., 1999. Phenotype of mast cells in the brain tumor. Capillary hemangioblastoma. Folia Neuropathol. 37, 138–142. Matysiak, M., Jurewicz, A., Jaskolski, D., Selmaj, K., 2002. TRAIL induces death of human oligodendrocytes isolated from adult brain. Brain 125, 2469–2480. Medic, N., Vita, F., Abbate, R., Soranzo, M.R., Pacor, S., Fabbretti, E., Borelli, V., Zabucchi, G., 2008. Mast cell activation by myelin through scavenger receptor. J. Neuroimmunol. 200, 27–40. Mekori, Y.A., Baram, D., 2002. Heterotypic adhesion-induced mast cell activation: biologic relevance in the inflammatory context. Mol. Immunol. 38, 1363–1367. Metcalfe, D.D., Baram, D., Mekori, Y.A., 1997. Mast cells. Physiol. Rev. 77, 1033–1079. Moscarello, M.A., 2007. The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem. Res. 32, 251–256. Orr, E.L., 1988. Presence and distribution of nervous system-associated mast cells that may modulate experimental autoimmune encephalomyelitis. Ann. N. Y. Acad. Sci. 540, 723–726. Osipchuk, Y., Cahalan, M., 1992. Cell-to-cell spread of calcium signals mediated by ATP receptors in mast cells. Nature 359, 241–244. Redondo, P.C., Harper, M.T., Rosado, J.A., Sage, S.O., 2006. A role for cofilin in the activation of store-operated calcium entry by de novo conformational coupling in human platelets. Blood 107, 973–979. Richter-Landsberg, C., 2001. Organization and functional roles of the cytoskeleton in oligodendrocytes. Microsc. Res. Tech. 52, 628–636. Richter-Landsberg, C., 2008. The cytoskeleton in oligodendrocytes. Microtubule dynamics in health and disease. J. Mol. Neurosci. 35, 55–63. Rozniecki, J.J., Hauser, S.L., Stein, M., Lincoln, R., Theoharides, T.C., 1995. Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann. Neurol. 37, 63–66. Ryu, S.D., Lee, H.S., Suk, H.Y., Park, C.S., Choi, O.H., 2009. Cross-linking of FcepsilonRI causes Ca2+ mobilization via a sphingosine kinase pathway in a clathrin-dependent manner. Cell Calcium 45, 99–108. Secor, V.H., Secor, W.A., Brown, M.A., 2000. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 191, 813–822. Selye, H., 1965. The Mast Cells. Butterworths, Washington, D.C. Shalit, M., Brenner, T., Shohami, E., Levi-Schaffer, F., 1993. Interaction between mast cells and glial cells: an in vitro study. J. Neuroimmunol. 43, 195–199. Soliven, B., 2001. Calcium signalling in cells of oligodendroglial lineage. Microsc. Res. Tech. 52, 672–679. Stead, R.H., Bienenstock, J., Stanisz, A.M., 1987. Neuropeptide regulation of mucosal immunity. Immunol. Rev. 100, 333–359. Stead, R.H., Dixon, M.F., Bramwell, N.H., Riddell, R.H., Bienenstock, J., 1989. Mast cells are closely apposed to nerves in the human gastrointestinal mucosa. Gastroenterology 97, 575–585. Suzuki, R., Furuno, T., McKay, D.M.,Wolvers, D., Teshima, R., Nakanishi,M., Bienenstock, J., 1999. Direct neurite-mast cell communication in vitro occurs via the neuropeptide substance P1. J. Immunol. 163, 2410–2415. Tojima, T., Takahashi, M., Ito, E., 2003. Dual regulation of LIM kinase 1 expression by cyclic AMP and calcium determines cofilin phosphorylation states during neuritogenesis in NG108-15 cells. Brain Res. 985, 43–55. van der Kleij, H.P., Redegeld, F.A., Kraneveld, A.D., Nijkamp, F.P., Bienenstock, J., 2003. Functional expression of neurokinin 1receptors on mast cells induced by IL-4 and stem cell factor. J. Immunol. 171, 2074–2079. Villa, I., Skokos, D., Tkaczyk, C., Peronet, R., David, B., Huerre, M., Mécheri, S., 2001. Capacity of mouse mast cells to prime T cells and to induce specific antibody responses in vivo. Immunology 102, 165–172. Wang, X.Y., Zarate, N., Soderholm, J.D., Bourgeois, J.M., Liu, L.W., Huizinga, J.D., 2007. Ultrastructural injury to interstitial cells of Cajal and communication with mast cells in Crohn’s disease. Neurogastroenterol. Motil. 19, 349–364. Xu, G.Y., Liu, S., Hughes, M.G., McAdoo, D.J., 2008. Glutamate-induced losses of oligodendrocytes and neurons and activation of caspase-3 in the rat spinal cord. Neuroscience 153, 1034–1047. Zhuang, X., Silverman, A.J., Silver, R., 1999. Distribution and local differentiation of mast cells in the parenchyma of the forebrain. J. Comp. Neurol. 408, 477–488.