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PubMed2003

Effect of selective vs. non-selective cyclo-oxygenase inhibitors on fetal membrane prostaglandin synthesis.

Increased expression of the inducible isoform of cyclo-oxygenase (COX-2) and prostaglandin output from fetal membranes is a key stage in human parturition. Prostaglandin production can be inhibited by non-steroidal anti-inflammatory drugs (NSAIDs), but these may also inhibit cyclo-oxygenase enzymes in fetal tissues, and hence cause potentially serious side effects. We have compared the concentrations of NSAIDs that inhibit maximal PGE2 synthesis from intact human fetal membrane explants in vitro with those found in human plasma after standard anti-inflammatory treatment. The concentrations of all six drugs that caused a 50% inhibition of fetal membrane prostaglandin output were lower than average plasma levels achieved during treatment. This effect was greatest for nimesulide and indomethacin, indicating that these drugs require further study at low doses in vivo, as this could achieve the same tocolytic effect with diminished adverse fetal effect. These drugs were also the most potent inhibitors of fetal membrane prostaglandin output, consistent with their effects on COX-2 activity.

Adult↗
PubMed1993

Inhibition of intercellular communication in rat hepatocytes by phenobarbital, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and gamma-hexachlorocyclohexane (lindane): modification by antioxidants and inhibitors of cyclo-oxygenase.

Several tumour promoting chemicals have been shown to inhibit intercellular communication (IC) through gap junctions in cell cultures. In the present investigation we studied the effect of the hepatic tumour promoters phenobarbital (PB), 1,1,1-trichloro-2,2-(p-chlorophenyl)ethane (DDT) and gamma-hexachlorocyclohexane (lindane) on IC in rat hepatocyte cultures. IC was evaluated by microinjection of fluorescent Lucifer Yellow CH dye and visualization of dye spread to adjacent hepatocytes. Incubation of hepatocytes with PB (2 mM), DDT (30 microM) and lindane (25 microM) decreased dye-coupling of the cells by about 30%, 42% and 35%, respectively; dye-coupling in untreated cultures was 88.1 +/- 0.7%. Inhibition of IC was reversible when the xenobiotics were removed from the medium. The antioxidant vitamin E (100 microM) prevented inhibition of dye-coupling by PB and lindane and partially that by DDT. Superoxide dismutase (100 units/microliters) counteracted the effect on dye-coupling by PB, but not that by the insecticides. Similarly, the cyclo-oxygenase inhibitors indomethacin and aspirin only reversed the effect of PB on IC, but not that of DDT or lindane. As indicated by further experiments, prevention by non-steroidal anti-inflammatory agents of PB-induced inhibition of IC is most likely not mediated by inhibition of cyclo-oxygenase. The results indicate significant differences in the action of PB, DDT and lindane on IC in hepatocyte cultures. This is suggested by the differential effects of superoxide dismutase and non-steroidal anti-inflammatory agents on the action of the three tumour promoting chemicals. Whereas superoxide radicals may be involved in the inhibition of dye-coupling by PB, radical intermediates of the insecticides may be responsible for the decrease in dye-coupling by DDT and lindane.

Animals↗
PubMed1996

Inhibition by acetylsalicylic acid, a cyclo-oxygenase inhibitor, and p-bromophenacylbromide, a phospholipase A2 inhibitor, of both cirrhosis and enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats.

