zondag 3 augustus 2014

Palmitoylethanolamide: a natural therapy for eye disorders: glaucoma and neurodegeneration

Eye disorders: Relevance of Palmitoylethanolamide

Palmitoylethanolamide-Treat-Glaucoma
Palmitoylethanolamide-Treat-Glaucoma
Palmitoylethanolamide can protect our eyes against neurodegeneration as well as against high intraocular pressure, such as in glaucoma. We will review a number of trials related to the effiacy of palmitoylethanolamide in eye disorders.

Improved endothelial function in glaucoma due to palmitoylethanolamide

A generalized peripheral endothelial dysfunction has been demonstrated in patients suffering from glaucoma (ocular hypertension) and related glaucoma related eye disorders. One important biological molecule belonging to the complex and pleiotropic endogenous lipid signaling system that is activated “on demand” following a perturbation of cell homeostasis to aid in the re-establishment of this homeostasis is the nutraceutical palmitoylethanolamide. PEA exerst an important role in endothelial protection.
In a randomized, double-blind, placebo-controlled, crossover, single-center study was conducted between September 2010 and March 2012, at the Ophthalmology Unit of University of Bologna, 40 untreated glaucoma patients and 40 healthy age-matched controls were enrolled. None of the healthy controls in this study was treated.
Patients and controls were assigned randomly to one of the two parallel treatment arms at baseline: 300 mg PEA or a matching placebo, per os, twice a day, for a period of 90 days.
All of the patients who were included at the onset of the study completed the study. At baseline, endothelium-dependent flow-mediated vasodilation (FMD) values of the OH patients were significantly lower than FMD values of the controls.
Results: patients who were undergoing PEA therapy showed a significant improvement in FMD values (8.46 ± 1.09% vs. 6.08 ± 0.62%, P < 0.001, r = 0.96) and a significant IOP reduction 22.18 ± 1.26 vs. 23.03 ± 0.88 mm Hg, P 0.05 and 22.95 ± 0.90 vs. 23.25 ± 0.76 mm Hg, P > 0.05,
In their study, the ophtalmologists could demonstrated that 600 mg PEA administered daily over a period of three months may improved systemic endothelial function in patients with ocular hypertension with no local side effects or systemic adverse events, and they showed that its protective action may last longer than its intake period as the effect on IOP.
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Tissue and cellular protection via palmitoylethanolamide

Palmitoylethanolamide: a tissue protector

Protection of PEA in the rat isolated heart against ischaemia has been found in a preclinical study conducted by Lepicier and colleagues in 2003. It was already by that time known that endogenous compounds such as palmitoylethanolamide were protective for tissue in disstress.
PEA and 2-AG have been detected in rat cardiac tissue already by Schmid et al. in 2000 but at that time little was known about the role played by these lipid signal molecules played in the heart. It was reported that the ability of a prior exposure to lipopolysaccharide to limit infarct size in rats is blocked by a CB2-receptor antagonists. (Lagneux & Lamontagne, 2001). The first aim of their study was to evaluate the cardioprotective effect of endocannabinoids and PEA in the rat isolated heart. Secondly, the contribution of protein kinase C (PKC) and mitogen-activated protein kinases (MAP kinases) in this cardioprotective effect was assessed.
The results were impressive, as we can see in the graph. PEA could reduce the infarct size of an inschemic myocardium considerably.
PEA protects the hart against ischemia
PEA protects the hart against ischemia
Their conclusion was:
None of the untreated hearts recovered from ischaemia during the reperfusion period. Perfusion with either 300nm palmitoylethanolamide (PEA) or 300nm 2-arachidonoylglycerol (2-AG), but not anandamide (up to 1 mm), 15 min before and throughout the ischaemic period, improved myocardial recovery and decreased the levels of coronary CK and LDH. PEA and 2-AG also reduced infarct size.
Philippe Le ́picier, Jean-Franc ̧ois Bouchard et al Endocannabinoids protect the rat isolated heart against ischaemia British Journal of Pharmacology (2003) 139, 805–815
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A major lipid signaling compound: palmitoylethanolamide

