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Infiltrate evaluation. On the 14th day after CCI, 5 μm nerve sections of formalin-fixed tissues were analyzed by Azan-Mallory stain, and the presence of inflammatory infiltrate was evaluated and quantified by an arbitrary scale starting from 1, mild infiltrate, up to 10, severe infiltrate. Effect of PEA repeated treatments (30 mg kg⁻¹ s.c. daily) was observed in (a) PPAR-α+/+ and in (b) -/- mice where the distal and the proximal tract of the ipsilateral ligated nerve of CCI was compared with the contralateral and with the sciatic nerve of sham-operated animals. Quantitative analysis was performed evaluating 5 animals for each group. P*<0.05 was considered as significantly different from sham, vehicle-treated mice. P°<0.05 was considered as significantly different from CCI, vehicle-treated mice.
Source publication
Neuropathic syndromes which are evoked by lesions to the peripheral or central nervous system are extremely difficult to treat, and available drugs rarely joint an antihyperalgesic with a neurorestorative effect. N-Palmitoylethanolamine (PEA) exerts antinociceptive effects in several animal models and inhibits peripheral inflammation in rodents. Ai...
Citations
... These effects were demonstrated both in chronic inflammation and neuropathic pain animal models, where PEA treatment resulted in pain perception control (by the modulation of mast cell activation), peripheral nerve morphology preservation, endoneural edema reduction, and a decrease in pro-inflammatory substance production at the injury site. Additionally, PEA prevented macrophage infiltration in the nerve and exerted anti-hyperalgesic and neuroprotective properties directly intervening in the nervous tissue alterations responsible for pain [19,55,56]. Furthermore, the exogenous supplementation of PEA has been shown to delay mast cell recruitment, protect mast cells against degranulation, and enhance the endogenous neuroprotective effect of PEA through the modulation of microglia activation [19]. ...
Background/Objectives: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune disease. Neuropathic pain (NP), related to peripheral inflammation, is among its earliest manifestations. This preliminary open-label investigation aimed to evaluate the efficacy of ultramicronized Palmitoylethanolamide (umPEA) in the management of NP. Methods: A total of 14 patients with CIDP, already undergoing immunoglobulin (Ig) therapy, were divided into two groups: Group A received umPEA 600 mg twice daily in addition to Ig for 60 days, followed by Ig alone until the end of the observation (180 days); Group B received Ig alone for 120 days and subsequently umPEA + Ig in the last 60 days of the study. Painful symptom intensity and quality of life were assessed by the Numeric Rating Scale, Neuropathic Pain Symptoms Inventory, and Five Dimensions Health Questionnaire. The safety umPEA profile was evaluated. Results: UmPEA in addition to immunoglobulins allowed for a significant improvement over time in all NP symptoms intensity (p = 0.0007) and in patients’ quality of life (p = 0.0036). Conclusions: This study suggests umPEA as a safe and effective treatment in addition to immunoglobulins to improve NP, ameliorating the patient’s health status. These results highlight the importance of neuroinflammation modulation in the management of CIDP’s painful symptoms, drawing attention to umPEA’s potential use also in neuropathies of different etiologies.
... It was observed that PEA prevented cellular infiltration and alterations in pain threshold mediated through the PPAR-α receptor. Additionally, PEA significantly prevented the increase in COX2 [98]. ...
Palmitoylethanolamine (PEA) is an endocannabinoid-like compound first encountered within the lipid fractions of specific foods and has intrigued researchers since the 1950s due to its therapeutic effects. This survey aims to explore the therapeutic promise held by PEA as an anti-inflammatory and immunomodulatory agent. The therapeutic impact of PEA reverberates across diverse physiological systems, such as the central nervous system, gastrointestinal tract, vascular network, and the digestive and respiratory system. Additionally, it is effective in pain management and reducing inflammation and immune responses. These attributes have fostered collaborations targeting conditions such as Alzheimer’s disease, multiple sclerosis, cerebral ischemia, neuroinflammation, general inflammation, pain, coagulopathy, steatohepatitis, and acute lung injury. PEA operates both independently and in synergy with other compounds, like paracetamol, luteolin, and oxymetazoline. This efficacy stems from its interactions with pivotal targets, including PPARα, PPAR-δ, PPAR-γ, CB1, CB2, GPR55, and TRPV1. Additionally, PEA exerts a direct influence on the inflammatory cascade, orchestrating precise adjustments in immune responses. Numerous animal studies have elucidated the inherent potential of PEA. Nevertheless, the imperative of reinforcing clinical investigation is evident. This review notably underscores the pivotal necessity for methodologically rigorous clinical trials to definitively establish the translational efficacy of PEA in ameliorating diverse inflammatory pathologies within the human milieu.
