Extended Treatment with Micron-Size Oral Palmitoylethanolamide (PEA) in Chronic Pain: A Systematic Review and Meta-Analysis.

Palmitoylethanolamide (PEA) emerged over the years as a promising approach in the management of chronic pain. Despite the fact that the efficacy of micron-size PEA formulations appears to be time-dependent, the optimal timing has not yet been elucidated. This systematic review and meta-analysis aim to estimate the possible advantage of an extended treatment in the relief of chronic pain. The literature search was conducted consulting scientific databases, to identify clinical trials in which micron-size PEA was administered for at least 60 days, and pain assessed by the Visual Analogue Scale (VAS) or Numeric Rating Scale (NRS). Nine studies matched the required criteria, for a total of 742 patients involved. The meta-analysis showed a statistically and clinically significant pain intensity reduction after 60 days of micron-size PEA supplementation, compared to 30 days (1.36 points, p < 0.01). The secondary analysis revealed a weighted NRS/VAS score decrease of 2.08 points within the first month of treatment. These two obtained scores corresponded to a 35.1% pain intensity reduction within the first month, followed by a further 35.4% during the second month. Overall, these results confirm the clinically relevant and time-depended pain-relieving effect of micron-size PEA and therefore the advantage of an extended treatment, especially in patient with incomplete pain management.

Efficacy of Palmitoylethanolamide, Epilobium and Calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type III.

OBJECTIVE: The management of chronic prostatitis/ chronic pelvic pain syndrome type III (CP/CPPS) has been always considered complex due to several biopsychological factors underlying the disease. In this clinical study, we aimed to evaluate the efficacy of the treatment with Palmitoylethanolamide, Epilobium and Calendula extract in patients with CP/CPPS III. MATERIALS AND METHODS: From June 2023 to July 2023, we enrolled 45 consecutive patients affected by CP/CPPS type III in three different institution. We included patients aged between 18 and 75 years with symptoms of pelvic pain for 3 months or more before the study, a total National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score ≥ 12 point and diagnosed with NIH category III, according to 4-glass test Meares-Stamey test. Patients were then allocated to receive rectal suppositories of PEA, Epilobium and Calendula, 1 suppository/ die for 1 month. All patients have been tested with standard urinalysis in order to assess urinary leukocytes (U-WBC). The primary endpoint of the study was the reduction of NIHCPSI. The secondary outcomes were the change of peak flow, post-void residual (PVR), IIEF-5, VAS score, PSA and decrease of U-WBC. RESULTS: A total of 45 patients concluded the study protocol. At baseline, the median age of all the patients included in the cohort was 49 years, the median PSA was 2.81 ng/ml, the median NIH-CPSI was 18.55, the median IIEF-5 was 18.27, the median U-WBC was 485.3/mmc, the median VAS score was 6.49, the median PVR was 26.5 ml and the median peak flow was 16.3 ml/s. After 1 month of therapy we observed a statistically significant improvement of NIH-CPSI, U-WBC, PSA, IIEF-5, peak flow, PVR and VAS. CONCLUSIONS: In this observational study, we showed the clinical efficacy of the treatment with PEA, Epilobium and Calendula, 1 suppository/die for 1 month, in patients with CP/CPPS III. The benefits of this treatment could be related to the reduction of inflammatory cells in the urine that could imply a reduction of inflammatory cytokines. These results should be confirmed in further studies with greater sample size.

Design of Mixed Medicinal Plants, Rich in Polyphenols, Vitamins B, and Palmitoylethanolamide-Based Supplement to Help Reduce Nerve Pain: A Preclinical Study.