Effects of inhibitors of arachidonic acid (AA) metabolism on the development of fatty liver, cirrhosis, glutathione-S-transferase placental form (GST-P)-positive nodules and the generation of 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid-reactive substances (TBARS), caused by a choline-deficient, L-amino acid-defined (CDAA) diet, were examined in male Fischer 344 rats by feeding CDAA diets supplemented with the inhibitors for 12 and 30 weeks. Acetylsalicylic acid (ASA) (at doses of 0.1 and 0.2%) and p-bromophenacylbromide (BPB) (0.1 and 0.2%) were used as inhibitors of, respectively, cyclo-oxygenase and phospholipase A2, and quercetin (QU) (0.75 and 1.5%) and nordihydroguaiaretic acid (NDGA) (0.1 and 0.2%) as inhibitors of lipoxygenase. None of the inhibitors affected the development of fatty liver caused by the CDAA diet. ASA at a doe of 0.2% almost completely prevented the appearance of cirrhosis, GST-P-positive nodules, 8-OHdG and TBARS in seven out of 11 (63.7%) rats. BPB at a dose of 0.2% also exerted inhibitory effects on all of these lesions but to a lesser extent than ASA. QU and NDGA exerted inhibitory effects limited to the GST-P-positive nodule case. The results indicate that a perturbed AA metabolism, particularly of the cyclo-oxygenase pathway, derived secondarily from depletion of labile methyl groups or phosphatidylcholine, might play key roles in the cirrhosis, hepatocarcinogenesis and oxidative stress caused by a CDAA diet. The results also indicated a possible involvement of the lipoxygenase pathway in hepatocarcinogenic processes.

Acetophenones↗
PubMed2006

Cyclo-oxygenase inhibition restores the attenuated vasodilation in manganese-deficient rat aorta.

Previously we showed that manganese (Mn) deficiency enhances the arterial contractile response to alpha(1) adrenergic stimuli and affects vasomotor tone. The aim of this study was to test the hypothesis that dietary Mn deficiency inhibits the vasodilation pathways of rat aorta. Vascular ring studies were conducted in aortic rings from weanling male Sprague-Dawley rats that were fed either a Mn deficient (MnD) or a Mn adequate/control diet (MnA) (<1 and 12 mg/kg Mn, respectively) for a 14-wk period. We investigated endothelium-dependent vasodilation induced by acetylcholine (Ach; 10(-8) to 3 x 10(-6) mol/L) in isolated 3-mm aortic rings precontracted with l-phenylephrine (l-Phe; 10(-6) mol/L). Seven concentrations of Ach were used in the presence or absence of inhibitors of nitric oxide synthase and cyclo-oxygenase. After a second precontraction, 8 doses of sodium nitroprusside (SNP; 10(-8) to 10(-5) mol/L) were added to assess endothelium-independent vasodilation. We observed a decrease in Ach-induced and SNP-induced vasodilation in MnD rat aortas when compared with MnA rat aortas (P </= 0.05). Vessel sensitivity of MnD and MnA aortas to Ach was similar. The addition of l-arginine had no effect on nitric oxide-mediated vasodilation in either group. Nitric oxide synthase-inhibition blunted endothelium-dependent vasodilation to the same degree for both diet groups. Cyclo-oxygenase inhibition enhanced both Ach-induced and SNP-induced vasodilation of MnD rings compared with MnA aortic rings (P </= 0.05). Manganese inhibits the synthesis or activity of a prostanoid-derived vasoconstrictor, which seems to be present at basal and at stimulated levels. This effect is independent of membrane-related events. Our results provide further information on the critical role of Mn on vasomotor tone.

Acetylcholine↗
PubMed1999

Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequences for nonsteroidal antiinflammatory drug efficacy.

Prostanoids produced via the action of cyclo-oxygenase-2 (COX-2) appear central to many inflammatory conditions. Here we show in LPS-treated rats, however, that COX-2 induction alone does not greatly increase prostanoid production in vivo. For this, a second, arachidonic acid liberating stimulus is also required. Thus, only after intravenous injection of bradykinin or exogenous arachidonic acid was a marked increase in prostanoid formation seen. There is, therefore, synergy between proinflammatory mediators: both induction of COX-2 protein and an increase in the supply of arachidonic acid are required to greatly enhance prostanoid production. Second, we show that supplying arachidonic acid to increase prostanoid production reduces the effectiveness of both currently used nonsteroidal antiinflammatory drugs (NSAIDs) (diclofenac) and novel COX-2-selective inhibitors (NS-398, celecoxib) as inhibitors of COX-2 activity. Our data lead to two important conclusions. First, increased prostanoid production in inflammation is a two-component response: increased COX-2 expression and increased arachidonic acid supply. Second, the supply of arachidonic acid to COX-2 determines the effectiveness of NSAIDs. NSAIDs and selective COX-2 inhibitors, therefore, will generally be less effective at more inflamed sites, providing a rationale for the very high doses of NSAIDs required in human conditions such as rheumatoid arthritis.--Hamilton, L. C., Tomlinson, A. M., Mitchell, J. A., Warner, T. D. Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequences for nonsteroidal antiinflammatory drug efficacy.

