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Thalamus pain, mast cells and PEA: a new treatment hypothesis

Thalamic pain after stroke is one of the most difficult to treat central painsyndromes. New therapeutic inroads are clearly needed, as the classical anti-neuropathic analgesics are not effective. In the future times we will need anti-gliopathic analgesics, as we pointed out elswere in our website.

The thalamus is a part of the brain were many mast cells reside. Mast cells play an important role in neuropathic pain. Palmitoylethanolamide (PEA) is a body-own fatty acid, synthetized in all our membranes, with mast cell stabilizing properties. PEA is registered in the catagory of medical food in Europe, and especially due to absence of side effects might be a promising new therapy for central thalamic pain. 

thalamic mastcells.jpg

Mast cells are located in the mammalian thalamus. Their presence in the central nervous system has been known for half a century by now. [1][2][3][4][5]

Mast cells in pathology and ischemia: new target for treatment 

And not only in the central nervous system mast cells reside, their number and inflammatory cytokines are elevated in blood of patients suffering from stroke. Recently it was found in carotic plaques of symptomatic patients with carotic occlusion that tumor necrosis factor-alpha and CCL5 serum levels as well as intercellular adhesion molecule-1 expression on circulating neutrophils were increased. In downstream regions of symptomatic plaques, macrophage, neutrophil, and mast cell infiltration were increased. [6]

It is widely accepted that the inflammatory response triggered by stroke is harmful and due to the influx and migration of blood-borne white blood cells into the vulnerable nervous tissue. Further more it is sugegsted that brain and meninges have their own resident immunocpmpetent cells that are capable of fast host response, which are well known to mediate immediate reactions such as anaphylaxis, known as mast cells (MCs).

The mast cell is increasingly recognized as a potent inflammatory cell that, already at the ontset of ischemia, is resident within the cerebral microvasculature. Finish researchers therefore recently (2010) suggested:

By releasing their cytoplasmic granules, which contain a host of vasoactive mediators such as tumor necrosis factor-alpha, histamine, heparin, and proteases, MCs act on the basal membrane, thus promoting blood-brain barrier damage, brain edema, prolonged extravasation, and hemorrhage. This makes mast cells a candidate for a new pharmacological target in attempts to even out the inflammatory responses of the neurovascular unit, and to stabilize the blood-brain barrier after acute stroke.[7]  

Recent neurobiological data also suggest that the recruitment of cerebral mast cells releasing histamine may contribute to ischemia-induced neuronal death in the brain.[8] Mast cells are early in ischemic processes activated, also in neonatal brain. Stabilization of mast cells is seen by brain researchers as provides lasting protection and therefor mast cells are suggested to be new targets for therapeutic interventions. [9][10] More in detail it is recently (2009) suggested that:

In the light of evidence suggesting that the control of mast cell activation at an early time during an inflammatory process may account for its resolution, it is reasonable to propose that cannabinomimetic compounds, including palmitoylethanolamide and its congeners, could represent possible candidates for treating several chronic inflammatory diseases.[11] 

Inhibition of mast cell degranulation is therefore also seen as a relevant mechanism in stroke, and in models of cerebral ischemia this idea has been substantiated. [12]

PEA, mast cell degranulation and post stroke pain 

Palmitoylethanolamide (PEA) is an endocannabinoid-like compound and the parent molecule of the aliamide family, a group of fatty acid amides able to act through the down-regulation of mast cell degranulation. PEA has been proven to exert both analgesic and anti-inflammatory activity. 

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide analogue of the endocannabinoid anandamide. [13] This makes the use of this non-psychomimetic drug as an novel analgesic for the treatment of neuropathic pain highly intersting.

Bioactive lipids such as PEA, an anandamide analogue, were described for the first time in 1957 when it was discovered that PEA, isolated from soybeans, peanuts, and egg yolk, has anti-inflammatory properties. 1965, the group of Bachur et al found that these bioactive lipids also existed in mammalian tissues, especially in the brain.