Neuropathy affects 7-10% of the general population and is caused by a lesion or disease of the somatosensory system. The limitations of current therapies highlight the necessity of a new innovative approach to treating neuropathic pain (NP) based on the close correlation between oxidative stress, inflammatory process, and antioxidant action. The advantageous outcomes of a novel combination composed of Hop extract, Propolis, Ginkgo Biloba, Vitamin B, and palmitoylethanolamide (PEA) used as a treatment was evaluated in this study. To assess the absorption and biodistribution of the combination, its bioavailability was first examined in a 3D intestinal barrier model that replicated intestinal absorption. Further, a 3D nerve tissue model was developed to study the biological impacts of the combination during the essential pathways involved in NP. Our findings show that the combination could cross the intestinal barrier and reach the peripheral nervous system, where it modulates the oxidative stress, inflammation levels, and myelination mechanism (increased NRG, MPZ, ERB, and p75 levels) under Schwann cells damaging. This study proves the effectiveness of Ginkgo Biloba, Propolis, Hop extract, Vitamin B, and PEA in avoiding nerve damage and suggests a potential alternative nutraceutical treatment for NP and neuropathies.

Persistent COVID-19 parosmia and olfactory loss post olfactory training: randomized clinical trial comparing central and peripheral-acting therapeutics.

PURPOSE: Although COVID-19 anosmia is often transient, patients with persistent olfactory dysfunction (pOD) can experience refractory parosmia and diminished smell. This study evaluated four putative therapies for parosmia in patients with chronic COVID-19 olfactory impairment. METHODS: After screening nasal endoscopy, 85 patients (49 female, 58%) with pOD and treatment-refractory parosmia were randomized to: (1) ultramicronized palmitoylethanolamide and luteolin + olfactory training (OT) (umPEALUT group, n = 17), (2) alpha-lipoic acid + OT (ALA group, n = 21), (3) umPEALUT + ALA + OT (combination group, n = 28), or 4) olfactory training (OT) alone (control group, n = 23). Olfactory function was assessed at baseline (T0) and 6 months (T1) using a parosmia questionnaire and Sniffin' Sticks test of odor threshold, detection, and identification (TDI). Analyses included one-way ANOVA for numeric data and Chi-Square analyses for nominal data on parosmia. RESULTS: The umPEALUT group had the largest improvement in TDI scores (21.8 ± 9.4 to 29.7 ± 7.5) followed by the combination group (19.6 ± 6.29 to 27.5 ± 2.7), both p < 0.01. The control and ALA groups had no significant change. Patients in the combination and umPEALUT groups had significantly improved TDI scores compared to ALA and control groups (p < 0.001). Rates of parosmia resolution after 6 months were reported at 96% for combination, 65% for control, 53% for umPEALUT and 29% for ALA (p < 0.001). All treatment regimens were well-tolerated. CONCLUSIONS: umPEALUT and OT, with or without ALA, was associated with improvement in TDI scores and parosmia, whereas OT alone or OT with ALA were associated with little benefit.

Effects of fatty acid metabolites on nocturia.

Dysregulation of circadian rhythm can cause nocturia. Levels of fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE), are higher in the serum of patients with nocturia; however, the reason remains unknown. Here, we investigated the circadian rhythm of fatty acid metabolites and their effect on voiding in mice. WT and Clock mutant (ClockΔ19/Δ19) mice, a model for nocturia with circadian rhythm disorder, were used. Levels of serum PEA, 9-HODE, and 4-HDoHEl were measured every 8 h using LC/MS. Voiding pattern was recorded using metabolic cages after administration of PEA, 9-HODE, and 4-HDoHE to WT mice. Levels of serum PEA and 9-HODE fluctuated with circadian rhythm in WT mice, which were lower during the light phase. In contrast, circadian PEA and 9-HODE level deteriorated or retreated in ClockΔ19/Δ19 mice. Levels of serum PEA, 9-HODE, and 4-HDoHE were higher in ClockΔ19/Δ19 than in WT mice. Voiding frequency increased in PEA- and 4-HDoHE-administered mice. Bladder capacity decreased in PEA-administered mice. The changes of these bladder functions in mice were similar to those in elderly humans with nocturia. These findings highlighted the novel effect of lipids on the pathology of nocturia. These may be used for development of biomarkers and better therapies for nocturia.

Anti-inflammatory activity of palmitoylethanolamide ameliorates osteoarthritis induced by monosodium iodoacetate in Sprague-Dawley rats.