Animals↗
PubMed1997

Carrageenan-induced hyperalgesia is associated with increased cyclo-oxygenase-2 expression in spinal cord.

The discovery of the inducible form of cyclo-oxygenase, known as cyclo-oxygenase-2 (COX-2), has provided insight into the mechanisms involved in the inflammatory response. Peripheral inflammation induced by intraplantar injection of carrageenan is associated with a marked increase in COX-2 mRNA and prostaglandins in the surrounding tissue and the accompanying oedema is sensitive to COX-2-selective drugs. In this study, we investigated whether COX-2 in spinal cord was similarly induced by carrageenan and whether the associated development of altered pain sensitivity, hyperalgesia was affected by the COX-2 selective inhibitor DuP 697. Intraplantar injection of carrageenan caused a marked hyperalgesia at 4 h which was significantly attenuated by treatment with DuP 697 (10 mg kg-1). At the same time levels of COX-2 mRNA in lumbar spinal cord were significantly increased two-fold by carrageenan treatment. However, DuP 697 potentiated COX-2 mRNA induction, which indicates the existence of a potential regulatory mechanism to overcome COX-2 inhibition.

Animals↗
PubMed1983

Purification and Characterization of a New Indole Oxygenase from the Leaves of Tecoma stans L.

A new indole oxygenase from the leaves of Tecoma stans was isolated and purified to homogenity. The purified enzyme system catalyzes the conversion of indole to anthranilic acid. It is optimally active at pH 5.2 and 30 degrees C. Two moles of oxygen are consumed and one mole of anthranilic acid is formed for every mole of indole oxidized. Dialysis resulted in complete loss of the activity. The inactive enzyme could be reactivated by the addition of concentrated dialysate. The enzyme is not inhibited by copper-specific chelators, non-heme iron chelators or atebrin. It is not a cuproflavoprotein, unlike the other indole oxygenases and oxidases.

Journal Article↗
PubMed1987

Role of oxygenases in pisatin biosynthesis and in the fungal degradation of maackiain.

Some isolates of the plant pathogen Nectria haematococca detoxify the isoflavonoid phytoalexin (-)maackiain by hydroxylation at carbon 6a. Precursor feeding studies strongly suggest that the penultimate step in (+)pisatin biosynthesis by Pisum sativum is 6a-hydroxylation of (+)maackiain. We have used (18)O labeling to test the involvement of oxygenases in these two reactions. When fungal metabolism of maackiain took place under (18)O(2), the product was labeled with 99% efficiency; no label was incorporated by metabolism in H(2) (18)O. Pisatin synthesized by pea pods in the presence of (18)O(2) or H(2) (18)O was a mixture of molecules containing up to three labeled oxygen atoms. Primary mass spectra of such mixtures were complex but were greatly simplified by tandem MS. This analysis indicated that the 6a oxygen of pisatin was derived from H(2)O and not from O(2). Labeling patterns for the other five oxygen atoms were consistent with the proposed pathway for biosynthesis of pisatin and related isoflavonoids. We conclude that the fungal hydroxylation of maackiain is catalyzed by an oxygenase, but the biosynthetic route to the 6a hydroxyl of pisatin is unknown.

Journal Article↗
PubMed2006

Crystallization and preliminary X-ray diffraction studies of the terminal oxygenase component of carbazole 1,9a-dioxygenase from Nocardioides aromaticivorans IC177.

Carbazole 1,9a-dioxygenase (CARDO) catalyzes the dihydroxylation of carbazole by angular-position (C9a) carbon bonding to the imino nitrogen and its adjacent C1 carbon. CARDO consists of a terminal oxygenase component and two electron-transfer components: ferredoxin and ferredoxin reductase. The terminal oxygenase component (43.9 kDa) of carbazole 1,9a-dioxygenase from Nocardioides aromaticivorans IC177 was crystallized at 293 K using the hanging-drop vapour-diffusion method with PEG 8000 as the precipitant. The crystals diffract to 2.3 A resolution and belong to space group C2.

