l-663536 and palmidrol

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

In addition to cytotoxic mechanisms directly impacting neurons, β-amyloid (Aβ)-induced glial activation also promotes release of proinflammatory molecules that may self-perpetuate reactive gliosis and damage neighbouring neurons, thus amplifying neuropathological lesions occurring in Alzheimer's disease (AD). Palmitoylethanolamide (PEA) has been studied extensively for its anti-inflammatory, analgesic, antiepileptic and neuroprotective effects. PEA is a lipid messenger isolated from mammalian and vegetable tissues that mimics several endocannabinoid-driven actions, even though it does not bind to cannabinoid receptors. Some of its pharmacological properties are considered to be dependent on the expression of peroxisome proliferator-activated receptors-α (PPARα).. In the present study, we evaluated the effect of PEA on astrocyte activation and neuronal loss in models of Aβ neurotoxicity. To this purpose, primary rat mixed neuroglial co-cultures and organotypic hippocampal slices were challenged with Aβ1-42 and treated with PEA in the presence or absence of MK886 or GW9662, which are selective PPARα and PPARγ antagonists, respectively. The results indicate that PEA is able to blunt Aβ-induced astrocyte activation and, subsequently, to improve neuronal survival through selective PPARα activation. The data from organotypic cultures confirm that PEA anti-inflammatory properties implicate PPARα mediation and reveal that the reduction of reactive gliosis subsequently induces a marked rebound neuroprotective effect on neurons.. In line with our previous observations, the results of this study show that PEA treatment results in decreased numbers of infiltrating astrocytes during Aβ challenge, resulting in significant neuroprotection. PEA could thus represent a promising pharmacological tool because it is able to reduce Aβ-evoked neuroinflammation and attenuate its neurodegenerative consequences.

Topics: Amides; Amyloid beta-Peptides; Animals; Animals, Newborn; Apoptosis; Brain; Cell Proliferation; Cells, Cultured; Coculture Techniques; Embryo, Mammalian; Endocannabinoids; Enzyme Inhibitors; Ethanolamines; Glial Fibrillary Acidic Protein; Hippocampus; Indoles; Microtubule-Associated Proteins; Neuroglia; Neurons; Neuroprotective Agents; Organ Culture Techniques; Palmitic Acids; PPAR alpha; Rats; Rats, Sprague-Dawley

Cannabinoids are associated with analgesia in acute and chronic pain states. A spectrum of central cannabinoid (CB(1)) receptor-mediated motor and psychotropic side effects limit their therapeutic potential. Here, we investigate the analgesic effect of the palmitoylethanolamide (PEA) analogue, palmitoylallylamide (L-29), which via inhibition of fatty acid amide hydrolase (FAAH) may potentiate endocannabinoids thereby avoiding psychotropic side effects.. The in vivo analysis of the effect of L-29 on measures of pain behaviour in three rat models of neuropathic pain.. Systemically administered L-29 (10 mg kg(-1)) reduced hypersensitivity to mechanical and thermal stimuli in the partial sciatic nerve injury (PSNI) model of neuropathic pain; and mechanical hypersensitivity in a model of antiretroviral (ddC)-associated hypersensitivity and a model of varicella zoster virus (VZV)-associated hypersensitivity. The effects of L-29 were comparable to those of gabapentin (50 mg kg(-1)). The CB(1) receptor antagonist SR141716a (1 mg kg(-1)) and the CB(2) receptor antagonist SR144528 (1 mg kg(-1)) reduced the effect of L-29 on hypersensitivity in the PSNI and ddC models, but not in the VZV model. The peroxisome proliferator-activated receptor-alpha antagonist, MK-886 (1 mg kg(-1)), partially attenuated the effect of L-29 on hypersensitivity in the PSNI model. L-29 (10 mg kg(-1)) significantly attenuated thigmotactic behaviour in the open field arena without effect on locomotor activity.. L-29 produces analgesia in a range of neuropathic pain models. This presents L-29 as a novel analgesic compound that may target the endogenous cannabinoid system while avoiding undesirable side effects associated with direct cannabinoid receptor activation.

Topics: Amides; Amines; Animals; Behavior, Animal; Camphanes; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Endocannabinoids; Ethanolamines; Gabapentin; gamma-Aminobutyric Acid; Hindlimb; Indoles; Injections, Intraperitoneal; Male; Pain; Pain Measurement; Pain Threshold; Palmitic Acids; Physical Stimulation; Piperidines; PPAR alpha; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Sciatic Neuropathy; Temperature; Zalcitabine

Human mast cells (HMC-1) take up anandamide (arachidonoyl-ethanolamide, AEA) with a saturable process (K(m)=200+/-20 nM, V(max)=25+/-3 pmol min(-1) mg protein(-1)), enhanced two-fold over control by nitric oxide-donors. Internalized AEA was hydrolyzed by a fatty acid amide hydrolase (FAAH), whose activity became measurable only in the presence of 5-lipoxygenase, but not cyclooxygenase, inhibitors. FAAH (K(m)=5.0+/-0.5 microM, V(max)=160+/-15 pmol min(-1) mg protein(-1)) was competitively inhibited by palmitoylethanolamide. HMC-1 cells did not display a functional cannabinoid receptor on their surface and neither AEA nor palmitoylethanolamide affected tryptase release from these cells.

Topics: 5,8,11,14-Eicosatetraynoic Acid; Amides; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Binding, Competitive; Biological Transport; Cannabinoids; Cell Line; Cyclooxygenase Inhibitors; Endocannabinoids; Ethanolamines; Humans; Ibuprofen; Indoles; Indomethacin; Kinetics; Lipoxygenase Inhibitors; Mast Cells; Palmitic Acids; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug; Tritium