Novel treatment strategies are urgently required for osteoarthritis (OA). Palmitoylethanolamide (PEA) is a naturally occurring fatty acid amide with analgesic and anti-inflammatory effects. We aimed to examine its effect on OA and elucidate the molecular mechanism of actions in monosodium iodoacetate (MIA)-induced OA Sprague-Dawley rats. The experimental animals were divided into normal control group (injected with saline + treated with phosphate-buffered saline (PBS), NOR), control group (injected with MIA + treated with PBS, CON), 50 or 100 mg/kg body weight (BW)/day PEA-treated group (injected with MIA + treated with 50 or 100 mg of PEA/kg BW/day, PEA50 or PEA100), and positive control group (injected with MIA + treated with 6 mg of diclofenac/kg BW/day, DiC). The changes in blood parameters, body parameters, gene expression of inflammatory mediators and cytokines, knee thickness, and joint tissue were observed. Oral administration of PEA had no adverse effects on the BW, liver, or kidneys. PEA reduced knee joint swelling and cartilage degradation in MIA-induced OA rats. The serum levels of leukotriene B4, nitric oxide, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and prostaglandin E2 considerably reduced in the PEA100 group compared with those in the CON group. In the synovia of knee joints, the mRNA expression of iNOS, 5-Lox, Cox-2, Il-1ß, Tnf-α, and Mmp-2, -3, -9, and -13 apparently increased with MIA administration. Meanwhile, Timp-1 mRNA expression apparently decreased in the CON group but increased to the normal level with PEA treatment. Thus, PEA can be an effective therapeutic agent for OA.

Co-Ultra PEALut Enhances Endogenous Repair Response Following Moderate Traumatic Brain Injury.

This study aimed to assess the neuro-regenerative properties of co-ultramicronized PEALut (Glialia®), composed of palmitoylethanolamide (PEA) and the flavonoid luteolin (Lut), in an in vivo model of traumatic brain injury (TBI) and patients affected by moderate TBI. An increase in neurogenesis was seen in the mice at 72 h and 7 d after TBI. The co-ultra PEALut treatment helped the neuronal reconstitution process to restore the basal level of both novel and mature neurons; moreover, it induced a significant upregulation of the neurotrophic factors, which ultimately led to progress in terms of memory recall during behavioral testing. Moreover, our preliminary findings in a clinical trial suggested that Glialia® treatment facilitated neural recovery on working memory. Thus, co-ultra PEALut (Glialia®) could represent a valuable therapeutic agent for intensifying the endogenous repair response in order to better treat TBI.

Randomized clinical trial "olfactory dysfunction after COVID-19: olfactory rehabilitation therapy vs. intervention treatment with Palmitoylethanolamide and Luteolin": preliminary results.

OBJECTIVE: Approximately 30% of patients with confirmed COVID-19 report persistent smell or taste disorders as long-term sequalae of infection. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is associated with inflammatory changes to the olfactory bulb, and treatments with anti-inflammatory properties are hypothesized to attenuate viral injury and promote recovery of olfaction after infection. Our study investigated the efficacy of a supplement with Palmitoylethanolamide (PEA) and Luteolin to support recovery of olfaction in COVID-19 patients. PATIENTS AND METHODS: We conducted a randomized-controlled pilot study in outpatients with history of confirmed COVID-19 with post-infection olfactory impairment that persisted ≥ 90 days after SARS-CoV-2 negative testing. Patients were randomized to two times a day olfactory rehabilitation alone or weekly olfactory rehabilitation plus daily oral supplement with PEA and Luteolin. Subjects with preexisting olfactory disorders were excluded. Sniffin' Sticks assessments were performed at baseline and 30 days after treatment.  Data on gender, age, and time since infection were collected. Kruskal-Wallis (KW) test was used to compare variances of Sniff scores between groups over time, and Spearman's correlation coefficients were calculated to assess for correlations between Sniff Score and gender or duration of infection. RESULTS: Among 12 patients enrolled (n=7, supplement; n=5, controls), patients receiving supplement had greater improvement in olfactory threshold, discrimination, and identification score versus controls (p=0.01). Time since infection was negatively correlated with Sniff Score, and there was no correlation between gender. CONCLUSIONS: Treatment combining olfactory rehabilitation with oral supplementation with PEA and Luteolin was associated with improved recovery of olfactory function, most marked in those patients with longstanding olfactory dysfunction. Further studies are necessary to replicate these findings and to determine whether early intervention including olfactory rehabilitation and PEA+Luteolin oral supplement might prevent SARS-CoV-2 associated olfactory impairment.