Bacterial Proteins↗
PubMed2006

Outcome of peptic ulcer bleeding among users of traditional non-steroidal anti-inflammatory drugs and selective cyclo-oxygenase-2 inhibitors.

BACKGROUND: Few data exist on the impact of non-steroidal anti-inflammatory drug use on peptic ulcer outcome. AIM: To examine the 30-day mortality from peptic ulcer bleeding associated with the use of traditional non-steroidal anti-inflammatory drugs and newer selective cyclo-oxygenase-2 inhibitors. METHODS: Cohort study of patients with a first hospitalization for peptic ulcer bleeding in three Danish counties between 1991 and 2003. Data on pre-admission non-steroidal anti-inflammatory drug use, use of other ulcer-related drugs and comorbidities were obtained from population-based registries. Follow-up data on mortality were obtained from the Danish Civil Registry System. RESULTS: Of 7,232 patients hospitalized for peptic ulcer bleeding, 28% were current non-steroidal anti-inflammatory drug users. Thirty-day mortality was 11% overall, and 13% among current non-steroidal anti-inflammatory drug users. Compared with never-use, the adjusted 30-day mortality rate ratios were 1.4 (95% CI: 1.1-1.9) for current use of non-steroidal anti-inflammatory drugs alone and 1.3 (95% CI: 1.0-1.7) for current use combined with other ulcer-related drugs. For users of celecoxib, alone and in combination, adjusted mortality rate ratios were 1.4 (95% CI: 0.5-3.9) and 2.0 (95% CI: 1.2-3.5), and for users of rofecoxib, 1.2 (95% CI: 0.4-3.9) and 0.9 (95% CI: 0.5-1.6). CONCLUSION: Among patients hospitalized with peptic ulcer bleeding, use of non-steroidal anti-inflammatory drugs, including some newer cyclo-oxygenase-2 inhibitors, is associated with increased short-term mortality.

Aged↗
PubMed1988

The in vitro 5-lipoxygenase and cyclo-oxygenase inhibitor L-652,343 does not inhibit 5-lipoxygenase in vivo in human skin.

1 3-hydroxy-5-trifluoromethyl-N-[2-(2-thienyl)-2-phenyl-ethenyl]-benzo(B) thiophene-2-carboxamide (L-652,343) is a 5-lipoxygenase and cyclo-oxygenase inhibitor in vitro. 2 In psoriasis increased concentrations of arachidonic acid transformation products are found in the lesional skin which may be important in the pathogenesis of the disease. We have measured the effect of orally administered L-652,343 on the concentration of LTB4 and prostaglandins in the lesional skin. 3 Eight patients with stable chronic plaque psoriasis received 500 and 250 mg of L-652,343, 12 h apart. A chamber technique was used to collect skin exudate samples from abraded plaques before and at 4, 24 and 48 h after the first dose. Exudates were analysed for LTB4 by a neutrophil chemokinesis assay and for PGE2 and PGD2 by RIA. 4 PGE2 and PGD2 levels were significantly reduced at 4 and 24 h after the first dose of L-652,343 but LTB4 levels were not affected indicating inhibition of the cyclo-oxygenase pathway but not of the 5-lipoxygenase pathway. This shows the importance of confirming that the action of 5-lipoxygenase inhibiting drugs in vitro occurs in vivo.

Adult↗
PubMed2005

Effect of naproxen, a non-selective cyclo-oxygenase inhibitor, on pentylenetetrazol-induced kindling in mice.

