5-hydroxy-6-8-11-14-eicosatetraenoic-acid and Edema

We investigated the anti-inflammatory effect of YPE-01, a novel diarylheptanoid derivative in vitro and in vivo.. In the in vitro study, rat basophilic leukemia (RBL-1) cells were used. For the in vivo study, ICR and ddY mice (male, 7 weeks old) were used.. In the in vitro study, the supernatant of RBL-1 cells lysate was incubated with 50 microM arachidonic acid (AA) and 0.01-100 microM test drugs for 15 min. RBL-1 cells were preincubated with 0.01-100 microM test drugs for 10 min before incubation with 0.5 microM calcium ionophore A23187 for 10 min. In the in vivo study, YPE-01 (0.1-3 mg/ear) was applied to the ear of mice at the same time as a 12-O-tetradecanoylphorbol 13-acetate (TPA) application or 1 h before an AA application.. In the in vitro study, the amounts of 5-hydroxyeicosatetraenoic acid and leukotrienes were measured by high-performance liquid chromatography and an enzyme immunoassay, respectively. In the in vivo study, a circular tissue sample from the ear of the mice was weighed. Statistical analysis was done using Dunnett's test.. YPE-01 inhibited the 5-lipoxygenase activity (IC50, 0.28 microM) and the leukotriene B4 (IC50, 0.035 microM) and C4 (IC50, 0.046 microM) production by RBL-1 cells without any inhibition of cyclooxygenase activity in vitro. The topical application of YPE-01 significantly suppressed both the AA- and TPA-induced ear edemas in vivo.. YPE-01 is a selective 5-lipoxygenase inhibitor with a suppressive effect against dermal inflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Calcimycin; Chemotactic Factors; Chromatography, High Pressure Liquid; Diarylheptanoids; Ear; Edema; Hydroxyeicosatetraenoic Acids; Ionophores; Ketones; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred ICR; Phenols; Rats; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

DL-omega-phenyl amino acid esters turned out to be inhibitors of the sheep vesicular gland prostaglandin H synthase in addition to their antiphlogistic action on the carrageenan-induced oedema of the rat paw and weak antihistaminic actions. The inhibition of the prostaglandin H synthase was dose-dependent, the inhibitory potencies were however much lower than that of indomethacin. Some but not all derivatives, such as DL-4-amino-4-phenylbutyric acid octyl ester, also caused inhibition of the pure lipoxygenase from rabbit reticulocytes and the conversion of arachidonic acid to leukotriene B4 and 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid by human polymorphonuclear leukocytes as well as inhibition of antigen-induced release of histamine from mast cells of ovalbumin-sensibilized rats. Since no clear relations between the data of the in vitro and in vivo models were obtained, further studies on the pharmacokinetics and possible biotransformations are required.

Topics: Amino Acids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase Inhibitors; Depression, Chemical; Dose-Response Relationship, Drug; Edema; Esters; Female; Guinea Pigs; Histamine Release; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mast Cells; Neutrophils; Prostaglandins H; Rats; Sheep; Structure-Activity Relationship

A recent report from our laboratory gave evidence showing that tetrahydrocannabinol (THC)-7-oic acid has antinociceptive activity in the mouse. We also pointed out that this substance, which is a major metabolite of THC in most species including humans, is probably responsible for the well known analgesic properties of the parent drug. The present report contains findings that suggest THC-7-oic acid may have considerable activity as an antagonist to platelet activating factor, which may also explain the known properties of THC as a bronchodilator, antipyretic and antirheumatic agent. In the mouse ear edema test, THC-7-oic acid appeared to be about as efficacious as phenidone; however, its potency was less than either phenidone or indomethacin. When compared with the parent drug, THC, in the platelet activating factor-induced paw edema assay, it acted more quickly and produced a greater reduction of edema. This is consistent with the possibility that THC must be metabolized to the 7-oic acid for activity to be seen. Its activity in preventing platelet activating factor-induced mortality was comparable to naproxen. In vitro studies suggest that THC-7-oic acid can inhibit both cyclooxygenase and 5-lipoxygenase activities in intact cells.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cannabinoids; Dronabinol; Edema; Female; Hydroxyeicosatetraenoic Acids; Mice; Naproxen; Platelet Activating Factor; Structure-Activity Relationship

Eicosanoids are known mediators of inflammation, vascular permeability, and are involved in microcirculatory blood flow regulation. To study their potential involvement in the pathophysiology of CNS trauma we used a rabbit spinal cord trauma model. Rabbits were subjected to lumbar spinal cord trauma produced by a modification of the Allen weight-drop method. TXB2, 6-keto-PGF1 alpha, PGE2, and 5-hydroxyeicosatetraenoic acid (5-HETE) release from spinal cord slices incubated ex vivo were measured by radioimmunoassay at 5, 30 min, 24 hrs, and 2 wks after trauma. Five and 30 min after trauma the TXB2/6-keto-PGF1 alpha ratio was elevated and the release of 5-HETE at 5 min after trauma increased in the injured spinal cord whereas release of 6-keto-PGF1 alpha and PGE2 remained at base-line levels. In the thoracic spinal cord, TXB2 and 6-keto-PGF1 alpha release were increased at 30 min after trauma. Release of 5-HETE from the injured spinal cord was also elevated 24 hrs after trauma. Two wks after trauma, TXB2 and 6-keto-PGF1 alpha release were also elevated in the injured spinal cord. Measurements of tissue water content by microgravimetry indicated progressive edema in the injury site while histopathological evaluation indicated progressive damage and tissue destruction. The results of this study suggest that eicosanoids may be involved in the pathophysiology of spinal cord trauma through two potential mechanisms: 1) site specific increase in the TXB2/6-keto-PGF1 alpha ratio immediately following trauma which is due primarily to an increase in TXA2 synthesis; 2) the increase synthesis of 5-HETE which signals the activation of the 5-lipoxygenase pathway of arachidonate metabolism and production of mediators that are involved in inflammatory mechanisms and may affect local blood flow regulation and blood-spinal cord barrier integrity.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Culture Techniques; Dinoprostone; Edema; Hydroxyeicosatetraenoic Acids; Male; Prostaglandins E; Rabbits; Spinal Cord; Spinal Cord Injuries; Thromboxane B2

AA-861, a selective 5-lipoxygenase inhibitor, suppressed A23187-induced formations of 5-HETE and LTB4 in rat peritoneal macrophages. Immunologically-stimulated generation of SRS-A was also inhibited in guinea pig lung and rat peritoneal cavity. AA-861 had no effects on histamine release from rat mast cells or passive cutaneous anaphylaxis in rats. Essentially no antagonistic activity to LTD4 or histamine was observed. This compound exerted an obvious inhibition of allergic bronchoconstriction in guinea pigs and a moderate reduction of carrageenin-induced paw edema and pleurisy in rats. These findings suggest that SRS-A plays an important role in asthmatic and inflammatory reactions.

Topics: Animals; Arachidonate Lipoxygenases; Asthma; Benzoquinones; Edema; Female; Guinea Pigs; Histamine Release; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Macrophages; Male; Mast Cells; Passive Cutaneous Anaphylaxis; Pleurisy; Quinones; Rats; Rats, Inbred Strains; SRS-A