4-(((r)-1-(benzo(b)thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl)-(3-chloro-benzyl)-amino)-butyric-acid and Inflammation

Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper μ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis.. The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO-an MOR agonist), 0.3 mg/kg BW (DPDPE-a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone-a non-selective OR antagonist, GLPG 0974-a FFAR2 antagonist, GSK 137647-a FFAR4 agonist and AH 7614-a FFAR4 antagonist) for 4 days.. Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group.. Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed.

Topics: Aniline Compounds; Animals; Butyrates; Colitis; Disease Models, Animal; Drug Synergism; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Inflammation; Ligands; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Peroxidase; Receptors, G-Protein-Coupled; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfonamides; Thiophenes; Xanthenes

Neuroinflammation contributes to neurodegenerative disorders, including Alzheimer's disease (AD). Gut microbes are involved in regulating systemic inflammation. Short-chain fatty acids (SCFAs), which are among the many metabolites released by gut microbes, can cross the blood-brain barrier (BBB) and interact with microglia. High concentrations of individual SCFAs decrease the inflammatory responses of peripheral monocytes; therefore, we hypothesized that SCFAs act on their own or in combinations to reduce the inflammatory response of microglia. Cultured human THP-1 monocytic cells and differentiated human HL-60 myelomonocytic cells were used to model select immune functions of human microglia. Acetate, propionate, butyrate, formate, and valerate were added to cells alone or as a mixture containing SCFAs at an approximate physiological concentration ratio. The SCFA mixture, as well as several individual SCFAs at the highest concentrations used in the mixture (15-236 μM), decreased the secretion of interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-α, and cytotoxins by immune-stimulated THP-1 cells. GLPG 0974, a free fatty acid receptor (FFAR) 2/3 antagonist, did not block the inhibitory effect of the SCFA mixture on IL-1β secretion by THP-1 cells while blocking the inhibitory effect of formate alone. We demonstrated that formate and valerate alone reduced the phagocytic activity of immune-stimulated THP-1 cells. Formate, but not valerate, alone also inhibited the N-formylmethionine-leucyl-phenylalanine (fMLP)-induced respiratory burst of HL-60 cells, reducing the production of reactive oxygen species (ROS). Our data indicate that SCFAs could regulate select microglial functions that are disrupted in AD.

Topics: Butyrates; Chemokine CCL2; Fatty Acids, Volatile; Humans; Inflammation; Microglia; Monocytes; Thiophenes; Tumor Necrosis Factor-alpha