Abstract

Poly(ADP-ribose) polymerase-1(PARP-1), plays an important role in the tissue injury in conditions associated with oxidative stress and inflammation. Oxidative and nitrosative stress can trigger DNA strand breakage, and activates the nuclear enzyme PARP-1. Since free radicals are involved in the pathogenesis of asthma [1], we aimed at evaluating the effects of the inhibition of PARP-1 activity on the antigen-induced bronchospasm in a model of allergic asthma in sensitized guinea pigs. Male albino guinea pigs sensitized with ovalbumin (OVA), were placed in whole body respiratory chambers and challenged with OVA. 3 aminobenzamide (3AB, 1 g/kg b.w.) or 5 aminoisoquinolinone (5-AIQ, 0.5 mg/kg b. w.) were given i.p. 3 hours before OVA challenge or by aerosol (10 mg/ml or 0.5 mg/ml respectively) 30 min before OVA challenge.The following parameters were recorded: latency time in bronchocostriction; cough severity score and onset of respiratory failure. The spasm latency in response to OVA aerosol is rather high in naive animals, while it decreases sharply in sensitised animals. Treatment with 3AB or with 5-AIQ, i.p or per aerosol, significantly reduced severity of cough and delayed appearance of bronchial spasm and respiratory failure. Furthermore, both compounds were able to prevent bronchiolar constriction and pulmonary air space inflation and to decrease myeloperoxidase activity and mast cell degranulation in lung tissue. These findings provide the first evidence that the PARP-1 inhibitors can counteract neutrophil- and mast cell-mediated acute allergic bronchospasm in actively sensitized guinea pigs and suggest a possible future use of these drugs in asthma. References: 1.Barnes PJ: Reactive oxygen species and airway inflammation. Free Radic Biol Med, 1990; 9: 235-243

Keywords: PARP-1, 3-aminobenzamide, 5-aminoisoquinolinone, allergic bronchospasm, guinea pig