bn-50730 and Disease-Models--Animal

To examine the effect of treatment with the platelet activating factor (PAF) receptor antagonist BN 50730 on the clinical and morphological evolution of collagen induced arthritis in mice.. Mice with collagen induced arthritis were treated with BN 50730 (0.3, 1, 3 mg/kg) or vehicle (0.1% Tween-20 in saline) once a day, from 3 days before the induction of the arthritis to 70 days after. Disease evolution was followed daily by inspection of inflammatory signs and measurement of the knee joint diameter on Days 0, 40, and 70. At the end of the treatment period, the morphological evaluation of the synovial membrane, the immunodetection of fibronectin, and the content of cartilage proteoglycans were studied.. On Day 40, mice receiving the highest dose of BN 50730 (3 mg/kg) showed a reduction in the knee joint diameter in comparison with untreated (2.1 +/- 0.2 vs 2.8 +/- 0.4 mm, p < 0.01). On Day 70, animals receiving 1 and 3 mg/kg had a normal knee diameter, while it remained enlarged in the untreated ones. In BN 50730 treated mice (3 mg/kg) we also observed a significant reduction of the inflammation score (0.1 +/- 0.1 vs 2.5 +/- 0.2 in the untreated) and deposition of fibronectin. Depletion of cartilage proteoglycans was also reversed with BN 50730.. The beneficial effects in this model of joint injury after administration of the PAF antagonist BN 50730 suggest that PAF could be implicated in the pathogenesis of chronic arthritis.

Topics: Animals; Arthritis, Rheumatoid; Azepines; Collagen; Disease Models, Animal; Female; Fibronectins; Immunohistochemistry; Joints; Mice; Mice, Inbred DBA; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Thienopyridines; Triazoles

Electroretinographic exploration is an effective approach to evaluate retinal function. In order to investigate physiopathological mechanisms and evaluate potentially protective therapies for retinal ischemia, we developed three experimental models: the first two on isolated retina, with ischemia induced by either stopping perfusion or clamping the ophthalmic artery, and the third, in vivo, with ischemia induced by ocular hypertonia. Since free radicals are implicated in the formation of post-ischemic lesions, we evaluated the protective effects of drugs known to be free radical scavengers and of an immunomediator antagonist, an anti-PAF (platelet activating factor) agent.

Topics: Analysis of Variance; Animals; Azepines; Dark Adaptation; Disease Models, Animal; Electroretinography; Free Radical Scavengers; Ginkgo biloba; Ischemia; Plant Extracts; Platelet Aggregation Inhibitors; Random Allocation; Rats; Rats, Sprague-Dawley; Retinal Diseases; Thienopyridines; Triazoles

The effect of phosphoramidon on the increase in pulmonary inflation pressure (PIP) induced by endothelin-1 (ET-1) administered by aerosol in ovalbumin (OA)-sensitized and challenged guinea-pigs was investigated after pretreatment or not of the animals with the neutral endopeptidase inhibitor, phosphoramidon, the cyclooxygenase inhibitor, indomethacin or the platelet activating factor (PAF) antagonist, BN 50730. When guinea-pigs were pretreated by phosphoramidon (0.1 mM, aerosol for 15 min), a significant enhancement of PIP was observed after administration of ET-1 (1 or 3 micrograms ml-1, aerosol for 2 min), whereas these doses of the peptide were only slightly active in control animals. In sensitized and unchallenged guinea-pigs, ET-1 (1 or 3 micrograms.ml-1, aerosol for 2 min) induced, as in controls, a moderate increase in PIP. In contrast, aerosol exposure of OA in sensitized guinea-pigs developed an increased PIP following ET-1 (1 and 3 micrograms.ml-1, aerosol for 2 min) administration, that was non significantly affected by pretreatment of the animals with phosphoramidon after the dose of 3 micrograms ml-1 ET-1. Guinea-pigs exposed to phorphoramidon and treated with indomethacin (10 mg kg-1, i.v.) or BN 50730 (25 mg kg-1, per os) significantly reduced the increase in PIP upon administration of ET-1 (3 micrograms.ml-1, aerosol for 2 min). No inhibitory effect of indomethacin was noted when ET-1 (3 micrograms.ml-1, aerosol for 2 min) was administered to sensitized and OA-exposed guinea-pigs, pretreated or not with phosphoramidon. In contrast, BN 50730 significantly reduced the increase in PIP induced by ET-1 observed in sensitized and OA-exposed guinea-pigs. Moreover, this drug was moderately active in reducing the increase in PIP induced by ET-1, when the animals were pretreated by phosphoramidon. These results suggest that a phosphoramidon-sensitive endopeptidase-like enzyme, present in the airway tissue modulates the effect of ET-1. Furthermore, the increase in PIP to ET-1 observed in aerosol-sensitized and antigen-exposed guinea-pigs appears to be mediated by PAF rather than cyclooxygenase metabolites, even though the participation of other mediators in this process is open.

Topics: Aerosols; Animals; Azepines; Bronchi; Disease Models, Animal; Endothelins; Glycopeptides; Guinea Pigs; Immunization; Indomethacin; Lung; Male; Neprilysin; Ovalbumin; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Respiratory Function Tests; Tetrazoles; Thienopyridines; Time Factors; Triazoles

Topics: Acrylates; Allergens; Animals; Azepines; Benzoates; Bronchial Spasm; Disease Models, Animal; Guinea Pigs; Immunization, Passive; Male; Ovalbumin; Phospholipases A; Platelet Activating Factor; Tetrazoles; Thienopyridines; Triazoles