Palmitoylethanolamide: a lipid transmitter

In the first part of palmitoylethanolamide’s story, between 1957 and 1993 it became clear that PEA had significant biological effects such as analgesia and anti-inflammation. In 1993 Montalcini unraveled the first mechanism of action of PEA: the modulation of the mast cell and the inhibition of the inflammatory effects of compounds such as histamine and Nerve Growth Factor (NGF).
In the period 1993 and 2000 most scientists though palmitoylethanolamide was an endocannabinoid, but little by little one started to understand palmitoylethanolamide is NOT an endocannabinoid, but a lipid neurotransmitter of its own. Or better, a lipid signaling molecule.
Lipids Signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses.
The groups of lipid signaling molecules consists of:
Ceramide
Eicosanoids
Endocannabinoids
Endogenous Cannabinoids
Palmitoylethanolamide and other N-acyl-ethanolamides
PI3 Kinase (PI3K)
Phosphatidylinositol bisphosphate (PIP2) Second Messenger Systems
Phosphoinositide 3-Kinase (PI3K)
Phospholipases
Ceramides for instance are lipids composed of sphingosine and a fatty acid and derive from the hydrolisis of sphingolipids. Sphingolipids have an important structural role in cell membrane but, when hydrolized by sphingomyelinase (wiki), they release ceramides in the cytosol that can act as second messengers, promoting differentiation, proliferation and apoptosis.
Exactly the same mechanism holds true for PEA: it is a fatty acid amine derived from a lipid fraction of the membranes, NAPE and is synthesized by NAPE hydrolyzing enzymes, the released PEA shuttles into the cytosol via protein carriers and travels to its target, for instance the PPAR receptor.
Signalling lipids such as eicosanoids, phosphoinositides, sphingolipids and fatty acids control important cellular processes, including cell proliferation, apoptosis, metabolism and migration. Extracellular signals from cytokines, growth factors and nutrients control the activity of a key set of lipid-modifying enzymes: phospholipases, prostaglandin synthase, 5-lipoxygenase, phosphoinositide 3-kinase, sphingosine kinase and sphingomyelinase. These enzymes and their downstream targets constitute a complex lipid signalling network with multiple nodes of interaction and cross-regulation. Imbalances in this network contribute to the pathogenesis of human disease. Although the function of a particular signalling lipid is traditionally studied in isolation, this review attempts a more integrated overview of the key role of these signalling lipids in inflammation, cancer and metabolic disease, and discusses emerging strategies for therapeutic intervention.
A recent symposium (april 2013) carries the title:
Unveiling the Significance of Lipid Signaling in Neurodegeneration and Neuroprotection…
We know lipid signaling is a hot topic and palmitoylethanolamide is one of those lipid mediators which has been available for the clinic since 5 years now. PEA has been tested in around 4000 patients for its analgesic and anti-inflammatory effects and currently is available world wide as the supplement PeaPure.

In the Journal ‘Pain” Daniele Piomelli, the Americal professor widely known for his work on lipid signaling drugs discusses the growing insight in the important biological roles of lipids like PEA. He uses a scedule to explain the biological action of PEA via the nucleas, see artist impression of his scedule:
Image
He discusses the role of lipid mediators, which are synthesized from membrane components:
Among these membrane-derived analgesics is a small family of lipid molecules in which a saturated or monounsaturated fatty acid – such as palmitic or oleic acid – is chemically linked to ethanolamine through an amide bond. In neurons and innate immune cells, these endogenous lipid amides are formed by cleavage of the phospholipid precursor, N-acylphosphatidylethanolamine, a process that is carried out by a specialized phospholipase D enzyme. One of the best-known members of this family, palmitoylethanolamide (PEA), produces profound analgesic and anti-inflammatory effects in animals by recruiting a nuclear receptor called peroxisome proliferator-activated receptor-a (PPAR-a).
He discussed new findings were data point into the direction that that PPAR-a stimulates the transcription of genes encoding for steroidogenic enzymes, resulting in an up-regulation of neurosteroids that contribute to the analgesic effects of PEA.
Commentary of Danielle Piomelli:
A thickening network of lipids in: PAIN 153 (2012) 3–4
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Palmitoylethanolamide against nerve injury due to pressure

Palmitoylethanolamide, TNF-α and sciatic injury model

Current evidence shows that tumor necrosis factor alpha (TNF-α) plays an important role in the onset of neuropathic pain. It has been shown that chronic constriction injury (CCI) model induces a bilateral increase of TNF-α expression at the dorsal root ganglion (DRG). Recently it has been determined that the palmitoylethanolamide (PEA) has analgesic effects on animal models of neuropathic pain.
The present study evaluated a potential relation between the analgesic effect of PEA and the changes on TNF-α expression at the DRG in neuropathic pain. CCI induced pain behaviors on ipsilateral paw and a bilateral increase of immunoreactivity (IR) to TNF-α in the L4 and L5 DRG was observed. Administration of PEA (10 mg/kg i.p.), reduced significantly both, thermal hyperalgesia and mechanical allodynia. Thermal threshold values (hyperalgesia) were - 2,96 ± 0,31 s (-7,36 ± 0,12 s control) on day 5 and -1,81 ± 0,30 s (-8,52 ± 0,18 s control) on day 7, while the mechanical threshold (allodynia) values were -1 ranks (-5 ranks control) on day 5 and -0,5 ranks (-6 ranks control) on day 7. In the present study it was also found that the administration of PEA (10 mg / kg, i.p.) reversed the bilateral increase of TNF-α IR in L4 and L5 DRG neurons observed after CCI.
Although these findings give clear evidence about the regulating role of PEA on the expression of TNF-α at the first sensory neuron, the bilateral effects support the hypotheses that the analgesic effect of PEA is not related with the effect on the expression of TNF-α at the DRG.
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One of the mechanisms of palmitoylethanolamide: an anti-oxydant protecting tissues