1. Epilepsy is one of the major neurological disorders of the brain, affecting approximately 0.5-1.0% of the population worldwide. Various neurotransmitter abnormalities, especially of GABA and glutamate, have been reported to play a key role in the pathophysiology of epilepsy. 2. Cyclo-oxygenase (COX) is the rate-limiting enzyme in the production of prostaglandins and, as such, is a key target for many anti-inflammatory drugs. Cyclo-oxygenase has been reported to play a significant role in neurodegeneration. Recent studies have reported that COX plays a significant role in the pathophysiology of epilepsy. 3. The aim of the present study was to explore the possible role of COX and the effect of COX inhibitors in epilepsy. 4. Kindling is a chronic model of epilepsy. In the present study, kindling was induced in mice by chronic administration of a subconvulsive dose of pentylenetetrazole (PTZ; 40 mg/kg) on every other day for a period of 15 days. Naproxen was administered daily 45 min before PTZ or vehicle. The kindling score was recorded after PTZ administration. Seizure severity was measured according to a prevalidated scoring scale. Biochemical estimations were performed immediately after recording behavioural parameters on the 16th day of PTZ treatment. 5. Chronic treatment with PTZ significantly induced kindling in mice. Pretreatment with the non-selective COX inhibitor naproxen (7 and 14 mg/kg, i.p.) showed significant protection against PTZ-induced kindling in mice. Biochemical analysis revealed that chronic treatment with PTZ significantly increased lipid peroxidation and nitrite levels (NO levels), but decreased reduced glutathione (GSH) levels in brain homogenates. 6. In conclusion, the results of the present study strongly suggest that COX plays an important role in the pathophysiology of PTZ-induced kindling in mice and that COX inhibitors could be a useful neuroprotective strategy for the treatment of epilepsy.

Animals↗
PubMed1992

Microvascular leakage induced by substance P in rat urinary bladder: involvement of cyclo-oxygenase metabolites of arachidonic acid.

1. Intravenous administration of substance P (SP) or of the NK1 selective agonist [beta-Ala4, Sar9, Met (O2)11] SP-(4-11) increased vascular permeability in the urinary bladder of urethane-anaesthetized rats, providing evidence for an NK1 receptor-mediated inflammatory response. 2. BW 755C, a dual inhibitor of arachidonate cyclo-oxygenase and lipoxygenase, significantly reduced the plasma extravasation induced by SP, but did not modify the effect of [beta-Ala4, Sar9, Met (O2)11] SP-(4-11). 3. SP-induced microvascular leakage was also inhibited by systemic pretreatment with indomethacin or with the prostaglandin receptor antagonist SC-19220, while it was unaffected by the selective 5-lipoxygenase inhibitor BW A4C or the leukotriene antagonist FPL 55712. 4. Pretreatment of rats with the mast cell degranulating agent compound 48/80 significantly attenuated the inflammatory effect of SP. Indomethacin administration to 48/80-pretreated animals failed to produce further inhibition. 5. These findings indicate that intravascular SP promotes plasma exudation in rat urinary bladder through an NK1-mediated effect on venular permeability and the release of cyclo-oxygenase metabolites of arachidonic acid. The latter effect largely derives from the interaction of the neuropeptide with mast cells.

Animals↗
PubMed1993

The effects of evening primrose oil on nerve function and capillarization in streptozotocin-diabetic rats: modulation by the cyclo-oxygenase inhibitor flurbiprofen.