Efficacy of a fixed combination of palmitoylethanolamide and acetyl-l-carnitine (PEA+ALC FC) in the treatment of neuropathies secondary to rheumatic diseases.

BACKGROUND: The neurologic complications of rheumatic diseases (RDs) are highly variable, and their manifestations are linked to the pathogenesis and clinical phenotype of the specific RDs. In rheumatoid arthritis, for example, the peripheral nervous system is most commonly involved and mononeuritis multiplex, nerve entrapment and vasculitic sensorimotor neuropathies are not uncommon. Often the therapy for these disorders is not easy and is characterized by the use of different drugs. Palmitoylethanolamide (PEA) has been tested in a wide variety of animal models and has been evaluated in several clinical studies for nerve compression syndromes, demonstrating that PEA acts as an effective and safe analgesic compound. Acetyl-L-Carnitine (ALC) has also been shown to be an effective and safe treatment in painful peripheral neuropathy. In the last years the synergistic effect between PEA and ALC has been demonstrated. The aim of our study was to evaluate the efficacy of supplementation of standard therapy (STh) with Kalanit® (Chiesi Italia Spa; Parma, Italy) in patients with peripheral neuropathy secondary to RDs. METHODS: Patients at the time of enrollment were affected by RDs with neuropathy from <12 months, documented by electromyography. The analyzed patients were treated with the STh chosen according to their rheumatic disease (RA or SpA) and for their neuropathy (e.g. analgesic, NSAIDs, pregabalin or gabapentin) as per clinical practice. The sample was divided into 2 groups: group 1, patients treated with STh, to which a fixed combination of PEA (600 mg) + ALC (500 mg) (Kalanit®) was added twice a day for 2 weeks and then once a day for 6 months; group 2, patients treated only with STh. Each patient underwent clinical evaluations and questionnaires were administered in order to evaluate their neuropathy and the efficacy of the therapy. RESULTS: In group 1, 18 patients suffering from sciatic pain, 16 patients from carpal tunnel syndrome and 8 patients with peripheral neuropathy of the lower limbs were included and PEA + ALC FC was added to STh. These patients were compared with patients from group 2, who had the same pathology and demographic characteristics: 20 patients with sciatic pain, 15 with carpal tunnel syndrome and 5 with peripheral neuropathy of the lower limbs, respectively; this group was treated with STh only. Patients treated with PEA + ALC FC had a significant improvement in pain VAS compared to patients treated with group 2 in all the diseases analyzed (P value: sciatic pain 0.032, carpal tunnel syndrome 0.025 and lower limbs neuropathy 0.041). Patients in group 1 showed a significant improvement compared to patients treated in group 2 also from a specific score. Specifically, LBP-IQ showed significant improvement in group one (P value: 0.031), as did CHFD (P=0.011) and NPQ (P=0.025). CONCLUSIONS: The synergistic effect of PEA and ALC seems to have a further advantage in the treatment of this type of pathology, including the anti-inflammatory effect but also in terms of therapy optimization and therefore of better adherence to treatments. Our study shows that it is important to identify the type of pain to follow an accurate diagnostic algorithm, considering the clinical characteristics of the patient and carefully evaluate the indication, preferring a multimodal approach.

Tolerability profile of topical cannabidiol and palmitoylethanolamide: a compilation of single-centre randomized evaluator-blinded clinical and in vitro studies in normal skin.