Palmitoylethanolamide as antioxidant and for tissue protection

N-Acylethanolamines (NAEs) (fatty acid ethanolamides) are naturally occurring hydrophobic molecules usually present in a very small amount in many mammalian tissues and cells [1] and [2]. Moreover, NAEs are normally present in biological fluids, such as blood [2], in very low concentrations. The physiological levels of important NAEs in mammalian blood plasma are in the range 2.8–5.2 pmol/ml for anandamide (AEA); 9.4–16.7 pmol/ml for PEA; 8.1–10.3 pmol/ml for oleylethanolamide (OEA) [2], [3] and [4]. However, the NAEs levels in blood plasma could be modified in pathological conditions, e.g., the physiological concentrations of AEA in human plasma are 4 pmol/ml, but these concentrations are increased up to 18–30 pmol/ml in sera of patients with endotoxic shocks [5]. In vivo studies demonstrated that NAEs could accumulate in injured tissues, such as, e.g., in myocardium infarcted areas [6], and in post decapitative brain ischemia [7].
AND:
Palmitoylethanolamide (C16:0) (PEA), a shorter and fully saturated analogue of anandamide, exhibits a number of biochemical, physiological and pharmacological effects [12] and [13]. However, its mechanism of action remains unclear [12] and [13] and its effects are not always reproducible. Among the others, it was identified as the anti-inflammatory principle present in many natural products, and its anti-inflammatory properties were confirmed by recent research [12], [13] and [14], although they seem less marked in human systems [13]. In vitro studies demonstrated that PEA inhibits the nitric oxide production in macrophages [15], affects the time course of capacitation of human spermatozoa [16], and increases the PLA2 hydrolytic activity [17]. In those studies, PEA concentrations inducing significant effects ranged from 5 [16] to 30 μM [17]. Physiologically relevant concentrations of PEA (3 nM–3 μM) [18] may also have important physiological and/or pharmacological effects. For example, 300 nM PEA was shown to protect rat isolated heart against ischemia [19].
Forms the introduction of a hallmark paper on the protective aspects of the natural painkiller palmitoylethanolamide, written by Zolese et al. Based on their knowledge of blood fats (cholesterol etc) and the detrimental effects of oxydation, the authors conducted a study in order to evaluate the possible effect of physiologically relevant concentrations of PEA on the resistance of plasma lipoproteins to oxidation.
They found in their in vitro experiments indicatations of anti-oxidative effects of PEA on the oxidation of LDL, isolated from plasma after incubation with this endogenous fatty acid amide.The protective effect of PEA occurs in physiological and supraphysiological conditions, such also takes place during for instance septic shock:
It has to be stressed that the anti-oxidant effect is obtained at low PEA concentrations in plasma is similar to those observed in pathological conditions, such as endotoxic shock
Main source:
Zolese G, Bacchetti T, Ambrosini A, Wozniak M, Bertoli E, Ferretti G. Increased plasma concentrations of palmitoylethanolamide, an endogenous fatty acid amide, affect oxidative damage of human low-density lipoproteins: an in vitro study. Atherosclerosis. 2005 Sep;182(1):47-55.
Other references
[1]
HS Hansen, B. Moesgaard, H.H. Hansen, G. Petersen
N-Acylethanolamines and precursor phospholipids—relation to cell injury
Chem Phys Lipids, 108 (2000), pp. 135–150
[2]
A. Giuffrida, D. Piomelli
Isotope dilution GC/MS determination of anandamide and other fatty acylethanolamides in rat blood plasma
FEBS Lett, 422 (1998), pp. 373–376
[3]
A. Giuffrida, F. Rodriguez de Fonseca, D. Piomelli
Quantification of bioactive acylethanolamides in rat plasma by electrospray mass spectrometry
