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Archived Comments for: Neuroinflammation and M2 microglia: the good, the bad, and the inflamed

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  1. Neuroinflammation, glia and palmitoylethanolamide as a glia modulator

    jan keppel hesselink, institute neuropathic pain

    10 June 2014

    The important and brilliant review of Cherry and colleagues highlights the various modifications of microglia and the complex functionality related to the various phenotypes.

    In their introduction they give a short history of the emergence of insight in glia and its functions. Here they mention Nissl as first author to describe glia in 1899, while in general Virchow is regarded to have described glia already in 1856 as nervous glue: 'Nervenkit.'

    The history of our insights in the functions of glia is extremely interesting. In a the textbook 'Lehrbuch der Histologie' from Szymonowicz (1925) the secretory functions of glia are already highlighted, based on the work of Nageotte and Collin. The history of glia is nicely described in a number of papers, and summarized on

    I miss in their elaborate review all references to palmitoylethanolamide, a natural, endogenous lipid messenger and glia modulator.

    Palmitoylethanolamide (PEA) has been explored since its first description in 1957 and found to be a clinically relevant inhibitor of inflammation and an analgesic compound. It is freely available in Europe as a food supplement in a capsules of 400 mg and thus one could very well state that palmitoylethanolamide is the first glia-modulator fit for prescribing. The more so, as the safety profile of the compound is impressive and no drug-drug interactions have been described.

    There are many preclinical and clinical trials supporting PEA's efficacy and safety. If we conduct a simple Pubmed search based on 'palmitoylethanolamide [AND] glia' we find 25 papers.

    It was the great Nobel laureate professor Rita Levi-Montalcini who first discovered PEA's mechanism of action in 1993 related to overactive mast cells. PEA is an endogenous modulator and restores active mast cells into resting phenotypes again.

    PEA's modulating effects on glia most probably is dependent on its affinity for the PPAR receptors, although PEA is a real pleiotropic molecule, as we discussed in some detail, and I am so bold to add two references of my papers related to these topics.

    One could even state that 'Proof of Concept' of glia as an important new target for treating chronic pain has been substantiated by the various clinical trials were PEA was tested in a variety of neuropathic pain states, for instance in nerve compression syndromes (sciatic pain, carpal tunnel syndrome), diabetic neuropathic pain, and pain and loss of function after chemotherapy.

    Neuropathic pain most probably is much more 'Gliopathic pain' than we ever thought. Non-neuronal cells therefore, such as glia and mast cells, need much more attention and the above review is an important milestone to treat the myopic focus on neurons alone.

    Keppel Hesselink JM. Professor Rita Levi-Montalcini on Nerve Growth Factor, Mast Cells and Palmitoylethanolamide, an Endogenous Anti-Inflammatory and Analgesic Compound. J Pain Relief 2013, 2:1

    Keppel Hesselink JMK, Kopsky DJ, Witkamp RF. Palmitoylethanolamide (PEA)-promiscuous anti-inflammatory and analgesic molecule at the interface between nutrition and pharma. Pharma Nutrition (2013), j.phanu.2013.11.127

    Competing interests

    No conflict of interest