Corrigendum: Oral ultramicronized palmitoylethanolamide: plasma and tissue levels and spinal antihyperalgesic effect.

[This corrects the article DOI: 10.3389/fphar.2018.00249.].

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.

Plumericin prevents intestinal inflammation and oxidative stress in vitro and in vivo.

Inflammatory bowel diseases (IBDs) are characterized by an inflammatory and oxidative stress condition in the intestinal tissue. In this study, we evaluated the effect of plumericin, one of the main bioactive components of Himatanthus sucuuba (Woodson) bark, on intestinal inflammation and oxidative stress, both in vitro and in vivo. The effect of plumericin (0.5-2 µM) in vitro was evaluated in rat intestinal epithelial cells (IEC-6) treated with lipopolysaccharides from E. coli (10 µg/mL) plus interferon-γ (10 U/mL). Moreover, a 2,4,6-dinitrobenzene sulfonic acid (DNBS)-induced colitis model was used to evaluate the anti-inflammatory and antioxidant activity of plumericin (3 mg/kg) in vivo. The results showed that plumericin significantly reduces intestinal inflammatory factors such as tumor necrosis factor-α, cyclooxygenase-2 and inducible nitric oxide synthase expression, and nitrotyrosine formation. Plumericin also inhibited nuclear factor-κB translocation, reactive oxygen species (ROS) release, and inflammasome activation. Moreover, plumericin activated the nuclear factor erythroid-derived 2 pathway in IEC-6. Using the DNBS-induced colitis model, a significant reduction in the weight loss and in the development of the macroscopic and histologic signs of colon injury, together with a reduced inflammatory and oxidative stress state, were observed in plumericin-treated mice. These results indicate that plumericin exerts a strong anti-inflammatory and antioxidant activity. Thus, it might be a candidate for the development of a new pharmacologic approach for IBDs treatment.

The association of adelmidrol with sodium hyaluronate displays beneficial properties against bladder changes following spinal cord injury in mice.

The disruption of coordinated control between the brain, spinal cord and peripheral nervous system caused by spinal cord injury (SCI) leads to several secondary pathological conditions, including lower urinary tract dysfunction. In fact, urinary tract dysfunction associated with SCI is urinary dysfunction could be a consequence of a lack of neuroregeneration of supraspinal pathways that control bladder function. The object of the current research was to explore the effects of adelmidrol + sodium hyaluronate, on bladder damage generated after SCI in mice. Spinal cord was exposed via laminectomy, and SCI was induced by extradural compression at T6 to T7 level, by an aneurysm clip with a closing force of 24 g. Mice were treated intravesically with adelmidrol + sodium hyaluronate daily for 48 h and 7 days after SCI. Adelmidrol + sodium hyaluronate reduced significantly mast cell degranulation and down-regulated the nuclear factor-κB pathway in the bladder after SCI both at 48 h and 7days. Moreover, adelmidrol + sodium hyaluronate reduced nerve growth factor expression, suggesting an association between neurotrophins and bladder pressure. At 7 days after SCI, the bladder was characterized by a marked bacterial infection and proteinuria; surprisingly, adelmidrol + sodium hyaluronate reduced significantly both parameters. These data show the protective roles of adelmidrol + sodium hyaluronate on bladder following SCI, highlighting a potential therapeutic target for the reduction of bladder changes.

Effects of a new compound containing Palmitoylethanolamide and Baicalein in myocardial ischaemia/reperfusion injury in vivo.

BACKGROUND: Myocardial ischemia/reperfusion (I/R) injury is the principal cause of death, happens after prolonged obstruction of the coronary arteries.  The first intervention to limit myocardial damage is directed to restoration of perfusion, to avoid inflammatory response and a significant oxidative stress triggered by infarction. Palmitoylethanolamide (PEA), is a well-known fatty acid amide-signaling molecule that possess an important anti-inflammatory and analgesic effects. PEA does not hold the ability to inhibit free radicals formation. Baicalein, a bioactive component isolated from a Chinese herbal medicine, has multiple pharmacological activities, such as a strong anti-oxidative effects. PURPOSE: A combination of PEA and Baicalein could have beneficial effects on oxidative stress produced by inflammatory response. STUDY DESIGN: In the present study we explored the effects of composite containing PEA and Baicalein in a model of myocardial I/R injury. METHODS: Myocardial ischemia/reperfusion injury was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 2 h of reperfusion. PEA-Baicalein (9:1), was administered (10 mg/kg) 5 min before the end of ischemia and 1 h after reperfusion. RESULTS: In this study, we clearly demonstrated that PEA-Baicalein treatment decreases myocardial tissue injury, neutrophils infiltration, markers for mast cell activation expression as chymase and tryptase and pro-inflammatory cytokines production (TNF-α, IL-1ß). Moreover, PEA-Baicalein treatment reduces stress oxidative and modulates Nf-kB and apoptosis pathways. CONCLUSION: These results support the idea that the association between PEA and Baicalein should be a potent candidate for the treatment of myocardial I/R injury.

Effect of pea protein plus grape seed dry extract on a murine model of Candida albicans induced vaginitis.

