Palmitoylethanolamide “PEA” – Review of Anti-inflammatory, Analgesic, Neuroprotective Mechanisms

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A review of palmitoylethanolamide, or PEA, has been published this June by Mireille Alhouayek and Guilio G. Muccioli from the Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Bruxelles, Belgium.

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The authors review the impact of PEA on inflammatory and neurodegenerative diseases, and show that inhibiting the breakdown of PEA (the hydrolysis) may increase levels of PEA. This could lead to treatment of inflammatory and neurodegenerative diseases.

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To address the loss of PEA that occurs in various diseases we must either

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1.  replace the decreased levels of endogenous PEA that is made by the brain by taking a capsule such as PeaPure,  a food supplement that contains 100% palmitoylethanolamide, to reconstitute the needed levels

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2.  inhibit the breakdown (hydrolysis) of PEA.

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.I directly quote palmitoylethanolamide4pain that has outlined key quotes from that scientific review:

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They start outlining the focus of the paper:

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Our focus here is on PEA, which is a known anti-inflammatory compound with analgesic, neuroprotective and antiallergic properties.

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Important for understanding the therapeutic relevance of PEA is the next remark:

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Evidence suggests that PEA metabolism is disturbed during inflammation, and that a decrease in PEA levels contributes to the inflammatory response.

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This explains why it is so useful to administer exogenous PEA as a supplement during states of chronic inflammation. Decreased PEA levels induce more inflammation and a vicious circle has started. Administering PEA (for instance as PeaPure capsules of 400 mg, a foodsupplement) can stop this circle and help the organism to restore the PEA levels and decrease inflammation.

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PEA’s mechanism of action

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The next quote is related to PEA’s main mechanism of action:

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Although it is now clear that PEA is a ligand for PPAR-a, some of its effects occur through as yet unidentified receptors.

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Although there are many ways PEA acts in the cell, the PPAR-a receptor indeed seems the most important one; through that receptor PEA can downregulate overactive inflammatory responses.

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PEA levels also decreased following sciatic nerve constriction injury or ligation of the sciatic nerve in spinal cord and brain areas involved in nociception

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PEA levels are not only decreased during chronic inflammation, also during chronic pain states, such as in sciatic pain.

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The fact that an anti-inflammatory treatment restores PEA levels reinforces the role of PEA as an anti-inflammatory mediator.

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PEA levels can be restored also by treatment with classical anti-inflammatory compounds such as NSAIDs, this however triggers many side effects and that can be avoided by treating with PEA itself!

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PEA as a protective molecule

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In the brain, PEA levels seem to be increased following injurious stimuli, and this has been proposed as a homeostatic mechanism aimed at counteracting inflammation and blunting the inflammatory response.

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PEA has self-reparative properties and indeed can be defined as the molecule of self-reparation and self-protection.

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This ‘pro-homeostatic’ increase, although probably slowing disease progression, seems insufficient to exert anti-inflammatory effects in itself, and should be further amplified…

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One of the classical ways to amplify PEA is to administer it as food supplement: start dose is 1200 mg/daily and in cases of insufficient response we suggest to double the dose.

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Although the first identification of PEA as an anti-inflammatory compound occurred more than 50 years ago, general interest in its anti-inflammatory and analgesic properties was not sparked again until the mid-1990s.

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It was due to the work of the Nobel laureate professor Rita Levi-Montalcini that the scientific community understood the importance of PEA in the 90s. However, as patents on this natural compound were not possible, no great interest emerged, as pharmaceutical companies were uninterested. It was due to the work of small companies, such as Epitech Srl and JP Russell Science that PEA was brought to the attention of the general public.

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Mechanism of action in addition to the PPAR receptor

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The authors nicely summarized the effects of PEA:

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PEA inhibits phosphorylation of kinases involved in activation of pro-inflammatory pathways, such as mitogen-activated protein kinase (MAPK), c- Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases (ERK), and the nuclear translocation of the transcription factors nuclear factor (NF)-kB and activator protein 1 (AP-1) and prevents degradation of the inhibitory IkB-a, which when associated to NF-kB prevents its nuclear translocation.