... Previous studies have confirmed that CSA can quantitatively reflect the severity of peripheral neuropathy, especially in nerve entrapment neuropathy with impaired blood return and cell edema, which can lead to decreased nerval echo and an enlarged nerval CSA, and in infectious lesions, which exhibit increased intraneural vascularization and CSA (Kara et al., 2012). Several classical peripheral nerve injury models, such as chronic constriction injury (CCI) and partial sciatic nerve ligation (PSNL), all interfered with the sciatic nerve trunk in the mid-femur, which can result in a diffuse swelling at the site of sciatic nerve ligation, as well as both proximal and distal to the ligation site (Bennett and Xie, 1988;Seltzer et al., 1990;Pacini et al., 2010;Di Cesare Mannelli et al., 2013). Ni et al. (2019) described the dynamic changes of ultrasound images of the rat sciatic nerve in a crush injury model and found an increase in nerve thickness, a decrease in the internal echo signal, and blurred and rough images of the outer nerve membrane after injury. ...
Background and objective
Ultrasound has been widely used in the diagnosis and minimally invasive treatment of peripheral nerve diseases in the clinic, but there is still a lack of feasibility analysis in rodent models of neurological disease. The purpose of this study was to investigate the changes in the cross-sectional area of the sciatic nerve of different genders and body weights and to explore the effectiveness and reliability of an ultrasound-guided block around the sciatic nerve in living rats.
Methods
Using ultrasound imaging anatomy of the sciatic nerve of rats, the cross-sectional area of the sciatic nerve in rats of different genders from 6 to 10 weeks old was calculated, and then analyzed its correlation with body weight. Further analyses were conducted through behavioral and cadaveric studies to evaluate the feasibility of ultrasound-guided perineural injection of the sciatic nerve in rats.
Results
We first reported that the sciatic nerve cross-sectional area of rats was increased with age (F = 89.169, P < 0.001), males had a higher sciatic nerve cross-sectional area than females (F = 60.770, P < 0.001), and there was a positive correlation with body weight (rMale = 0.8976, P < 0.001; rFemale = 0.7733, P < 0.001). Behavioral observation of rats showed that the lower extremity complete block rate was 80% following the administration of drugs around the sciatic nerve under ultrasound guidance and staining with methylene blue occurred in all sciatic nerves and surrounding muscles and fascia using 20 ultrasound-guided injections.
Conclusions
Ultrasound visualization technology can be used as a new auxiliary evaluation and intervention therapy for animal models of peripheral nerve injury, and will provide overwhelming new references for the basic research of neurological diseases.
... Moreover, PEA is an agonist of the peroxisome proliferator-activated receptor type α (PPAR-α), a nuclear transcription factor able to inhibit both pro-inflammatory cytokine release [28] and the activity of enzymes such as cyclooxygenase [29]. In a model of chronic constriction injury, we have previously demonstrated that pain-relieving effects of PEA depend, at least in part, on a PPAR-α-mediated mechanism [30]. ...
