Palmitoylethanolamide Modulates Inflammation-Associated Vascular Endothelial Growth Factor (VEGF) Signaling via the Akt/mTOR Pathway in a Selective Peroxisome Proliferator-Activated Receptor Alpha (PPAR-α)-Dependent Manner

Abstract

Background and AimAngiogenesis is emerging as a pivotal process in chronic inflammatory pathologies, promoting immune infiltration and prompting carcinogenesis. Ulcerative Colitis (UC) and Crohn’s Disease (CD) represent paradigmatic examples of intestinal chronic inflammatory conditions in which the process of neovascularization correlates with the severity and progression of the diseases. Molecules able to target the angiogenesis have thus the potential to synergistically affect the disease course. Beyond its anti-inflammatory effect, palmitoylethanolamide (PEA) is able to reduce angiogenesis in several chronic inflammatory conditions, but no data about its anti-angiogenic activity in colitis have been produced, yet.MethodsThe effects of PEA on inflammation-associated angiogenesis in mice with dextran sulphate sodium (DSS)-induced colitis and in patients with UC were assessed. The release of Vascular Endothelial Growth Factor (VEGF), the hemoglobin tissue content, the expression of CD31 and of phosphatidylinositol 3-kinase/Akt/mammalian-target-of-rapamycin (mTOR) signaling axis were all evaluated in the presence of different concentrations of PEA and concomitant administration of PPAR-α and -γ antagonists.ResultsOur results demonstrated that PEA, in a selective peroxisome proliferator activated receptor (PPAR)-α dependent mechanism, inhibits colitis-associated angiogenesis, decreasing VEGF release and new vessels formation. Furthermore, we demonstrated that the mTOR/Akt axis regulates, at least partly, the angiogenic process in IBD and that PEA directly affects this pathway.ConclusionsOur results suggest that PEA may improve inflammation-driven angiogenesis in colonic mucosa, thus reducing the mucosal damage and potentially affecting disease progression and the shift towards the carcinogenesis.

Bioactive lipids ALIAmides differentially modulate inflammatory responses of distinct subsets of primary human T lymphocytes

“…As expected, these ALIAmide-induced immunomodulatory activities were mediated by their respective anti-inflammatory receptors, namely PPAR-a and CB 2 . This observation is in line with previous studies showing that PPAR-a mediates most, if not all, antiinflammatory and antinociceptive effects of both OEA and PEA (31,32). However, our findings do not rule out the involvement of other molecular targets of these 2 ALIAmides, including G-protein-coupled receptor (GPR)119 and GPR55, although the latter receptors are expressed in specific tissues only or bear proinflammatory effects.…”

The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations

“…Therefore, the role of PPAR‐α in inflammatory bowel diseases was also studied, and in a mouse model of DSS‐induced ulcerative colitis as well as in cultured human biopsies deriving from patients with ulcerative colitis, PEA treatment improved the macroscopic signs of ulcerative colitis, decreased the expression and release of pro‐inflammatory cytokines as well as neutrophil infiltration (Esposito et al, ), all these anti‐inflammatory effects being abolished by PPAR‐α antagonists (Esposito et al, ). More recently, the effects of PEA on inflammation‐associated angiogenesis in mice with DSS‐induced ulcerative colitis and in patients with ulcerative colitis were also studied (Sarnelli et al, ). PEA treatment, in a PPAR‐α‐dependent manner, inhibited colitis‐associated angiogenesis by decreasing VEGF release and new vessel formation via the mammalian target of rapamycin/PKB (mTOR/Akt) axis (Sarnelli et al, ).…”

Medical Cannabis and Cannabinoids: An Option for the Treatment of Inflammatory Bowel Disease and Cancer of the Colon?

“…In line with these results, inhibition of the PEA-degrading enzyme N-acylethanolamine hydrolyzing acid amidase increased PEA levels and also protected against colitis [51]. Furthermore, Sarnelli et al [52] reported that inhibition of inflammation-associated angiogenesis by PEA in a DSS model was dependent on PPARα. Additionally, they showed that the release of vascular endothelial growth factor and the formation of vessels were decreased, leading to a reduction in mucosal damage [52].…”

“…Furthermore, Sarnelli et al [52] reported that inhibition of inflammation-associated angiogenesis by PEA in a DSS model was dependent on PPARα. Additionally, they showed that the release of vascular endothelial growth factor and the formation of vessels were decreased, leading to a reduction in mucosal damage [52]. Recently, the PEA analog adelmidrol was found to exert anti-inflammatory effects that were partly mediated via PPARγ [53].…”