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Besides reducing inflammatory cells activation and recruitment, PEA modulates the expression of enzymes involved in pro-inflammatory processes, such as COX-2 and inducible nitric oxide synthase (iNOS) and reduces nitric oxide and pro-inflammatory cytokines production in vitro and in vivo.

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Relevance for Alzheimer, Parkinson’s and MS

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The neuroprotective effects of PEA are in part the result of its effects on downregulating the inflammatory cascade. Indeed, many neurodegenerative diseases are associated with a strong inflammatory component, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) or MS

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The follow stating:

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This neuroinflammation is no longer simply considered as a consequence of neurodegeneration, but might be a primary factor in some cases; therefore, anti-inflammatory treatments might represent interesting therapeutic strategies in these diseases

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After discussing modern pharmaceutical ways to block the hydrolysis of PEA with pharmaceutical new compounds, they end their overview with an important statement:

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The potential of using PEA as a beneficial endogenous bioactive lipid in the setting of inflammation is well established

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My thanks to palmitoylethanolamide4pain for the outline of key points in this review of PEA.

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The material on this site is for informational purposes only.

It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Painful Peripheral Neuropathy from Chemotherapy involves Toll-Like Receptor 4 (TLR4)

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Painful peripheral neuropathy is a limiting side effect of some cancer chemotherapy agents such as paclitaxel.

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Yan Li et al from MD Anderson Cancer Center in the current issue of the Journal of Pain show that the TLR4 receptor is involved in painful neuropathy induced by paclitaxel and that TLR4 antagonists reduce hyperalgesia and neuropathic pain caused by the nerve injury. It would be informative if they had used the commonly available low dose naltrexone which is a TLR4 antagonist, but they did not.

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Several publications since 2000 have shown “that proinflammatory cytokines produce sensory fiber dysfunction and pain in many diverse models of neuropathic and inflammatory pain, and that these are also induced by the major chemotherapy drugs.”

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Since 2007, it “has become widely recognized that glial cells …react following peripheral inflammation or nerve injury and contribute to the pathophysiology of the resulting hyperalgesia. Moreover, a key component in the glial response is mediated by TLR4.”

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Toll-Like Receptor 4 Signaling Contributes to

Paclitaxel-Induced Peripheral Neuropathy

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Abstract

This paper tests the contribution of the toll-like receptors, TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. TLR4 and its immediate downstream signaling molecules—myeloid differentiation primary response gene 88 (MyD88) and toll/interleukin 1 receptor domain–containing adapter-inducing interferon-β (TRIF)—were found to be increased in the dorsal root ganglion (DRG) using Western blot by day 7 of paclitaxel treatment. The behavioral phenotype, the increase of both TLR4 and MyD88, was blocked by cotreatment with the TLR4 antagonist lipopolysaccharide–Rhodobacter sphaeroides during chemotherapy. A similar, but less robust, behavioral effect was observed using intrathecal treatment of MyD88 homodimerization inhibitory peptide. DRG levels of TLR4 and MyD88 reduced over the next 2 weeks, whereas these levels remained increased in spinal cord through day 21 following chemotherapy. Immunohistochemical analysis revealed TLR4 expression in both calcitonin gene-related peptide–positive and isolectin B4–positive small DRG neurons. MyD88 was only found in calcitonin gene-related peptide–positive neurons, and TRIF was found in both calcitonin gene-related peptide–positive and isolectin B4–positive small DRG neurons as well as in medium- and large-size DRG neurons. In the spinal cord, TLR4 was only found colocalized to astrocytes but not with either microglia or neurons. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide–R. sphaeroides transiently reversed preestablished chemotherapy-induced peripheral neuropathy mechanical hypersensitivity. These results strongly implicate TLR4 signaling in the DRG and the spinal cord in the induction and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy.

Perspective

The toll-like receptor TLR4 and MyD88 signaling pathway could be a new potential therapeutic target in paclitaxel-induced painful neuropathy.

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The material on this site is for informational purposes only.

It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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