AIM: The objective of this research was to evaluate the antifungal properties of the association between grape seed and pea by using a nonpharmacological medical device that contains them. MATERIALS & METHODS: A murine model of vulvovaginal candidiasis, induced by Candida albicans infection, was used. RESULTS: We showed that topical treatment with the device significantly reduced the fungal burden in vagina and preserved vagina tissue architecture from C. albicans infection. CONCLUSION: We can support the potential beneficial effect of the association between grape and pea extract present in the medical device. Together these results supported this device as a favorable antifungal agent and a promising synergist with fluconazole in the clinical management of vulvovaginal candidiasis caused by C. albicans biofilms.

Topical Application of Adelmidrol + Trans-Traumatic Acid Enhances Skin Wound Healing in a Streptozotocin-Induced Diabetic Mouse Model.

Impaired wound healing is considered to be one of the severe complications associated with diabetes. Adelmidrol and trans-traumatic acid are commonly called Nevamast®. This gel consists precisely of 2% adelmidrol and 1% trans-traumatic acid. Thanks to its components, it is capable of favoring the natural process of skin re-epithelialization. This study tests the theory that topical usage of adelmidrol + trans-traumatic acid has important effects on the healing and closure of diabetic wounds in a streptozotocin (STZ)-induced diabetic mouse model. Diabetes was induced by intraperitoneal injection of STZ (60 mg/kg) in 0.01 M citrate buffer (pH 4.5) administrated for 5 consecutive days. After diabetes induction, two longitudinal incisions were made on the dorsum of the mice. The animals were killed between 6 and 12 days from wound induction. We found that diabetic mice compared to control mice presented: a retarded wound closure, characterized by an important reduction in the levels of transforming growth factor-ß, plus an important increase of vascular endothelial growth factor and endothelial-type nitric oxide synthase expression, together with a reduction of adhesion molecules such as intercellular adhesion molecule-1 and P-selectin and a prolonged elevation of the levels of matrix metalloproteinase-9 and matrix metalloproteinase-2 in wound tissues. This study demonstrates that topical application of adelmidrol + trans-traumatic acid has important effects on the healing and closure of diabetic wounds in an STZ-induced diabetic mouse model.

Protective Effects of Xyloglucan in Association with the Polysaccharide Gelose in an Experimental Model of Gastroenteritis and Urinary Tract Infections.

Acute infectious gastroenteritis (GE) and urinary tract infection (UTI) are common diseases and are normally perceived as mild and limiting illnesses. Xyloglucan is a natural plant polymer with protective barrier properties, also known as "mucosal protectors", which is the main ingredient of medical devices developed for the management of different diseases, such as gastrointestinal diseases, urinary tract infections, or respiratory allergic diseases. The aim of this study was to evaluate the protective effect of xyloglucan in association with gelose (also called agar) in an experimental model of bacterial GE and UTI in rats. Two kinds of infection were induced by oral administration of Salmonella enterica and Enterococcus hirae for three days. Two days before the bacterial administration, preventive oral treatment with xyloglucan + gelose (10 mg/kg + 5 mg/kg) was performed daily until the seventh day. Twenty-four hours after the last treatment, rats were sacrificed and urinary tracts and intestines for different analysis were collected. The results showed that xyloglucan plus gelose was able to reduce intestinal morphological changes (p < 0.05 for both), tight junctions (TJ) permeability (p < 0.001 for both), and neutrophil infiltration (p < 0.05 for both) induced by bacterial infections, highlighting its barrier proprieties. Moreover, the compound reduced the number of bacterial colonies in the urinary tract favoring elimination by feces. The results obtained in the present study suggest that the protective barrier properties of xyloglucan plus gelose allow the prevention of GE and UTI in models of infections in rats.

Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-hyperalgesic Effect.

Palmitoylethanolamide (PEA) is a pleiotropic lipid mediator with established anti-inflammatory and anti-hyperalgesic activity. Ultramicronized PEA (PEA-um) has superior oral efficacy compared to naïve (non-micronized) PEA. The aim of the present study was two-fold: (1) to evaluate whether oral PEA-um has greater absorbability compared to naïve PEA, and its ability to reach peripheral and central tissues under healthy and local inflammatory conditions (carrageenan paw edema); (2) to better characterize the molecular pathways involved in PEA-um action, particularly at the spinal level. Rats were dosed with 30 mg/kg of [13C]4-PEA-um or naïve [13C]4-PEA by oral gavage, and [13C]4-PEA levels quantified, as a function of time, by liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry. Overall plasma levels were higher in both healthy and carrageenan-injected rats administered [13C]4-PEA-um as compared to those receiving naïve [13C]4-PEA, indicating the greater absorbability of PEA-um. Furthermore, carrageenan injection markedly favored an increase in levels of [13C]4-PEA in plasma, paw and spinal cord. Oral treatment of carrageenan-injected rats with PEA-um (10 mg/kg) confirmed beneficial peripheral effects on paw inflammation, thermal hyperalgesia and tissue damage. Notably, PEA-um down-regulated distinct spinal inflammatory and oxidative pathways. These last findings instruct on spinal mechanisms involved in the anti-hyperalgesic effect of PEA-um in inflammatory pain.