Evaluating the prophylactic potential of the phtalimide derivative LASSBio 552 on allergen-evoked inflammation in rats.

Abstract

A previous study showed that the novel tetrazolephtalimide derivative LASSBio 552 (2-4-[3-(1H-1,2,3,4-tetraazol-5-yl)propoxy]phenethyl-1,3-isoindolinedione) prevents LTD(4)-evoked tracheal contraction. This led us to examine the putative anti-inflammatory effect of LASSBio 552 in comparison with the leukotriene CysLT(1) receptor antagonist zafirlukast using a model of allergic pleurisy in rats. Treatment with either LASSBio 552 (24-96 micromol/kg, i.p.) or zafirlukast (9-72 micromol/kg, i.p.), 1 h before challenge, inhibited eosinophil and mononuclear cell influx into the pleural cavity 24 h post-challenge, but failed to alter the increased levels of eotaxin, plasma leakage, mast cell degranulation and neutrophil infiltration noted 6 h post-challenge. CD4(+) T cell recruitment 24 h post-challenge was also sensitive to LASSBio 552. This treatment failed to alter cysteinyl leukotriene production at 6 h, but clearly inhibited the phenomenon 24 h and 48 h post-challenge. In in vitro settings LASSBio 552 inhibited allergen-evoked cysteinyl leukotriene generation from isolated mast cells, while histamine release remained unchanged. It also slightly inhibited cysteinyl leukotriene production by eosinophils and mononuclear cells triggered by Ca(+2) ionophore A23187. A leukotriene CysLT(1) receptor transfected cell-based assay revealed that LASSBio 552 did not prevent LTD(4)-evoked Ca(+2) influx, indicating that it was not a leukotriene CysLT(1) receptor antagonist. These findings indicate that LASSBio 552 is able to inhibit eosinophil influx triggered by allergen chalenge in a mechanism at least partially associated with suppression of CD4(+) T cell influx and cysteinyl leukotriene production.

• Authors: Josiane S Neves, Lídia M Lima, Carlos A M Fraga, Eliezer J Barreiro, Ana L P Miranda, Bruno L Diaz, Alex Balduino, Rodrigo de Azeredo Siqueira, Patrícia M R e Silva, Marco A Martins
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 511 Issue 2-3 Pg. 219-27 (Mar 28 2005) ISSN: 0014-2999 [Print] Netherlands
• PMID: 15792791 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-4-(3-(1H-1,2,3,4-tetraazol-5-yl)propoxy)phenethyl-1,3-isoindolinedione
• Allergens
• Anti-Asthmatic Agents
• Ccl11 protein, rat
• Chemokine CCL11
• Chemokines, CC
• Indoles
• Isoindoles
• Leukotrienes
• Membrane Proteins
• Phenylcarbamates
• Receptors, Leukotriene
• Sulfonamides
• Tetrazoles
• Tosyl Compounds
• cysteinyl-leukotriene
• Leukotriene D4
• Cysteine
• leukotriene D4 receptor
• Calcium
• zafirlukast

Topics

• Allergens (immunology)
• Animals
• Anti-Asthmatic Agents (pharmacology)
• CD4-Positive T-Lymphocytes (cytology, drug effects)
• CHO Cells
• Calcium (metabolism)
• Cell Movement (drug effects)
• Chemokine CCL11
• Chemokines, CC (biosynthesis)
• Cricetinae
• Cricetulus
• Cysteine (metabolism)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Eosinophils (cytology, drug effects)
• Female
• Indoles (chemistry, pharmacology)
• Inflammation (immunology, prevention & control)
• Isoindoles
• Leukotriene D4 (pharmacology)
• Leukotrienes (metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Phenylcarbamates
• Pleura (drug effects, immunology)
• Pleurisy (immunology, metabolism, prevention & control)
• Rats
• Rats, Wistar
• Receptors, Leukotriene (genetics, metabolism)
• Sulfonamides
• Tetrazoles (chemistry, pharmacology)
• Tosyl Compounds (pharmacology)
• Transfection