Anal Biochem, 280 (2000), pp. 87–93
[4]
A. Giuffrida, F. Rodriguez de Fonseca, F. Nava, P. Loubet-Lescoulie, D. Piomelli
Elevated circulating levels of anandamide after administration of the transport inhibitor, AM404
Eur J Pharmacol, 408 (2000), pp. 161–168
[5]
Y. Wang, Y. Liu, Y. Ito et al.
Simultaneous measurement of anandamide and 2-arachidonoylglycerol by polymyxin B-selective adsorption and subsequent high-performance liquid chromatography analysis: increase in endogenous cannabinoids in the sera of patients with endotoxic shock
Anal Biochem, 294 (2001), pp. 73–82
[6]
H.H.O. Schmid, P.C. Schmid, V. Natarajan
N-Acylated glycerophospholipids and their derivatives
Prog Lipid Res, 29 (1990), pp. 1–43
[7]
H.H.O. Schmid, P.C. Schmid, E.V. Berdyshev
Cell signaling by endocannabinoids and their congeners: questions of selectivity and other challenges
Chem Phys Lipids, 121 (2002), pp. 111–134
[SD-008]
[8]
L. De Petrocellis, D. Melck, T. Bisogno, V. Di Marzo
Endocannabinoids and fatty acid amides in cancer, inflammation and related disorders
Chem Phys Lipids, 108 (2000), pp. 191–209
[9]
E.V. Berdyshev, P.C. Schmid, R.J. Krebsbach et al.
Cannabinoid-receptor-independent cell signalling by N-acylethanolamines
Biochem J, 360 (2001), pp. 67–75
[10]
R. Mechoulam, E. Fride, V. Di Marzo
Endocannabinoids
Eur J Pharmacol, 359 (1998), pp. 1–18
[11]
K.O. Jonsson, S. Vandevoorde, D.M. Lambert, G. Tiger, C.J. Fowler
Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide
Br J Pharmacol, 133 (2001), pp. 1263–1275
[SD-008]
[12]
C.J. Fowler
Plant-derived, synthetic and endogenous cannabinoids as neuroprotective agents. Non-psychoactive cannabinoids, ‘entourage’ compounds and inhibitors of N-acyl ethanolamine breakdown as therapeutic strategies to avoid pyschotropic effects
Brain Res Brain Res Rev, 41 (2003), pp. 26–43
[13]
D.M. Lambert, S. Vandevoorde, K.O. Jonssonand, C.J. Fowler
The palmitoylethanolamide family: a new class of anti-inflammatory agents?
Curr Med Chem, 9 (2002), pp. 663–674
[SD-008]
[14]
H.H. Schmid, E.V. Berdyshev
Cannabinoid-receptor-inactive N-acylethanolamines and other fatty acid amides: metabolism and function
Prostaglandins Leukot Essent Fatty Acids, 66 (2002), pp. 363–376
[15]
R.A. Ross, H.C. Brockie, R.G. Pertwee
Inhibition of nitric oxide production in RAW264.7 macrophages by cannabinoids and palmitoylethanolamide
Eur J Pharmacol, 401 (2000), pp. 121–130
[16]
A. Ambrosini, G. Zolese, M. Wozniak et al.
Idiopathic infertility: susceptibility of spermatozoa to in-vitro capacitation, in the presence and the absence of palmitylethanolamide (a homologue of anandamide), is strongly correlated with membrane polarity studied by Laurdan fluorescence
Mol Hum Reprod, 9 (2003), pp. 381–388
[17]
G. Zolese, M. Wozniak, P. Mariani, L. Saturni, E. Bertoli, A. Ambrosini
Different modulation of phospholipase A2 activity by saturated and monounsaturated N-acylethanolamines
J Lipid Res, 44 (2003), pp. 742–753
E.V. Berdyshev, E. Boichot, N. Germain, N. Allain, J.P. Anger, V. Lagente
Influence of fatty acid ethanolamides and delta9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells
Eur J Pharmacol, 330 (1997), pp. 231–240
[19]
P. Lepicier, J.F. Bouchard, C. Lagneux, D. Lamontagne
Endocannabinoids protect the rat isolated heart against ischaemia
Br J Pharmacol, 139 (2003), pp. 805–815
[20]
N.M. Gulaya, A.I. Kuzmenko, V.M. Margitich et al.
Long-chain N-acylethanolamines inhibit lipid peroxidation in rat liver mitochondria under acute hypoxic hypoxia
Chem Phys Lipids, 97 (1998), pp. 49–54
[21]
N.L. Parinandi, H.H. Schmid
Effects of long-chain N-acylethanolamines on lipid peroxidation in cardiac mitochondria
FEBS Lett, 237 (1988), pp. 49–52
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Neurogenic inflammation can be treated with palmitoylethanolamide: a natural anti-inflammatory agent

