l-663536 and Colitis--Ulcerative

Enteric glia activation has been reported to amplify intestinal inflammation via the enteroglial-specific S100B protein. This neurotrophin promotes macrophage recruitment in the mucosa, amplify colonic inflammation and interacts with toll-like receptors (TLR). Molecules inhibiting S100B-driven enteric activation might mitigate the course of ulcerative colitis (UC). This study aims to investigate the effects of palmitoylethanolammide (PEA), a drug able to counteract astroglial activation in the central nervous system, on intestinal inflammation, in humans and mice.. Mouse models of dextran sodium sulphate (DSS)-induced colitis, colonic biopsies deriving from UC patients and primary cultures of mouse and human enteric glial cells (EGC), have been used to assess the effects of PEA, alone or in the presence of specific PPARα or PPARγ antagonists, on: macroscopic signs of UC (DAI score, colon length, spleen weight, macrophages/neutrophils infiltration); the expression and release of proinflammatory markers typical of UC; TLR pathway in EGCs.. PEA treatment improves all macroscopic signs of UC and decreases the expression and release of all the proinflammatory markers tested. PEA anti-inflammatory effects are mediated by the selective targeting of the S100B/TLR4 axis on ECG, causing a downstream inhibition of nuclear factor kappa B (NF-kB)-dependent inflammation. Antagonists at PPARα, but not PPARγ, abolished PEA effects, in mice and in humans.. Because of its lack of toxicity, its ability in reducing inflammation and its selective PPARα action, PEA might be an innovative molecule to broaden pharmacological strategies against UC.

Topics: Amides; Anilides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Colitis; Colitis, Ulcerative; Colon, Sigmoid; Cyclooxygenase 2; Dextran Sulfate; Dinoprostone; Endocannabinoids; Ethanolamines; Female; Glial Fibrillary Acidic Protein; Humans; Indoles; Male; Mice; Middle Aged; Nerve Tissue Proteins; Neuroglia; Neutrophil Infiltration; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Palmitic Acids; PPAR alpha; PPAR gamma; Rectum; S100 Calcium Binding Protein beta Subunit; Severity of Illness Index; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Leukotrienes (LTs) have been implicated as mediators of the inflammation and ulceration associated with ulcerative colitis and Crohn's disease. In the present study, the effects of a novel, orally active inhibitor of LT synthesis (MK-886) were examined in a rat model of chronic colitis. Colitis was induced by intracolonic administration of trinitrobenzenesulfonic acid. Colonic LTB4 synthesis was measured after incubation of tissue samples in vitro and by in vivo equilibrium dialysis. A single dose of MK-886 (10 mg/kg) significantly inhibited colonic LTB4 synthesis for greater than 24 h. Daily treatment with this dose significantly reduced colonic damage, as assessed macroscopically and histologically, when the treatment was performed 2 h before induction of colitis and daily thereafter for 1 wk, but not when treatment was performed during the second week after induction of colitis. A less marked beneficial effect of MK-886 was observed when the pretreatment dose was excluded, suggesting a role for LTs in the early events of the inflammatory process. Inhibition of LT synthesis during the first 24 h after induction of colitis did not alter the extent of infiltration of neutrophils into the colon, as measured by tissue myeloperoxidase activity. Daily treatment with sulfasalazine (100 mg/kg po) either during the first or second week after induction of colitis did not significantly affect the rates of healing. At the dose used, sulfasalazine only produced a transient inhibition of colonic LTB4 synthesis. This study therefore demonstrates that a specific, orally active inhibitor of LT synthesis can significantly accelerate healing in this animal model of colitis when the treatment is performed during the early phase of the inflammatory response.

Topics: Administration, Oral; Animals; Colitis, Ulcerative; Colon; Disease Models, Animal; Indoles; Inflammation; Leukotriene B4; Male; Rats; Rats, Inbred Strains; Sulfasalazine; Trinitrobenzenesulfonic Acid