Antihistamines and corticoids co-treatment rationale. Potentiation of glucocorticoids anti-inflammatory effects

ZAPPIA C D; SHAYO C; MONCZOR F; FERNANDEZ NATALIA; FITZSIMONS C; SOTO A; GOLDMAN A

Buenos Aires

Congreso; IV International Congress in Translational Medicine; 2018

Facultad de Farmacia y Bioquimica, UBA-Facultad de Medicina, UBA.

Histamine H1 receptor(H1R) antagonists and glucocorticoid receptor (GR) agonists are used to treat manyinflammatory conditions, such as allergic rhinitis and asthma, and theirreceptors are the targets with the greatest number of approved drugs. In manysituations their ligands are co-administered, although this drug associationhas no clear rationale and has arisen from clinical practice. We hypothesized that H1R signaling couldaffect GR-mediated activity, affecting its transcriptional outcome. To test ourhypothesis, we used HEK293T cells co-transfected with plasmids coding for GR,H1R and a GR-responsive luciferase reporter plasmid to study transactivation(TAT3-Luc) or transrepression(IL6-Luc) of responsive genes. Our results show a dual regulation of GRactivity by the H1R: a potentiation mediated by G-protein βγ subunits and aparallel inhibitory effect mediated by Gαq-PLC pathway. Activation of the H1Rby its full agonists resulted in a composite potentiating effect. Intriguingly,inactivation of the Gαq-PLC pathway by H1R inverse agonists resulted also in apotentiation of GR activity. To analyzethe consequences of this modulation, we studied genes involved in inflammatoryprocesses in patho-physiologically relevant cell lines. In lung A549 cells andin promonocytic U937 cells, clinically relevant antihistaminessynergized with the GR agonist dexamethasone to induce gene transactivation (GILZ,MKP1) and transrepression (IL8, COX2and GMCSF). Finally, we testedthe clinical relevance by using Dexamethasone (Dex) and the H1 antihistamineAzelastine (Aze) on a murine model of asthma. Balb/c mice were ip sensitizedand airway challenged with ovoalbumin, and then treated with Dex alone (1 mg/kgoptimal dose or 0.1 mg/kg suboptimal dose) or in combination with 0.5 mg/kgAze. Vehicle and Aze alone-treated mice were used as experimental controls. Wefound that levels ofallergen-specific immunoglobulin IgEand bronchoalveolar lavage eosinophiliawere reduced only in animals treated with 1 mg/kg Dex or co-treated with 0.1 mg/kg Dex + Aze compared to allergic control mice (p<0.05). From atherapeutic point of view, our results suggest that the potentiating effect ofantihistamines on Dex response could result in the reduction of the Dex dosesneeded to reach anti-inflammatory effects, particularly in asthma.