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Palmitoylethanolamide (PEA) is a nutraceutical compound that has been demonstrated to improve intestinal inflammation. We aimed at evaluating its antiproliferative and antiangiogenic effects in human colon adenocarcinoma Caco-2 cell line. Caco-2 cells were treated with increasing concentrations of PEA (0.001, 0.01 and 0.1 μM) in the presence of peroxisome proliferator-activated receptor-a (PPAR-α) or PPAR-γ antagonists. Cell proliferation was evaluated by performing a MTT assay. Vascular endothelial growth factor (VEGF) release was estimated by ELISA, while the expression of VEGF receptor and the activation of the Akt/mammalian target of rapamycin (mTOR) pathway were evaluated by western blot analysis. PEA caused a significant and concentration-dependent decrease of Caco-2 cell proliferation at 48 h. PEA administration significantly reduced in a concentration-dependent manner VEGF secretion and VEGF receptor expression. Inhibition of Akt phosphorylation and a downstream decrease of phospho-mTOR and of p-p70S6K were observed as compared with untreated cells. PPAR-α, but not PPAR-γ antagonist, reverted all effects of PEA. PEA is able to decrease cell proliferation and angiogenesis. The antiangiogenic effect of PEA depends on the specific inhibition of the AkT/mTOR axis, through the activation of PPAR-α pathway. If supported by in vivo models, our data pave the way to PEA co-administration to the current chemotherapeutic regimens for colon carcinoma. Copyright © 2016 John WileySons, Ltd.

Pharmacological inhibition of beta-amyloid (Abeta) induced reactive gliosis may represent a novel rationale to develop drugs able to blunt neuronal damage and slow the course of Alzheimer's disease (AD). Cannabidiol (CBD), the main non-psychotropic natural cannabinoid, exerts in vitro a combination of neuroprotective effects in different models of Abeta neurotoxicity. The present study, performed in a mouse model of AD-related neuroinflammation, was aimed at confirming in vivo the previously reported antiinflammatory properties of CBD.Mice were inoculated with human Abeta (1-42) peptide into the right dorsal hippocampus, and treated daily with vehicle or CBD (2.5 or 10 mg kg(-1), i.p.) for 7 days. mRNA for glial fibrillary acidic protein (GFAP) was assessed by in situ hybridization. Protein expression of GFAP, inducible nitric oxide synthase (iNOS) and IL-1beta was determined by immunofluorescence analysis. In addition, ELISA assay of IL-1beta level and the measurement of NO were performed in dissected and homogenized ipsilateral hippocampi, derived from vehicle and Abeta inoculated mice, in the absence or presence of CBD.In contrast to vehicle, CBD dose-dependently and significantly inhibited GFAP mRNA and protein expression in Abeta injected animals. Moreover, under the same experimental conditions, CBD impaired iNOS and IL-1beta protein expression, and the related NO and IL-1beta release.The results of the present study confirm in vivo anti-inflammatory actions of CBD, emphasizing the importance of this compound as a novel promising pharmacological tool capable of attenuating Abeta evoked neuroinflammatory responses.

1 In the present study we investigated the role of mast cells during inflammation in rat skin. As the release of several pro-inflammatory mediators, such as histamine and tumour necrosis factor alpha (TNF alpha), occurs following mast cell activation we studied whether mast cell degranulation and the release of both histamine (H) and TNF alpha occurred in a model of lipopolysaccharide (LPS)-induced plasma leakage in rat skin. 2 Plasma leakage in the rat skin was measured over a period of 2 h as the local accumulation of intravenous injection of I-125-human serum albumin (I-125-HSA) in response to intradermal injection of LPS. LPS (10 mu g site(-1)) produced an increase of plasma leakage (50.1+/-2.3 mu l site(-1)) as compared to saline (9.0+/-3.2 mu l site(-1)). Histological analysis of rat tissue showed that LPS induced a remarkable mast cell degranulation (59.8+/-2.1%) as compared to saline (13.5+/-2.2%). 3 Ketotifen (10(-9)-10(-7) mol site(-1)), a well-known mast cell-membrane stabilizer, produced a dose-related inhibition of LPS-induced plasma leakage by 36+/-3.5%, 47+/-4.0%, 60+/-3.3% respectively. In addition, ketotifen(10(-7) mol site(-1)) inhibited mast cell degranulation by 59.2+/-2.7%. 4 Chlorpheniramine maleate (CPM) (10(-9)-10(-7) mol site(-1)), an H-1 histamine receptor antagonist only partially inhibited LPS-induced plasma leakage in rat skin (38+/-1.1% at the highest dose). Furthermore, CPM (10(-7) mol site(-1)) did not prevent mast cell degranulation. 5 A polyclonal antibody against TNF alpha (1 : 500, 1 : 100, 1 : 50 v v(-1) dilution), locally injected, decreased LPS-induced plasma leakage in the skin by 15+/-2.0%, 24+/-2.1% and 50+/-3.0% respectively. 6 Taken together these results suggest that LPS-induced plasma leakage in rat skin is mediated, at least in part, by mast cell degranulation and by the release of histamine and TNF alpha from these cells.