Palmitoylethanolamide inhibits neurogenic inflammation

PEA has been proven by many studies to be a natural anti-inflammatory compound and a natural painkiller. Here we present some interesting findings from 2005, when the scientific community was still unaware of the exact mechanism of action of PEA. However, interesting is that PEA also in the models of respiratory inflammation was clearly protective.
In the paper ‘Endogenous Cannabinoid Receptor Agonists Inhibit Neurogenic Inflammations in Guinea Pig Airways‘ by
Shigemi Yoshiharaa and colleages the authors examined the effects palmitoylethanolamide, on the activation of C fibers in guinea pig airway tissues.
The authors suggested that PEA has inhibitory effects on airway inflammation induced by the activation of C fibers via the opening of maxi-K+ channels. Their interpretation at that time was that this happened via the cB 2 receptors, but now we know this must have been an incorrect finding, as PEA does not have any affinity for CB 2 receptors.
Their results suggested that PEA might endogenously and negatively regulate the release of tachykinins from the endings of C fibers in guinea pig airways via the opening of maxi-K+ channels.

Effects of PEA on Isolated Guinea Pig Bronchial Smooth Muscle Contraction

The effects of PEA on isolated guinea pig bronchial smooth muscle contraction was examined. After electrical field stimulation in the presence of atropine and propranolol, isolated guinea pig bronchial smooth muscles evoked tachykinin-dependent prolonged contraction. Electrical field stimulation and 1 nM neurokinin A elicited the guinea pig isolated bronchial smooth muscle contraction and palmitoylethanolamide (0.0033–3.3 μM), dose-dependently inhibited electrical field stimulation-induced tachykinin-dependent contraction.
The authors also tested anadamide, but palmitoylethanolamide worked stronger.
The facts that the selective cannabinoid CB1 (SR 141716A) and CB2 (SR 144528) receptor antagonists. SR 144528 (10 nM) reduced the inhibitory effects of anandamide and palmitoylethanolamide on the guinea pig bronchial smooth muscle contraction induced by electrical field stimulation lead them to believe CB 1 and 2 were the mechanisms of action. Meanwhile we know these antagonsts are not specific enough and PEA does not have any affinity for these receptors, but works via other mechanisms (GRP55 and PPAR-alpha).
Anandamide (0.43 and 4.3 μM) and palmitoylethanolamide (0.05 and 0.5 μM) both significantly inhibited the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. Palmitoylethanolamide being a lot stronger in its efficacy than anandamide.
The authors remained puzzled by the mechanism of action, as they wrote:
Although there is no doubt about the anti-inflammatory effect of these endogenous cannabinoid receptor agonists in rodents, the molecular mechanisms underlying their actions have been puzzles. In this study, we found that both anandamide and palmitoylethanolamide inhibited electrical field stimulation-induced isolated guinea pig bronchial smooth muscle contraction and capsaicin-induced guinea pig bronchoconstriction. These reactions are dependent on tachykinins because they were inhibited by tachykinin receptor antagonists
They concluded:
When excitatory C fibers are stimulated, not only substance P but other neuropeptides, e.g. neurokinin A and calcitonin gene-related peptide, are also released from their nerve endings and exert various respiratory reactions. The inflammatory effects of these neuropeptides on airway tissues may be of pathological relevance in human bronchial hyperreactivity, and we showed that antiasthmatic compounds, disodium cromoglycate and nedocromil sodium, inhibited hypertonic saline-induced plasma extravasation in guinea pig airways by the inactivation of C fibers. We conclude that endogenous cannabinoid receptor agonists, anandamide and palmitoylethanolamide, which inhibit the activation of C fibers and the release of these neuropeptides from their endings via the opening of maxi-K+ channels by the activation of CB2 receptors, might be involved in the clinical effects of antiasthmatic compounds described above.
Source:
Shigemi Yoshiharaa et al. Endogenous Cannabinoid Receptor Agonists Inhibit Neurogenic Inflammations in Guinea Pig Airways Int Arch Allergy Immunol 2005;138:80-87
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Palmitoylethanolamide can counteract side effects of chemotherapy in cancer

Palmitoylethanolamide in cancer

In 2011 the group of Professor Cruccu of the university of Rome published a paper showing that PEA could reduce the harm done by chemotherapy to nerves. Pain was less and nerve-functions were better, if patients with cancer and chemotherapy were also treated with palmitoylethanolamide (1200 mg/day).
This idea, to protect important cells against the damage done by chemotherapy has been brought forward in 1975 already. As this paper has great value, and is very unknown and difficult to find we document the ideas in that paper in this article.
Palmitoylethanolamide against chemotherapy damage
The paper started with the remark that PEA is a specific anti-toxic agent and that its use to counteract toxicity of chemotherapy would be interesting:
Schermafbeelding 2013-02-21 om 15.37.30
And after testing a variety of chemotherapeutic agents in various coctails, the results showed a clear add-on effect of PEA, and this even had positive impact on the survival time after the emergence of the cancer, as can be easily seen via the survival plot enclosed.
PEA in cancer and chemotherapyThe authors stipulated that the presence of PEA helped to reach a higher level of chemotherapy, without the troublesome dose-limiting side effects.
PEA enhances chemotherapy in cancer
In te final graph the effects of PEA were very clear: less mortality due to side effects, and less mortality due to the cancer itself. Results under speak for themselves. Based  on this animal study and the recent data in patients with cancer, PEA seems a very wise addition, decreasing side effects of chemo-therapy, and enhancing the therapeutic effects against the cancer.
PEA protects against side effects of chemoSchermafbeelding 2013-02-21 om 15.58.04
These effects have been duplicated in 2002, in the study:  Effect on cancer cell proliferation of palmitoylethanolamide, a fatty acid amide interacting with both the cannabinoid and vanilloid signalling systems., by De Petrocellis L, Bisogno T, Ligresti A, Bifulco M, Melck D, Di Marzo V. In: Fundam Clin Pharmacol. 2002 Aug;16(4):297-302.
Recently the lipids such as PEA have been reviewed as modulators of the endocannabinoid system in various cancer types reveals that it can mediate antiproliferative and apoptotic effects by both cannabinoid receptor-dependent and -independent path- ways. PEA exerts is action via CB independent pathways.
With 2 preclinical studies and one clinical study, all pointing in the same direction, PEA needs to be considered by patients and doctors if patients are being treated with chemo-therapy.
At the East European congress for pain (2013) professor Khasabova spoke about her data on PEA in cancer models and referred to PEA as promising against cancer and cancer related pains. (personal communication).
Most probably PEA can enhance the efficacy of analgesic regimes, and the compound might have an extra cancer-inhibiting effect.
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Palmitoylethanolamide as a promising cure for neuropathy

Palmitoylethanolamide as a cure for (diabetic) neuropathy?

In a doctoral thesis under the guidance of professor B. Costa: BETTONI, I. (2012). Morphological characterization of anti-nociceptive effect of endogenous lipid palmitoylethanolamide in two murine models: peripheral mononeuropathy and diabetic polyneuropathy. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2012).: the following is described:
Recent evidences suggest that mast cell activation and degranulation have a key role in the beginning and maintenance of a persistent pain, such as neuropathic one. Particularly mast cells are known to release NGF (Leon et al. 1994) and to express trkA (Horigome et al. 1993) receptors able to bind NGF. NGF loop may cause mast cell degranulation, leading to a further release of the neurotrophic factor NGF and many other pro-nociceptive and pro-inflammatory mediators. The release of NGF and other pro-inflammatory cytokines leads to a degeneration of nerve fibers. Therefore inhibition of mast cell degranulation could represent a good strategy in the cure of neuropathic pain. A class of molecules able to negatively modulate mast cell degranulation is represented by ALIAmides (from the acronym Autacoid Local Injury Antagonist), naturally-occurring lipid amide deriving from membrane fatty amides and structurally releted to endocannabinoids (Facci et al.1993, Mazzari et al., 1996).

