In our continuing debate with international colleagues we received a letter with the following statement related to our articles on gliopathic pain:

Indeed I believe this new glial field in pain research highly exciting. Furthermore, the aspect you mentioned regarding the mast cells is also very promising as possible potent modulators of peripheral modulation of nerve endings in multiple organs.

This prompted us to look for further support to use and evaluate mast cell stabilisers in clinical practice. One indication we came across was myocardial infarction:

Morrey C, and colleagues from the department of Pharmacology, Weill Cornell Medical College, New York, pointed out that renin, the rate-limiting enzyme in the activation of the renin-angiotensin system (RAS), is synthesized and stored in cardiac mast cells.

During ischemia and reperfusion, the cardiac sensory nerves release compound such as substance P that, by degranulating mast cells, might promote renin release, thus activating a local RAS and lead to cardiac pathology.

They tested this hypothesis in various models and found that substance P-containing nerves are juxtaposed to renin-containing cardiac mast cells.

Chemical stimulation of these nerves brought about substance P release as well as renin release, and the latter could be prevented by mast cell stabilization.

Their experimental findings demonstrate important links  between sensory cardiac nerves and renin-containing mast cells. Substance P released from sensory nerves plays a significant role in the release of mast cell renin in ischemia/reperfusion and in the activation of a local cardiac RAS. This culminates in angiotensin production, norepinephrine release, and arrhythmic cardiac dysfunction.^[1]

So cardiac mast cells seem to proliferate in cardiovascular diseases. Meanwhile it is a well known fact that in myocardial ischemia, mast cell mediators contribute to coronary vasoconstriction, arrhythmias, leukocyte recruitment, and tissue injury and repair.

In a previous paper the authors stated:

Our discovery of renin in cardiac mast cells and its release in pathophysiological conditions uncovers an important new pathway in the development of mast-cell-associated heart diseases. Several steps in this novel pathway may constitute future therapeutic targets.^[2] 

Already in the last century, the role of the mast cell in myocardial infarction has been descibed.  For instance, in infarct-related coronary arteries, the number of degranulated mast cells in the adventitia backing ruptured plaques was found to be increased. Histamine released from the degranulated mast could locally further provoke coronary spasm and thus contribute to the onset of myocardial infarction. ^[3] Recent animal studies  showed the cardioprotective affects of cannabidiol in the acute phase of myocardial ischaemia and reperfusion via reducing ventricular arrhythmias and attenuating infarct size. ^[4]

Mast cell stabiliser: palmitoylethalonamide within cardiology

One of the most effective and benign mast cell stabiliser is palmitoylethalonamide.   

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide analogue of the endocannabinoid anandamide. ^[5]  PEA belongs to the class of N-Acylethanolamides (NAEs) (amides of ethanolamine with long-chain fatty acids) and these are defined as endogenously generated lipid-signaling molecules. These lipids are widely distributed in a variety of plant, invertebrate, and mammalian tissues.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.

In 1965, the group of Bachur et al found that these bioactive lipids also existed in mammalian tissues, and in the 90s the relation between anandamide and PEA was described, and the expression on mastcells of receptors sensitive for those molecules was demonstrated. ^[6] In the same period more data supported its neuroprotective effects. ^[7] Recent data even show that palmitoylethanolamide can be used in the treatment of atopic dermatitis! ^[8] Mast cell stablilisation seems to be an important mechanism of action.

Increased numbers of mast cells have also been reported in explanted human hearts and accordingly, mast cells have been implicated to play a major role in the pathophysiology of these cardiovascular disorders.

In vitro studies have verified that mast cell proteases are capable of activating collagenase, gelatinases and stromelysin. In chronic ventricular volume overload, there is an elevation in mast cell density, which is associated with a concomitant increase in matrix metalloproteinase (MMP) activity and extracellular matrix degradation. ^{[9] [10]}

This is all quite exciting, as PEA is devoid from side effects and could have an important perspective even in difficult to prevent and treat states such as radiation-induced heart disease. (RIHD)^[11] 

November, Jan M. Keppel Hesselink, MD, PhD 

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