Persistent pain can be managed with opioids, but their use is limited by the onset of tolerance. Ultramicronized N-palmitoylethanolamine (PEA) in vivo delays morphine tolerance with mechanisms that are still unclear. Since glial cells are involved in opioid tolerance and mast cells (MCs) are pivotal targets of PEA, we hypothesized that a potential mechanism by which PEA delays opioid tolerance might depend on the control of the crosstalk between these cells. Morphine treatment (30 mM, 30 min) significantly increased MC degranulation of RBL-2H3 cells, which was prevented by pre-treatment with PEA (100 mM, 18 h), as evaluated by β-hexosaminidase assay and histamine quantification. The impact of RBL-2H3 secretome on glial cells was studied. Six-hour incubation of astrocytes with control RBL-2H3-conditioned medium, and even more so co-incubation with morphine, enhanced CCL2, IL-1β, IL-6, Serpina3n, EAAT2 and GFAP mRNA levels. The response was significantly prevented by the secretome from PEA pre-treated RBL-2H3, except for GFAP, which was further upregulated, suggesting a selective modulation of glial signaling. In conclusion, ultramicronized PEA down-modulated both morphine-induced MC degranulation and the expression of inflammatory and pain-related genes from astrocytes challenged with RBL-2H3 medium, suggesting that PEA may delay morphine tolerance, regulating MC-astrocyte crosstalk.
... Binding of PEA to the PPAR-α receptor leads to attenuation of nociceptive and inflammatory responses, as confirmed in PPAR-α null mice [50,51]. The activation of PPAR-α can aid in the regeneration of mice peripheral nerves at the level of axon repair [52], PPARα activation downregulates nuclear factor kB (NF-kB) followed by the decrease of pro-inflammatory proteins, such as inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2), tumor necrosis factor-α (TNFα) or interleukin 1 and 6 or prostaglandin E2 (PGE2) [41,53], which all can contribute to the anti-inflammatory properties of AM/ACM grafts. ...
Background:
Human amniotic and amniochorionic membranes (AM, ACM) represent the most often used grafts accelerating wound healing. Palmitoylethanolamide, oleoylethanolamide and anandamide are endogenous bioactive lipid molecules, generally referred as N-acylethanolamines. They express analgesic, nociceptive, neuroprotective and anti-inflammatory properties. We assessed the distribution of these lipid mediators in placental tissues, as they could participate on analgesic and wound healing effect of AM/ACM grafts.
Methods:
Seven placentas were collected after caesarean delivery and fresh samples of AM, ACM, placental disc, umbilical cord, umbilical serum and vernix caseosa, and decontaminated samples (antibiotic solution BASE 128) of AM and ACM have been prepared. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used for N-acylethanolamines analysis.
Results:
N-acylethanolamines were present in all studied tissues, palmitoylethanolamide being the most abundant and the anandamide the least. For palmitoylethanolamide the maximum average concentration was detected in AM (350.33 ± 239.26 ng/g), while oleoylethanolamide and anandamide were most abundant in placenta (219.08 ± 79.42 ng/g and 30.06 ± 7.77 ng/g, respectively). Low levels of N-acylethanolamines were found in serum and vernix. A significant increase in the levels of N-acylethanolamines (3.1-3.6-fold, P < 0.001) was observed in AM when the tissues were decontaminated using antibiotic solution. The increase in decontaminated ACM was not statistically significant.
Conclusions:
The presence of N-acylethanolamines, particularly palmitoylethanolamide in AM and ACM allows us to propose these lipid mediators as the likely factors responsible for the anti-hyperalgesic, but also anti-inflammatory and neuroprotective, effects of AM/ACM grafts in wound healing treatment. The increase of N-acylethanolamines levels in AM and ACM after tissue decontamination indicates that tissue processing is an important factor in maintaining the analgesic effect.
... In humans, PEA accumulates in painful tissues, as observed in the trapezius muscle of women suffering from chronic neck pain [58]. Moreover, PEA protected nerve tissue in neuropathic conditions [37] and prevented neurotoxicity and neurodegeneration [59,60]. Furthermore, PEA also alleviated painful diabetic neuropathy, chemotherapy neuropathy, idiopathic axonal neuropathy, nonspecific neuropathy, and sciatic and lumbosacral spine disease pain [61]. ...
... Therefore, neurite extension might become a secondary process and, as a result, PEA remains unable to express any protective effects. These data are agreed with previous studies on PEA effects on preserving myelin sheet thickness and axonal diameter and preventing myelin degeneration [37]. PEA reduced myelin loss caused by sciatic nerve injury, maintained neuron cell diameters, reduced nerve edema, and restored nerve function, all of which were associated with decreased hypersensitivity [64]. ...