BACKGROUND: An increasing number of studies have investigated the adverse effect profile of oral cannabinoids; however, few studies have provided sufficient data on the tolerability of topical cannabinoids in human participants. AIM: To assess the tolerability profile of several commercial topical formulations containing cannabidiol (CBD) and palmitoylethanolamide (PEA) on the skin of healthy human participants. METHODS: Three human clinical trials and one in vitro study were conducted. The potential for skin irritation, sensitization and phototoxicity of several products, were assessed via patch testing on healthy human skin. The products assessed included two formulations containing CBD and PEA, one containing hemp seed oil and four concentrations of CBD alone. Ocular toxicity was tested using a traditional hen's egg chorioallantoic membrane model with three CBD, PEA and hemp seed oil formulations. RESULTS: There was no irritation or sensitization of the products evident via patch testing on healthy participants. Additionally, mild phototoxicity of a hemp seed oil product was found at the 48-h time point compared with the negative control. The in vitro experiment demonstrated comparable effects of cannabinoid products with historically nonirritating products. CONCLUSION: These specific formulations of CBD- and PEA-containing products are nonirritating and nonsensitizing in healthy adults, and further encourage similar research assessing their long-term safety and efficacy in human participants with dermatological diseases. There are some limitations to the study: (i) external validity may be limited as formulations from a single manufacturer were used for this study, while vast heterogeneity exists across unregulated, commercial CBD products on the market; and (ii) products were assessed only on normal, nondiseased human skin, and therefore extrapolation to those with dermatological diseases cannot be assumed.

Neurodevelopmental Outcomes and Gut Bifidobacteria in Term Infants Fed an Infant Formula Containing High sn-2 Palmitate: A Cluster Randomized Clinical Trial.

A few studies suggested high stereo-specifically numbered (sn)-2 palmitate in a formula might favor the gut Bifidobacteria of infants. The initial colonization and subsequent development of gut microbiota in early life might be associated with development and later life functions of the central nervous system via the microbiota-gut-brain axis, such as children with autism. This study aims to assess the hypothesized effect of increasing the amount of palmitic acid esterified in the sn-2 position in infant formula on neurodevelopment in healthy full-term infants and to explore the association of this effect with the altered gut Bifidobacteria. One hundred and ninety-nine infants were enrolled in this cluster randomized clinical trial: 66 breast-fed (BF group) and 133 formula-fed infants who were clustered and randomly assigned to receive formula containing high sn-2 palmitate (sn-2 group, n = 66) or low sn-2 palmitate (control group, n = 67), where 46.3% and 10.3% of the palmitic acid (PA) was sn-2-palmitate, respectively. Infants' neurodevelopmental outcomes were measured by the Ages and Stages Questionnaire, third edition (ASQ-3). Stool samples were collected for the analysis of Bifidobacteria (Trial registration number: ChiCTR1800014479). At week 16, the risk of scoring close to the threshold for fine motor skills (reference: scoring above the typical development threshold) was significantly lower in the sn-2 group than the control group after adjustment for the maternal education level (p = 0.036) but did not differ significantly versus the BF group (p = 0.513). At week 16 and week 24, the sn-2 group (week 16: 15.7% and week 24: 15.6%) had a significantly higher relative abundance of fecal Bifidobacteria than the control group (week 16: 6.6%, p = 0.001 and week 24:11.2%, p = 0.028) and did not differ from the BF group (week 16: 14.4%, p = 0.674 and week 24: 14.9%, p = 0.749). At week 16, a higher relative abundance of Bifidobacteria was associated with the decreased odds of only one domain scoring close to the threshold in the formula-fed infants group (odds ratio (OR), 95% confidence interval (CI): 0.947 (0.901-0.996)). Elevating the sn-2 palmitate level in the formula improved infants' development of fine motor skills, and the beneficial effects of high sn-2 palmitate on infant neurodevelopment was associated with the increased gut Bifidobacteria level.

Micronized / ultramicronized palmitoylethanolamide (PEA) as natural neuroprotector against COVID-19 inflammation.