PEA: an endogenous lipid transmitter

Palmitoylethanolamide (PEA), an endogenous lipid, is the most studied, in addition Petrosino and colleagues (2007) demonstrated that endogenous palmitoylethanolamide level decreased in the spinal cord of neuropathic mice.
In our previous study (Costa et al., 2008) we demonstrated that palmitoylethanolamide (PEA), administered i.p. at the dose of 10 mg/kg for 7 days from the chronic constriction injury, a well established model of peripheral mononeuropathy, evoked a relief of both thermal hyperalgesia (increased sensitivity to thermal stimulus) and mechanical allodynia (pain due to a mechanical stimulus which does not normally provoke pain) in neuropathic mice (chronic constriction injury model) and significantly reduced the NGF levels in the sciatic nerve of neuropathic mice. In addition Costa and colleagues demonstrated PEA efficacy on allodynia which develops in diabetic mice and to partially increase NGF level.
Starting by this assumption we wanted to characterize mast cell degranulation in the same animal model and after the same PEA treatment.
In the chronic constriction injury model in addition to prolonged treatment (7 days), animals received PEA for a short period (2 days) because rapid mast cell activation was supposed. On 3rd and 8th day, 24h after the last administration, mice were sacrificed and the sciatic nerve and the spinal cord were removed from 3d and 8d group in each experimental group (sham/vehicle, CCI/vehicle and CCI/PEA). Sciatic nerves were processed in paraffin wax or Epon-Araldite resin to obtain respectively longitudinal (6 µm) or semi thin transversal (1 µm) sections, while spinal cord was in paraffin wax to obtain transversal (6 µm) sections.
Another experiment was performed to collect spinal cords for a biochemical analysis. Spinal cord was removed because recent evidences suggest that microglia cells, in particular activated microglia, play a key role in the induction and maintenance of neuropathic pain. In the sciatic nerve longitudinal sections of control mice (3d and 8d group) arranged and consistent nerve morphology with a homogeneous localization of nuclei Schwann cells was observed, and limited number of intact and degranulated mast cells was present, indicative of physiological resident mast cells. Sciatic nerve of CCI mice (both groups) appeared oedematous without compactness of the fibers.
In particular, in CCI mice of 3d group, the mast cells were localized in the surrounding tissue with a strong recruitment of intact mast cells, while in CCI mice of 8d group mast cells infiltrated in the inner central part of the sciatic nerve. In neuropathic mice treated with PEA of 3d and 8d group a mild inflammation and mast cell recruitment was observed. The evaluation of mast cell density (expressed as total mast cell/mm2) confirmed a time-dependent mast cell recruitmant after 3 and 8 days from the injury, indicating that mast cells degranulation plays a key role in the beginning and maintenance of neuropathic pain.
The 2 days PEA treatment acted on mast cell recruitment; in fact mast cell density was comparable to that observed in sham mice. The 7 days PEA treatment modulated mast cell degranulation; in fact a significant reduction of average ratio of degranulated mast cells over intact mast cell compared to CCI mice was observed. The presence and implication of mast cell was confirmed by double immunostaining images obtained from longitudinal sections showing a co-expression of mast cell proteases I (MMCP-I) and trkA receptor. In the tranversal sections of sham mice of both groups no histological abnormalities were present: typically myelinated axons are packed in the sciatic nerve in an orderly, parallel arrangement with minimal interaxonal space. In transversal sections of CCI nerves of 3d and 8d group a lot of myelinated fibers underwent a Wallerian-like degeneration, suggested by a dense and flocculent axoplasmic matrix. In mice treated with PEA for 2 and 7 days a mild degeneration of fibers and compact arrangement like sham transversal section was observed. The quantitative analysis confirmed that the intact axons density (expressed as intact axons/mm2) and the myelin thickness (expressed as µm2) in CCI mice (both groups) significantly decreased respect to sham mice, and PEA treatment partially reduced fiber degeneration at both times, emphasizing its role role to prevent the reduction of myelin thickness at both 3 and 7 days after the injury.
In order to verify the presence of activated microglia in neuropathic mice treated with PEA, the expression of F4/80 protein in transversal sections of the dorsal horn of the lumbar (L4-L5) spinal cord was investigated. This region was considered because the afferent fibers from the periphery (sciatic nerve) arrive here. Representative images show that in CCI mice a time-dependent increase of activated microglia was observed in the dorsal horn of L4 and L5 spinal cord compared to sham mice. In the contralateral horn of the spinal cord a milder activation of microglia was detected in L4 and L5 only in the 8d group.
These results were confirmed by the densitometric analysis of F4/80 expression obtained by western blotting. The treatment with PEA for two consecutive days attenuated the limited microglia activation, restoring to physiological level the expression of F4/80 protein.
In the third part of this project we evaluated the involvement of mast cell in the anti-allodinic effect of PEA in diabetic and neuropathic mice. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ, 120 mg/kg). Mice were divided into two groups: 17d and 14d group. In the 17d group mice developed allodynia 14 days after STZ injection. Before the beginning of the treatment and at the end of experiment, hyperglycaemia was evaluated. On 14th day, PEA treatment started and three experimental groups were present: non diabetic, diabetic mice treated with vehicle and diabetic mice treated with PEA.
PEA was administered i.p. at the dose 10 mg/kg for three consecutive days. 24 hours after the last administration PEA had an anti-allodinic effect and the following organs were removed: sciatic nerves (right and left), kidneys and pancreas. In 14d group PEA treatment started on 7th day, when mice were diabetic but non allodinic, and 24 hours from the last administration pancreas was removed.
Since Costa and colleagues demonstrated that a mild insulin level in the blood was present in PEA treated mice of 14d group but non that of 17d group, morphological analysis and a subsequant quantative analysis was performed on pancreas tissue. Longitudinal and transversal sections of sciatic nerve were stained with toluidine blue in order to examine morphology of mast cell and axons. In longitudinal sections intact mast cell, degranulating and degranulated mast cells were uniformely distributed throughout the nerve of the three experimental groups and the count of total mast cell (total number of mast cell/mm2) didn’t show any difference among the three experimental groups. In transversal sections axons undergoing degeneration were present in diabetic mice treated with vehicle or PEA respect to non diabetic mice. The count of intact axons revealed that at the end of treatment diabetic mice treated with vehicle showed a significant decrease of intact axons and that this decrease remained constant in diabetic mice treated for three consecutive days with PEA. Nephropathy is another consequence of diabetes; therefore renal transversal sections were stained with periodic acid Shiff (PAS) reagent to investigate the presence of an expansion of mesangium in the glomeruli. Diabetic mice showed an increase of mesangial matrix and subsequently an increase of the glomeruli area compared to non-diabetic mice. In mice treated with three consecutive injections of PEA appeared similar to the images observed in diabetic mice treated with vehicle. The evaluation of the glomeruli area (expressed in µm2) confirmed the increase of mesangial area. In fact in diabetic mice treated with vehicle a significant increase of the area was recorded compared to non diabetic mice and the same increase was measured in diabetic mice treated with PEA for three consecutive days. In pancreas sections of diabetic mice treated with vehicle of 17d group, the islet of Langerhans appeared smaller and less numerous, while in diabetic mice treated with PEA could be observed a mild improvement. A quantitative analysis (the density expressed as number/mm2 and the area expressed as µm2) of islet of Langerhans demonstrated a significantly decreased in diabetic mice treated with vehicle and PEA had a protective partial effect on density and area of islets of Langerhans. In the group 14d pancreas sections of non diabetic mice appeared well organized with large and uniformely distributed islet of Langerhans. In diabetic mice treated with vehicle pancreas appeared with few islets which were small.
In PEA treated mice an improvement was present: in fact islets were numerous and they appeared bigger than in diabetic mice. The quantitative analysis confirmed the previously considerations: in fact the density and the area of islets of Langerhans significantly decreased in diabetic mice treated with vehicle compared to non diabetic mice and 7 days PEA treatment highlighted the protective effect on the islets of Langerhans.