1. The aims of this study were first, to examine whether deficits in nerve conduction in streptozotocin-diabetic rats could be reversed by a 10% dietary supplement of evening primrose oil. Second, to determine the time-course of reversal, and third, to assess whether the effects could be blocked by the cyclo-oxygenase inhibitor flurbiprofen (5 mg kg-1 day-1). 2. One-month diabetes produced 20% and 15% deficits in sciatic motor and saphenous sensory conduction velocity respectively, which were maintained over 2 months diabetes. 3. The effect of 1-month evening primrose oil treatment on abnormalities caused by an initial month of untreated diabetes was examined. Motor and sensory nerve conduction velocity were restored to the non-diabetic level. 4. Resistance to hypoxic conduction failure was investigated for sciatic nerve trunk in vitro. The 80% conduction failure times were 29% and 55% prolonged by 1- and 2-month diabetes respectively. Evening primrose oil did not reverse the increased hypoxic resistance following 1-month untreated diabetes. 5. Sciatic nerve endoneurial capillary density was not significantly affected by diabetes, but was 16% increased in diabetic rats with reversal by evening primrose oil treatment for 1 month compared to 2-month untreated diabetes. 6. Serial motor conduction velocity measurement after 3-month untreated diabetes revealed complete normalization by evening primrose oil within 4 days. Cessation of treatment resulted in a rapid decline in conduction velocity over 24 h. 7. In a preventive study of 2-month duration, 6 groups of rats were used. These comprised non-diabetic controls, diabetic rats, and evening primrose oil-treated diabetic rats, both with and without flurbiprofen treatment. Flurbiprofen had no significant effect in non-diabetic rats, but produced an 11% worsening of motor conduction velocity and a 21% reduction of sciatic capillary density in diabetic rats. Evening primrose oil prevented the decreases in conduction velocity and increased hypoxic resistance with diabetes, and caused a 23% increase in capillary density. Flurbiprofen completely blocked the effect of evening primrose oil on conduction velocity, resistance to hypoxia, and capillarization.8. Six main conclusions were reached. First, evening primrose oil rapidly reverses conduction deficits in diabetic rats. Second, the effects of treatment may be very short-lived, suggesting a primary metabolic action. Third, evening primrose oil cannot reverse established changes in hypoxic resistance over 1-month treatment. Fourth, long-term treatment causes angiogenesis, suggesting a vascular action. Fifth,products of cyclo-oxygenase-mediated metabolism are necessary for maintaining vasa nervorum integrity in diabetic rats. Sixth, evening primrose oil probably acts by providing substrate for vasodilator prostanoid synthesis by vasa nervorum.

Action Potentials↗
PubMed1994

Induction of cyclo-oxygenase-2 by cytokines in human pulmonary epithelial cells: regulation by dexamethasone.

1. Cyclo-oxygenase metabolizes arachidonic acid to prostaglandin H2 (PGH2) and exists in at least two isoforms. Cyclo-oxygenase-1 (COX-1) is expressed constitutively whereas COX-2 is induced by lipopolysaccharide (LPS) and some cytokines in vitro and at the site of inflammation in vivo. Epithelial cells may be an important source of prostaglandins in the airways and we have, therefore, investigated the expression of COX-1 or COX-2 isoforms in primary cultures of human airway epithelial cells or in a human pulmonary epithelial cell line (A549). 2. COX-1 or COX-2 protein was measured by western blot analysis using specific antibodies to COX-2 and selective antibodies to COX-1. The activity of COX was assessed by the conversion of either endogenous or exogenous arachidonic acid to four metabolites, PGE2, PGF2 alpha, thromboxane B2 or 6-oxo PGF1 alpha measured by radioimmunoassay. Thus, COX-1 or COX-2 activity was measured under two conditions; initially the accumulation of the COX metabolites formed from endogenous arachidonic acid was measured after 24 h. In other experiments designed to measure COX activity directly, cells were treated with cytokines for 12h before fresh culture medium was added containing exogenous arachidonic acid (30 microM) for 15 min after which COX metabolites were measured. 3. Untreated primary cells or A549 cells contained low amounts of COX-1 or COX-2 protein. Bacterial LPS (1 micro g ml-1 for 24 h) induced COX-2 protein in the primary cells, a process which was enhanced by interferon-gamma, with no further increase in the presence of a mixture of cytokines (interleukin-1 beta, tumour necrosis factor-alpha and interferon-gamma, 10 ng ml-1 for all). In contrast, A549 cells contained only low levels of COX-2 protein after exposure to LPS or LPS plus interferon-y, but contained large amounts of COX-2 protein after exposure to the mixture of cytokines.4. Untreated human pulmonary primary cells or A549 cells released low levels of all COX metabolites measured over a 24 h incubation period. This release was enhanced by treatment of either cell type with the mixture of cytokines (interleukin-1 beta , tumour necrosis factors- and interferon-gamma, 10 ng ml-1 for all).PGE2 was the principal COX metabolite released by cytokine-activated epithelial cells. The release of PGE2 induced by cytokines occurred after a lag period of more than 6 h.5. The glucocorticosteroid, dexamethasone (1 micro M; 30 min prior to cytokines) completely suppressed the cytokine-induced expression of COX-2 protein and activity in both primary cells and A549 cells.6. In experiments where COX-2 activity was supported by endogenous stores of arachidonic acid,treatment of A549 cells with interleukin-l beta but not tumour necrosis factor a or interferon-gamma alone caused a similar release of PGE 2 to that seen when the cytokines were given in combination. However, both interleukin-l beta and necrosis factor- alone produced similar increases in COX-2 activity (measured in the presence of exogenous arachidonic acid) as seen when the mixture of interleukin-l beta, tumour necrosis factor- alpha and interferon-gamma were used to stimulate the cells.7. These findings show that COX-2 expression correlates with the exaggerated release of prostaglandins from cytokine-activated human pulmonary epithelial cells and that the induction of the enzyme is suppressed by a glucocorticosteroid. These findings may be relevant to inflammatory diseases of the lung, such as asthma.