Coronavirus Disease 2019 (COVID-19) is upsetting the world and innovative therapeutic solutions are needed in an attempt to counter this new pandemic. Great hope lies in vaccines, but drugs to cure the infected patient are just as necessary. In the most severe forms of the disease, a cytokine storm with neuroinflammation occurs, putting the patient's life at serious risk, with sometimes long-lasting sequelae. Palmitoylethanolamide (PEA) is known to possess anti-inflammatory and neuroprotective properties, which make it an ideal candidate to be assumed in the earliest stage of the disease. Here, we provide a mini-review on the topic, pointing out phospholipids consumption in COVID-19, the possible development of an antiphospholipid syndrome secondary to SARS-CoV-2 infection, and reporting our preliminary single-case experience concerning to a 45-year-old COVID-19 female patient recently treated with success by micronized / ultramicronized PEA.

Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia.

BACKGROUND & AIMS: Acid hypersensitivity is claimed to be a symptomatic trigger in functional dyspepsia (FD); however, the neuroimmune pathway(s) and the mediators involved in this process have not been investigated systematically. Palmitoylethanolamide (PEA) is an endogenous compound, able to modulate nociception and inflammation, but its role in FD has not been assessed. METHODS: Duodenal biopsy specimens from FD and control subjects, and peroxisome proliferator-activated receptor-α (PPARα) null mice were cultured at a pH of 3.0 and 7.4. Mast cell (MC) number, the release of their mediators, and the expression of transient receptor potential vanilloid receptor (TRPV)1 and TRPV4, were evaluated. All measurements also were performed in the presence of a selective blocker of neuronal action potential (tetradotoxin). FD and control biopsy specimens in acidified medium also were incubated in the presence of different PEA concentrations, alone or combined with a selective PPARα or PPAR-γ antagonist. RESULTS: An acid-induced increase in MC density and the release of their mediators were observed in both dyspeptic patients and controls; however, this response was amplified significantly in FD. This effect was mediated by submucosal nerve fibers and up-regulation of TRPV1 and TRPV4 receptors because pretreatment with tetradotoxin significantly reduced MC infiltration. The acid-induced endogenous release of PEA was impaired in FD and its exogenous administration counteracts MC activation and TRPV up-regulation. CONCLUSIONS: Duodenal acid exposure initiates a cascade of neuronal-mediated events culminating in MC activation and TRPV overexpression. These phenomena are consequences of an impaired release of endogenous PEA. PEA might be regarded as an attractive therapeutic strategy for the treatment of FD.

Palmitoylethanolamide: A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries-A Systematic Review.

Neuroinflammation is a physiological response aimed at maintaining the homodynamic balance and providing the body with the fundamental resource of adaptation to endogenous and exogenous stimuli. Although the response is initiated with protective purposes, the effect may be detrimental when not regulated. The physiological control of neuroinflammation is mainly achieved via regulatory mechanisms performed by particular cells of the immune system intimately associated with or within the nervous system and named "non-neuronal cells." In particular, mast cells (within the central nervous system and in the periphery) and microglia (at spinal and supraspinal level) are involved in this control, through a close functional relationship between them and neurons (either centrally, spinal, or peripherally located). Accordingly, neuroinflammation becomes a worsening factor in many disorders whenever the non-neuronal cell supervision is inadequate. It has been shown that the regulation of non-neuronal cells-and therefore the control of neuroinflammation-depends on the local "on demand" synthesis of the endogenous lipid amide Palmitoylethanolamide and related endocannabinoids. When the balance between synthesis and degradation of this bioactive lipid mediator is disrupted in favor of reduced synthesis and/or increased degradation, the behavior of non-neuronal cells may not be appropriately regulated and neuroinflammation exceeds the physiological boundaries. In these conditions, it has been demonstrated that the increase of endogenous Palmitoylethanolamide-either by decreasing its degradation or exogenous administration-is able to keep neuroinflammation within its physiological limits. In this review the large number of studies on the benefits derived from oral administration of micronized and highly bioavailable forms of Palmitoylethanolamide is discussed, with special reference to neuroinflammatory disorders.