PEA as a promising cure for neuropathy

The findings presented herein strongly suggest that PEA, without any side effects, is a promising compound in the cure of neuropathy. It may prevent mast cell degranulation through the already described ALIA (Autacoid Local Inflammation Antagonism) mechanism, modulates microglia activation in the spinal cord and this effect accounts for the antinociceptive property of PEA. In addition, PEA administered to diabetic and neuropathic mice elicited allodynia and exerts a time-dependent protective effect on islets of Langerhans.
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Palmitoylethanolamide (PeaPure): a remarkable supplement as a natural painkiller

About Palmitoylethanolamide (PeaPure): introduction and use of a natural painkiller

Natural Painkiller: Palmitoylethanolamide (PEA), take home message

A very special molecule, produced in our own body, and now available as supplement (PeaPure). It has been explored since 1957 and has a clear analgesic and anti-inflammatory efficacy, and virtually no side effects. Meanwhile within the context of clinical trials 5000 patients have been using PEA, and its efficacy and safety has been documented in more than 400 scientific papers.
Since 2012 it is also available in the USA and it is shipped to the the USA via the Netherlands. Meanwhile there are many hundreds of satisfied US citizens using this natural painkiller. PEA is available as capsules of 400 mg (step in dose: take 1200 mg daily) and as PEA cream. It can be combined without any difficulties with any other drug or supplement. Supplementation with PEA encourages the body’s own natural healing and painkilling capacity to do its thing.
PEA:
  1. painkiller and anti-inflammatory compound
  2. produced in our cells, natural compound
  3. protects cells
  4. is proven to be effective and safe in many clinical trials in more than 5000 patients
  5. can be combined with any other compound