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of several chemotherapeutic agents, such as Paclitaxel. The main symptoms of CIPN are pain and numbness in the hands and feet. Paclitaxel is believed to accumulate in the dorsal root ganglia and free nerve endings. Novel therapeutic agents might help to mitigate or prevent Paclitaxel toxicity on dorsal root ganglion (DRG) neurons. Thus, we used primary DRG neurons as a model to investigate the potential neuroprotective effects of the endocannabinoid-like substance, palmitoylethanolamide (PEA). DRG neurons were isolated from cervical to sacral segments of spinal nerves of Wister rats (6–8 weeks old). After isolation and purification of neuronal cell populations, different concentrations of Paclitaxel (0.01–10 µM) or PEA (0.1–10 µM) or their combination were tested on cell viability by MTT assay at 24 h, 48, and 72 h post-treatment. Furthermore, morphometric analyses of neurite length and soma size for DRG neurons were performed. Adverse Paclitaxel effects on cell viability were apparent at 72 h post-treatment whereas Paclitaxel significantly reduced the neurite length in a concentration-dependent manner nearly at all investigated time points. However, Paclitaxel significantly increased the size of neuronal cell bodies at all time windows. These phenotypic effects were significantly reduced in neurons additionally treated with PEA, indicating the neuroprotective effect of PEA. PEA alone led to a significant increase in neuron viability regardless of PEA concentrations, apparent improvements in neurite outgrowth as well as a significant decrease in soma size of neurons at different investigated time points. Taken together, PEA showed promising protective effects against Paclitaxel-related toxicity on DRG neurons.
... Interestingly, our data indicated a significant negative correlation between the VPS and salivary OEA and PEA levels in the migraine group. This is congruent with previous studies, where chronic administration of PEA reduced pain behaviors and counteracted spinal neuronal hyper-excitability in murine models of persistent pain [40,41]. ...
The endocannabinoid system is involved in physiological and pathological processes, including pain generation, modulation, and sensation. Its role in certain types of chronic orofacial pain (OFP) has not been thoroughly examined. By exploring the profiles of specific salivary endocannabinoids (eCBs) in individuals with different types of OFP, we evaluated their use as biomarkers and the influence of clinical parameters and pain characteristics on eCB levels. The salivary levels of anandamide (AEA), 2-arachidonoyl glycerol (2-AG), and their endogenous breakdown product arachidonic acid (AA), as well as the eCB-like molecules N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), were assessed in 83 OFP patients and 43 pain-free controls using liquid chromatography/tandem mass spectrometry. Patients were grouped by diagnosis: post-traumatic neuropathy (PTN), trigeminal neuralgia (TN), temporomandibular disorder (TMD), migraine, tension-type headache (TTH), and burning mouth syndrome (BMS). Correlation analyses between a specific diagnosis, pain characteristics, and eCB levels were conducted. Significantly lower levels of 2-AG were found in the TN and TTH groups, while significantly lower PEA levels were found in the migraine group. BMS was the only group with elevated eCBs (AEA) versus the control. Significant correlations were found between levels of specific eCBs and gender, health-related quality of life (HRQoL), BMI, pain duration, and sleep awakenings. In conclusion, salivary samples exhibited signature eCBs profiles for major OFP disorders, especially migraine, TTH, TN, and BMS. This finding may pave the way for using salivary eCBs biomarkers for more accurate diagnoses and management of chronic OFP patients.
... Chronic administration of PEA also showed a protective effect on lesioned peripheral nerves in a murine model of neuropathic pain, as the chronic constriction injury of the sciatic nerve (CCI). Furthermore, PEA, by engaging the PPAR-α, prevented the CCI-induced thinning of the myelin sheath and reduction in axonal diameter, as well as edema and macrophage infiltration [93]. Some authors have suggested that PEA exerts its antinociceptive activity at the spinal level by inhibiting responses of dorsal horn wide dynamic range neurons [94]. ...
Palmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid compound endowed with a plethora of pharmacological functions, including analgesic, neuroprotective, immune-modulating, and anti-inflammatory effects. Although the properties of PEA were first characterized nearly 65 years ago, the identity of the receptor mediating these actions has long remained elusive, causing a period of research stasis. In the last two decades, a renewal of interest in PEA occurred, and a series of interesting studies have demonstrated the pharmacological properties of PEA and clarified its mechanisms of action. Recent findings showed the ability of formulations containing PEA in promoting oligodendrocyte differentiation, which represents the first step for the proper formation of myelin. This evidence opens new and promising research opportunities. White matter defects have been detected in a vast and heterogeneous group of diseases, including age-related neurodegenerative disorders. Here, we summarize the history and pharmacology of PEA and discuss its therapeutic potential in restoring white matter defects.