The Protective Effects of Pre- and Post-Administration of Micronized Palmitoylethanolamide Formulation on Postoperative Pain in Rats.

BACKGROUND: Postoperative pain (PO) is a common form of acute pain. Inadequate PO treatment is an important health problem, as it leads to worse outcomes, such as chronic post-surgical pain. Therefore, it is necessary to acquire new knowledge on PO mechanisms to develop therapeutic options with greater efficacy than those available today and to lower the risk of adverse effects. For this reason, we evaluated the ability of micronized palmitoylethanolamide (PEA-m) to resolve the pain and inflammatory processes activated after incision of the hind paw in an animal model of PO. METHODS: The animals were subjected to surgical paw incision and randomized into different groups. PEA-m was administered orally at 10 mg/kg at different time points before or after incision. RESULTS: Our research demonstrated that the pre- and post-treatment with PEA-m reduced the activation of mast cells at the incision site and the expression of its algogenic mediator nerve growth factor (NGF) in the lumbar spinal cord. Furthermore, again at the spinal level, it was able to decrease the activation of phospho-extracellular signal-regulated kinases (p-ERK), ionized calcium binding adaptor molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and the expression of brain-derived neurotrophic factor (BDNF). PEA-m also reduced the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) spinal pathway, showing a protective effect in a rat model of PO. CONCLUSION: The results obtained reinforce the idea that PEA-m may be a potential treatment for the control of pain and inflammatory processes associated with PO. In addition, pre- and post-treatment with PEA-m is more effective than treatment alone after the surgery and this limits the time of taking the compound and the abuse of analgesics.

Natural Products: Evidence for Neuroprotection to Be Exploited in Glaucoma.

Glaucoma, a leading cause of irreversible blindness worldwide, is an optic neuropathy characterized by the progressive death of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is recognized as the main risk factor. Despite effective IOP-lowering therapies, the disease progresses in a significant number of patients. Therefore, alternative IOP-independent strategies aiming at halting or delaying RGC degeneration is the current therapeutic challenge for glaucoma management. Here, we review the literature on the neuroprotective activities, and the underlying mechanisms, of natural compounds and dietary supplements in experimental and clinical glaucoma.

Sodium chromo-glycate and palmitoylethanolamide: A possible strategy to treat mast cell-induced lung inflammation in COVID-19.

A novel human coronavirus SARS-CoV-2 (also referred to as CoV-19) that emerged in late 2019 causes Covid-19 disease a respiratory tract infection which provokes about 4 million deaths per year. Unfortunately, to date, there is no specific antiviral treatment for COVID-19. Mast cells (MCs) are immune cells implicated in the pathogenesis of viral infections, where they mediate inflammation. Microbes, including virus, activate MCs through TLR releasing chemical pro-inflammatory compounds and cytokines. Although, in biomedical literature there are only few reports on MCs activation by SARS-CoV-2 infection. The production of pro-inflammatory cytokines by MC viral activation leads to increase pulmonary inflammation and fibrosis. Sodium Chromo-Glycate (SCG) described as a MC stabilizer, prevents the release of inflammatory chemical compounds, improve mouse survival and respiratory pathological changes in lung viral infection and suppresses inflammation. Furthermore, palmitoylethanolamide (PEA) a nuclear factor agonist, an endogenous fatty acid amide, which exerts a variety of biological effects, related to chronic inflammation and pain, is involved also in MCs homeostasis with an inhibitory and protective effect on the respiratory tract during viral infections. Here, we hypothesize for the first time, that SCG and/or PEA suppress MC activation and pro-inflammatory mediators release, playing an anti-inflammatory therapeutic role in the inflamed lung of patients with COVID-19.

The Effect of Orally Dosed Levagen+™ (palmitoylethanolamide) on Exercise Recovery in Healthy Males-A Double-Blind, Randomized, Placebo-Controlled Study.