PEA: safety, efficacy and purity, further details

Very few side effects are reported, and this painkiller is also easy to combine with all kinds of other medication and analgesics, and is proven to be effective in many chronic pain states. The efficacy of PEA is impressive, expressed as Numbers Needed to Treat (NNT) is 1.5 for sciatic pain (based on a full powered double blind, placebo controlled trial). Numbers Needed to Treat is the most up to date way to express efficacy, and the NNT of 1.5 means one needs to treat 3 patients with severe pain, to help 2 to find adequate pain reduction. Most painkillers have NNT of 2-6 (Meaning one has to treat 2 to 6 patients to help one…).
In table 1 we see the efficacy of PEA compared to many other painkillers. There is one issue to understand, because PEA modulates via various natural mechanisms of the body, the analgesic effects are build up day by day; most people notice the effects within 1 week, but sometimes 6-8 weeks is required, especially for chronic pain syndromes. To reset the system the molecule needs some time.
PeaPure is documented  with a certificate of analysis for review and is produced according to the highest standards of GMP. In addition to PeaPure there are a number of other PEA containing products, but these all have a much lower % of PEA per serving, and to date, certificates of analysis are not available for these products to review.
There are also uncertified PEA supplements available containing herbal material of unknown origin. Recently there was an analysis of all PEA products, and the conclusion wast: the preference should be for the time being to treat patients with pure PEA without any of these additives. (Kriek, 2014)
PEA products such as PeaPure and PEA cream are based on a totally new therapeutic principle, based on activation of our own natural systems. This is due to the fact that the active principle in PeaPure is palmitoylethanolamide (PEA).

Nobel price winner Professor Rita Levi-Montalcini discovered the mechanism of action of PEA

The mother of the PEA principle is the Nobel laureate professor Rita Levi-Montalcini. In a separate section she will explain in a number of cartoons the essence of palmitoylethanolamide.
PEA is a body-own fatty compound, and is produced by our own living cells to restore balance in chronic pain and chronic inflammation. Its anti-inflammatory and painkilling properties are known in science many decades since the first description of this compound in 1957. in 1993 the Nobel price winner professor Rita Levi-Montalcini pointed out the relevance of PEA for medicine and since then more than 300 scientific papers on PEA have been published. She also was the first person discovering the mechanism of action of PEA. She worked with PEA in its purest version.
Rita Levi-Montalcini
Rita Levi-Montalcini, MD, PhD, Nobel laureate
Many of the scientific data related to palmitoylethanolamide are discussed at this site in order to enrich modern medicine with more insight in the properties and the value of this all natural painkiller and anti-inflammatory compound. In references 1-5 you will find free PDF’s in peer reviewed journals summerizing all clinical data of palmitoylethanolamide.

5000 patients in clinical trials

To date around 5000 patients have been entered in double blind clinical trials, and the efficacy in chronic pain and inflammation of this natural compound is clearly documented (1-5). This makes PEA one of the best documented effective and safe nutraceuticals. Sadly enough pain physicians do not often read literature on supplements, and seem to believe that only pharmaceuticals can be effective (but not so safe).
At the 8th European congress on Pain (EFIC) in Florence (2013) palmitoylethanolamide was presented in one of the main symposia as a new kid on the block, we hope this will help opening the eyes of doctors that patients can be helped also with natural compounds, without side effects….
PEA has been used by more than 1 million patients, mostly in Europe. In the Netherlands and Germany since the beginning of 2011 many ten thousands of patients are using it. Mostly to their satisfaction. Meanwhile many other patients elsewhere, especially at the west coast of the USA, in Australia and Canada, are using PeaPure
A new natural painkiller, palmitoylethanolamide (PEA) is available under the brandname PeaPure, produced in the Netherlands and available via the webshop from the distributor.  In Italy PEA is available at pharmacists under different brandnames, such as PeaVera, Normast, PeaLut, Glialia, Adolene and Pelvilen.  These products all contain PEA, but in different amounts (see below).
Information for prescribing doctors and for pharmacists related to PEA you find under this link.
PEA and the scientific support for its use
PEA has been evaluated in a great number of scientific papers, more than 400! PEA is sometimes referred to as an ‘autocoid’. An autocoid is special modulating molecule, produced by our own tissue, and able to modify our own biological balance. PEA has been found useful in a variety of chronic diseases, amongst others in severe neuropathic pain, sciatic pain, prostate pain, pain after stroke and in MS and pelvic pain. Side effects are neglectable, due to the fact that this molecule is part of our own body. It has special analgesic properties, and in sciatic pain for instance, it is much more effective compared to the chemical analgesic Lyrica (pregabaline)!
PEA has been demonstrated in recent trials to decrease pain in diabetic neuropathic pain, zoster pain lumbosacral pain (sciatic pain), carpal tunnel syndrome and nervus medianus compression pain, endometriosis pains, menstrual pains, etc. It has been proven to be effective and safe in many different disorders, from chronic pains up to flu and common cold, due to its intrinsic anti-inflammatory and analgesic properties.

How to use Pea?

PeaPure comes in capsules of 400 mg, containing finely powdered (micronized) pure PEA, nopharmaceutical additives or fillers or any artificial additive.
You can start taking three 4 400 mg capsules a day, in 2 or 3 gifts. The dose can be increased up to 2400 mg daily. Mostly we advise patients to double the  dose only after 4 weeks, and only in case of issuficient efficaccy.
If pain improves after some weeks to 2 months one might want to decrease dose to 2 times 400 mg.
If no improvement after 2-3 months, stop. Painkillers such as PEA, but also Neurontin, Lyrica and Amitriptyline (brand name Elavil all need time to reset the system, mostly 1-2 months.
Always inform your physician just to keep him/her in the loop.
For physicians and pharmacists all relevant information can be found via the links to peer reviewed journals in:
Further references
 Read More on palmitoylethanolamide (PEA)

Patient stories on palmitoylethanolamide (PEA)

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