Estudo dos mecanismos imunomoduladores do alcaloide sintético MHTP na Síndrome da Asma e Rinite Alérgica Combinadas (CARAS) experimental induzida por ovalbumina

Abstract

Combined Allergic Rhinitis and Asthma Syndrome (CARAS) is a chronic inflammatory disease of the respiratory tract of atopic individuals. In CARAS the type 2 immune response predominates. In the clinic, the therapeutic classes used promote adverse reactions, such as glaucoma and sedation, which compromise the quality of life of individuals. Thus, it is necessary to search for molecules with therapeutic potential for the treatment of CARAS. In this context, the synthetic alkaloid MHTP [2-methoxy-4- (7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) phenol] has low preclinical acute toxicity (LD50> 1,000 mg/kg), without genotoxicity, antiedematogenic and anti-inflammatory activity, in models of acute inflammation dependent on the negative modulation of the TLR4-p38MAPK/NF-κB(p65) signaling pathway. In a model of allergic pulmonary inflammation, the levels of TCD4+ cells decreased. The objective of this work was to investigate the immunomodulatory mechanisms of treatment with MHTP, by intranasal (in) or oral (vo) routes, in the experimental model of CARAS induced by ovalbumin (OVA). For this purpose, female BALB/c mice were sensitized with OVA on days 0 and 7 and from days 21 to 37, for three consecutive days a week they were challenged with OVA by nasal instillation. From the 38th to the 42nd day, they were challenged with an OVA aerosol. The treatment took place one hour before each challenge and on the 43rd day of the protocol, biological material was collected. Clinical signs were quantified after the last weekly challenge and after the last aerosol challenge. Nasal reactivity induced by histamine was performed on the 37th day. The treatment of healthy animals with MHTP (in or vo pathways) did not alter the animals' physiological parameters. Animals with CARAS treated with the alkaloid (in or vo) showed a reduction (p <0.05) of clinical signs (sneezing and nasal friction); in nasal hyper-reactivity to histamine; in the migration of total cells and mostly eosinophils in the nasal (NALF) and bronchoalveolar (BALF) fluids; in inflammation and in the overproduction of mucus in the nasal and pulmonary cavities; bronchial hyperreactivity and pulmonary tissue remodeling; serum levels of total and OVA-specific IgE; in cytokine levels, in BALF: IL-33, TSLP, IL-4, IL-13, IL-5, TGF-β and IL-17. MHTP increased the levels of INF-γ and consequently the IFN-γ / IL-4 ratio. The frequency of activation of MAPK p-ERK1/2 and p-p38 in granulocytes and lymphocytes was reduced by treatment with MHTP as well as NF-κB(p65) in lymphocytes. Oral MHTP increased levels of IL-10. The results obtained in the present study propose that the MHTP immunomodulatory mechanisms, regardless of the route of administration (in or vo), are related to the negative modulation of MAPK (ERK1/2 and p38) in granulocytes and lymphocytes and NF-κB(p65) in lymphocytes which led to the suppression of the pathological condition of CARAS. In addition, the regulation of the TH2 profile by the TH1 profile was observed in both routes of administration of MHTP and by the oral route the alkaloid also promoted regulation via increased IL-10 in the BALF. In view of the above, we suggest that MHTP is a potential candidate to become a drug in the sense of being inserted into the therapeutic arsenal in the treatment of CARAS once the appropriate clinical trials have been carried out.