The aim of this study was to evaluate the effect of palmitoylethanolamide (PEA), a cannabimimetic compound and lipid messenger, on recovery from muscle damaging exercise. Twenty-eight healthy young male participants attended the laboratory four times on subsequent days. In the first visit, baseline characteristics were recorded before participants were randomized to consume either liquid PEA (167.5 mg Levagen+ with 832.5 mg maltodextrin) or a matched placebo (1 g maltodextrin) drink. Leg press exercise consisted of four sets at 80% of one repetition maximum followed by a performance set. Muscle soreness, thigh circumference, blood lactate concentration, biomarkers of muscle damage and inflammation, and transcription factor pathways were measured pre- and immediately post-exercise and again at 1, 2, 3, 24, 48, and 72 h post-exercise. The leg press exercise increased (p < 0.05) blood lactate concentration and induced muscle damage as evidenced by increased muscle soreness, thigh circumference, biomarkers of muscle damage, and concentrations of tumor necrosis factor-α. PEA reduced (p < 0.05) myoglobin and blood lactate concentrations and increased protein kinase B phosphorylation following exercise. Taken together, these results indicate PEA supplementation may aid in muscle recovery from repeat bouts of exercise performed within a short duration by reducing myoglobin and lactate concentration.

Effect of 3-O-acetylaleuritolic acid from in vitro-cultured Drosera spatulata on cancer cells survival and migration.

BACKGROUND: Drosera spatulata is a source of many compounds such as naphthoquinones, phenolic acids, flavonoids, anthocyanins, and naphthalene derivatives. Unfortunately, the information regarding the biological activity and chemical profile of those compounds is still incomplete. Herein, we investigated the biological activity of 3-O-acetylaleuritolic acid (3-O-AAA) in cancer cell lines. METHODS: The cell viability of HeLa, HT-29, MCF7, and MCF12A cells was assessed using MTT assay. Proliferation potential was assessed using the clonogenic assay and flow cytometry. Migration modulation was tested using a scratch assay. Protein expression was analyzed by immunoblotting. RESULTS: 3-O-AAA significantly inhibited the growth of all tested tumor cells. The results of the colony formation assay suggested cytostatic properties of the studied compound. The scratch assay showed that 3-O-AAA was an efficient migration inhibitor in a dose-dependent manner. Moreover, it caused modulation of mTOR, beclin1, and Atg5 proteins suggesting a possible role of the compound in autophagy induction. CONCLUSION: Collectively, these results demonstrated that 3-O-AAA inhibited the proliferation and migration of cancer cell lines as well as contributed to autophagy induction showing some anticancer properties.

First evidence on the role of palmitoylethanolamide in energy homeostasis in fish.

The objective of this study was to investigate the role of palmitoylethanolamide (PEA) in the regulation of energy homeostasis in goldfish (Carassius auratus). We examined the effects of acute or chronic intraperitoneal treatment with PEA (20 µg·g-1 body weight) on parameters related to food intake and its regulatory mechanisms, locomotor activity, glucose and lipid metabolism, and the possible involvement of transcription factors and clock genes on metabolic changes in the liver. Acute PEA treatment induced a decrease in food intake at 6 and 8 h post-injection, comparable to that observed in mammals. This PEA anorectic effect in goldfish could be mediated through interactions with leptin and NPY, as PEA increased hepatic expression of leptin aI and reduced hypothalamic expression of npy. The PEA chronic treatment reduced weight gain, growth rate, and locomotor activity. The rise in glycolytic potential together with the increased potential of glucose to be transported into liver suggests an enhanced use of glucose in the liver after PEA treatment. In addition, part of glucose may be exported to be used in other tissues. The activity of fatty acid synthase (FAS) increased after chronic PEA treatment, suggesting an increase in the hepatic lipogenic capacity, in contrast with the mammalian model. Such lipogenic increment could be linked with the PEA-induction of REV-ERBα and BMAL1 found after the chronic treatment. As a whole, the present study shows the actions of PEA in several compartments related to energy homeostasis and feeding behavior, supporting a regulatory role for this N-acylethanolamine in fish.