Evaluating the prophylactic potential of the phtalimide derivative LASSBio 552 on allergen-evoked inflammation in rats.
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.
Neves
Josiane S
JS
Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz-FIOCRUZ, Av. Brasil 4365, Caixa Postal 926, Rio de Janeiro, Brazil.
Lima
Lídia M
LM
Fraga
Carlos A M
CA
Barreiro
Eliezer J
EJ
Miranda
Ana L P
AL
Diaz
Bruno L
BL
Balduino
Alex
A
Siqueira
Rodrigo de Azeredo
Rde A
e Silva
Patrícia M R
PM
Martins
Marco A
MA
D000485:Allergens / Q000276:immunology*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000096:biosynthesis; D006224:Cricetinae; D003412:Cricetulus; D003545:Cysteine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D005260:Female; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D054833:Isoindoles; D017998:Leukotriene D4 / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D048448:Phenylcarbamates; D010994:Pleura / Q000187:drug effects / Q000276:immunology; D010998:Pleurisy / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000494:pharmacology; D014162:Transfection
C502306:2-4-(3-(1H-1,2,3,4-tetraazol-5-yl)propoxy)phenethyl-1,3-isoindolinedione; D000485:Allergens; D018927:Anti-Asthmatic Agents; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D019742:Chemokines, CC; D007211:Indoles; D054833:Isoindoles; D015289:Leukotrienes; D008565:Membrane Proteins; D048448:Phenylcarbamates; D018077:Receptors, Leukotriene; D013449:Sulfonamides; D013777:Tetrazoles; D014105:Tosyl Compounds; C112381:cysteinyl-leukotriene; D017998:Leukotriene D4; D003545:Cysteine; C083169:leukotriene D4 receptor; D002118:Calcium; C062735:zafirlukast