IN 1968 the first paper on PEA is indexed in Pubmed [14] and since than more than 200 entries can be found! In the 90s the relation between anandamide and PEA was described, and the expression on mastcells of receptors sensitive for those 2 molecules was demonstrated. [15] In the same period more data supported its neuroprotective effects. [16] Recent data even show that palmitoylethanolamide can be used in the treatment of atopic dermatitis! [17]

Meanwhile it is also an established fact that anandamide (AEA) and PEA regulate directly or indirectly many of the same pathophysiological processes, including pain perception, inflammation, convulsions and neuroprotection. The mastcell plays a quite crucial role in all these inflammatory-related disease processes, and PEA stabiizes the mastcells, among many other different mechanisms of action, we do not discuss here in this section.

PEA therefore might serve as a model of a new generation of analgesic drugs, combating pain via its anti-gliopathic activity, and due to its modulative effects on many inflammatory cascades. The absence of side effects is a great advantage over the old class of neuropathic analgesics such as the antiepileptics and the antidepressants. Proof of principle studies are underway.

Prof. dr. Jan M. Keppel Hesselink, october 2010.

Referentie

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[2] Olsson Y. | Mast cells in the nervous system. | Int Rev Cytol. | 1968;24:27-70.

[3] Dropp JJ. | Mast cells in the central nervous system of several rodents. | Anat Rec. | 1972 Oct;174(2):227-37.

[4] Goldschmidt RC, Hough LB, Glick SD, Padawer J. | Mast cells in rat thalamus: nuclear localization, sex difference and left-right asymmetry. | Brain Res. | 1984 Dec 10;323(2):209-17.

[5] Dropp JJ. | Mast cells in mammalian brain. | Acta Anat (Basel). | 1976;94(1):1-21.

[6] Montecucco F, Lenglet S, Gayet-Ageron A, Bertolotto M, Pelli G, Palombo D, Pane B, Spinella G, Steffens S, Raffaghello L, Pistoia V, Ottonello L, Pende A, Dallegri F, Mach F. | Systemic and intraplaque mediators of inflammation are increased in patients symptomatic for ischemic stroke. | Stroke. | 2010 Jul;41(7):1394-404. Epub 2010 Jun 10.

[7] Lindsberg PJ, Strbian D, Karjalainen-Lindsberg ML. | Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage. | J Cereb Blood Flow Metab. | 2010 Apr;30(4):689-702. Epub 2010 Jan 20.

[8] Biran V, Cochois V, Karroubi A, Arrang JM, Charriaut-Marlangue C, Héron A. | Stroke induces histamine accumulation and mast cell degranulation in the neonatal rat brain. | Brain Pathol. | 2008 Jan;18(1):1-9. Epub 2007 Oct 9.

[9] Jin Y, Silverman AJ, Vannucci SJ. | Mast cells are early responders after hypoxia-ischemia in immature rat brain. | Stroke. | 2009 Sep;40(9):3107-12. Epub 2009 Jun 11.

[10] Strbian D, Kovanen PT, Karjalainen-Lindsberg ML, Tatlisumak T, Lindsberg PJ. | An emerging role of mast cells in cerebral ischemia and hemorrhage. | Ann Med. | 2009;41(6):438-50.

[11] De Filippis D, D'Amico A, Iuvone T. | Cannabinomimetic control of mast cell mediator release: new perspective in chronic inflammation. | J Neuroendocrinol. | 2008 May;20 Suppl 1:20-5.

[12] Strbian D, Karjalainen-Lindsberg ML, Tatlisumak T, Lindsberg PJ. | Cerebral mast cells regulate early ischemic brain swelling and neutrophil accumulation. | J Cereb Blood Flow Metab. | 2006 May;26(5):605-12.

[13] Re G, Barbero R, Miolo A, Di Marzo V. | Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: potential use in companion animals. | Vet J. | 2007 Jan;173(1):21-30. Epub 2005 Dec 1.

[14] Benvenuti F, Lattanzi F, De Gori A, Tarli P. | [Activity of some derivatives of palmitoylethanolamide on carragenine-induced edema in the rat paw]. | Boll Soc Ital Biol Sper. | 1968 May 15;44(9):809-13.

[15] Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A. | Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. | Proc Natl Acad Sci U S A. | 1995 Apr 11;92(8):3376-80.

[16] Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L, Leon A. | The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. | Proc Natl Acad Sci U S A. | 1996 Apr 30;93(9):3984-9.

[17] Kircik L. | A nonsteroidal lamellar matrix cream containing palmitoylethanolamide for the treatment of atopic dermatitis. | J Drugs Dermatol. | 2010 Apr;9(4):334-8.

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