... Neuroprotective effects of PEA are mediated by peroxisome proliferator-activated receptor-alpha (PPAR-α) activation (Lo Verme et al., 2005) according to experimental evidence regarding PD, Alzheimer's disease, traumatic brain injury and several neuropsychiatric disorders (Skaper et al., 1996;Genovese et al., 2008;Ahmad et al., 2012;D'Agostino et al., 2012;Esposito et al., 2012;Di Cesare Mannelli et al., 2013;Mondola, 2013, 2014;Scuderi et al., 2014). The molecular mechanisms underlying PEA neuroprotective action via PPARα activation are still unknown. ...
Impaired gas exchange close to labor causes perinatal asphyxia (PA), a neurodevelopmental impairment factor. Palmitoylethanolamide (PEA) proved neuroprotective in experimental brain injury and neurodegeneration models. This study aimed to evaluate PEA effects on the immature-brain, i.e., early neuroprotection by PEA in an experimental PA paradigm. Newborn rats were placed in a 37°C water bath for 19 min to induce PA. PEA 10 mg/kg, s.c., was administered within the first hour of life. Neurobehavioral responses were assessed from postnatal day 1 (P1) to postnatal day 21 (P21), recording the day of appearance of several reflexes and neurological signs. Hippocampal CA1 area ultrastructure was examined using electron microscopy. Microtubule-associated protein 2 (MAP-2), phosphorylated high and medium molecular weight neurofilaments (pNF H/M), and glial fibrillary acidic protein (GFAP) were assessed using immunohistochemistry and Western blot at P21. Over the first 3 weeks of life, PA rats showed late gait, negative geotaxis and eye-opening onset, and delayed appearance of air-righting, auditory startle, sensory eyelid, forelimb placing, and grasp reflexes. On P21, the hippocampal CA1 area showed signs of neuronal degeneration and MAP-2 deficit. PEA treatment reduced PA-induced hippocampal damage and normalized the time of appearance of gait, air-righting, placing, and grasp reflexes. The outcome of this study might prove useful in designing intervention strategies to reduce early neurodevelopmental delay following PA.
... Moreover, in a chronic constriction injury model of neuropathic pain, PEA not only reduced edema and macrophage infiltration, but also counteracted the decrease in axon diameter and myelin thickness, the effects being lost in PPAR-α-null mice [95]. Recently, it has also been reported that the activation of PPARs may interfere with the production of pro-inflammatory cytokines in CIPN, potentially attenuating and preventing the symptoms of neuropathy [96]. ...
Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of antineoplastic drugs, particularly paclitaxel (PTX). It can affect the quality of patients’ lives and increase the risk of developing mood disorders. Although several drugs are recommended, they yielded inconclusive results in clinical trials. The aim of the present work is to investigate whether the palmitoylethanolamide (PEA) would reduce PTX-induced CIPN and associated mood disorders. Moreover, the role PPAR-α and the endocannabinoid system will also be investigated. CIPN was induced by intraperitoneally injection of PTX (8 mg/kg) every other day for a week. PEA, 30 mg/kg, was orally administrated in a bioavailable form (i.e., ultramicronized PEA, um-PEA) one hour after the last PTX injection, for 7 days. In the antagonism experiments, AM281 (1 mg/kg) and GW6471 (2 mg/kg) were administrated 30 min before um-PEA. Our results demonstrated that um-PEA reduced the development of hypersensitivity with the effect being associated with the reduction in spinal and hippocampal pro-inflammatory cytokines, as well as antidepressive and anxiolytic effects. Moreover, the PPAR-α and CB1 receptor antagonists blocked the behavioral and antinociceptive effects of um-PEA. Our findings suggest that um-PEA is a promising adjunct in CIPN and associated mood disorders through the activation of PPAR-α, which influences the endocannabinoid system.
