Post-allergen challenge inhibition of poly(ADP-ribose) polymerase harbors therapeutic potential for treatment of allergic airway inflammation.
BACKGROUND
Identifying therapeutic drugs that block the release or effects of T-helper type 2 (Th2) cytokines after allergen exposure is an important goal for the treatment of allergic inflammatory diseases including asthma. We recently showed, using a murine model of allergic airway inflammation, that poly(ADP-ribose) polymerase (PARP) plays an important role in the pathogenesis of asthma-related lung inflammation. PARP inhibition, by single injection of a novel inhibitor, thieno[2,3-c]isoquinolin-5-one (TIQ-A), before ovalbumin (OVA) challenge, prevented airway eosinophilia in C57BL/6 mice with concomitant suppression of Th2 cytokine production and mucus secretion.


OBJECTIVE
To evaluate the efficacy of the drug when it is given after OVA challenge for its possible therapeutic potential.


METHODS
This study was conducted using a murine model of allergic airway inflammation.


RESULTS
A single injection of TIQ-A (6 mg/kg) one or 6 h post-allergen challenge conferred similar reduction in OVA challenge-induced eosinophilia. More significantly, post-allergen challenge administration of the drug exerted even better suppression on the production of IL-4, IL-5, IL-13, and IgE and prevented airway hyperresponsiveness to inhaled-methacholine. The significant decrease in IL-13 was accompanied by a complete absence of airways mucus production indicating a potential protection against allergen-induced airway remodelling.


CONCLUSIONS
The coincidence of the inflammation trigger and the time of drug administration appear to be important for the drug's more pronounced protection. The observed time window for efficacy, 1 or 6 h after allergen challenge may be of great clinical interest. These findings may provide a novel therapeutic strategy for the treatment of allergic airway inflammation, including asthma.
Naura
A S
AS
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Hans
C P
CP
Zerfaoui
M
M
You
D
D
Cormier
S A
SA
Oumouna
M
M
Boulares
A H
AH
D000485:Allergens / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy*; D007546:Isoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000187:drug effects / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000188:drug therapy*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D000485:Allergens; D016207:Cytokines; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013876:Thiophenes; C475227:thieno(2,3-c)isoquinolin-5-one; D010047:Ovalbumin; D011065:Poly(ADP-ribose) Polymerases