Arachidonic Acid↗
PubMed1989

Suppression of experimental autoimmune encephalomyelitis by dual cyclo-oxygenase and 5-lipoxygenase inhibition.

The release of leukotriene C4 (LTC4), an important 5-lipoxygenase product of the arachidonic acid metabolism from polymorphonuclear leucocytes (PMNLs) of guinea pigs with experimental allergic encephalomyelitis (EAE), the animal model of MS, has been found to be significantly increased compared with healthy animals. Subsequently, the dual cyclo-oxygenase and 5-lipoxygenase inhibitor BW755C was applied to 15 guinea pigs with EAE. Two control groups (15 each) were treated with the cyclo-oxygenase inhibitor indomethacin or physiological saline, respectively. In the BW755C treated group, no animal developed symptoms of the disease in contrast to, respectively, 5 and 3 animals in the 2 other groups. Histological examination of the CNS revealed a highly significantly lower inflammation score in the BW755C treated animals, and the release of LTC4 from PMNLs was highly significantly decreased in this group compared with each of the others. The findings suggest that the vascular permeability enhancing LTC4 plays a pathogenetic role in EAE and indicate that inhibition of this sulfidopeptide leukotriene suppresses the disease. Therefore, the application of leukotriene inhibitors could contribute to the future treatment of MS.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Platelet cyclo-oxygenase deficiency in a Japanese.

A case of platelet cyclo-oxygenase deficiency in a Japanese was investigated. There was a marked decrease of aggregation with collagen and absence of aggregation with epinephrine and arachidonic acid. The platelet response to a labile aggregation stimulating substance (LASS) was normal. There was no biosynthesis of prostaglandin endoperoxides from arachidonate. The platelets, including granular volume, showed no ultrastructural abnormalities. The responses to various inducers of platelet aggregation, except for arachidonate, were different from the cases described by others. It is concluded that the defective platelet function, due to a deficiency of platelet cyclo-oxygenase, is heterogeneous.

Adult↗
PubMed1983

Cyclo-oxygenase inhibition by indomethacin and recirculation following cerebral ischemia.

In this study we examined the effect of pretreatment with the cyclo-oxygenase inhibitor indomethacin (10 mg . kg-1) on local cerebral blood flow (DBF) in the immediate recirculation period following complete and incomplete ischemia. Ischemia of 15 min duration was induced in lightly anaesthetized and artificially ventilated rats, and local CBF was measured with a 14C-iodoantipyrine autoradiographic technique after recirculation periods of 5 min. Following complete ischemia indomethacin-treated animals showed a reduced incidence of perfusion defects of the "no-reflow" type. Perfused structures had somewhat higher flow rates than in untreated rats. A similar enhancement of immediate reflow was observed following incomplete ischemia provided that the structures in question had been severely ischemic. In structures that suffered only mild ischemia, the drug reduced postischemic CBF. It is concluded that, in the rat brain, cyclo-oxygenase inhibition does not curtail postischemic reactive hyperemia. Furthermore, the previously reported beneficial effect of indomethacin on brain circulation following complete ischemia seems to be due to an enhancement of immediate reflow, and to amelioration of an initial hindrance to reflow.

Animals↗