MHTP, a synthetic alkaloid, attenuates combined allergic rhinitis and asthma syndrome through downregulation of the p38/ERK1/2 MAPK signaling pathway in mice.

The combined allergic rhinitis and asthma syndrome (CARAS) is a chronic airway inflammation of allergic individuals, with a type 2 immune response. Pharmacotherapy is based on drugs with relevant side effects. Thus, the goal of this study was to evaluate the synthetic alkaloid, MHTP in the experimental model of CARAS. Therefore, BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with MHTP by intranasal or oral routes. Treated animals showed a decrease (p < 0.05) of sneezing, nasal rubbings, and histamine nasal hyperactivity. Besides, MHTP presented binding energy and favorable interaction for adequate anchoring in the histamine H1 receptor. MHTP treatment inhibited the eosinophil migration into the nasal (NALF) and the bronchoalveolar (BALF) fluids. Histological analysis showed that the alkaloid decreased the inflammatory cells in the subepithelial and perivascular regions of nasal tissue and in the peribronchiolar and perivascular regions of lung tissue. The MHTP treatment also reduced the pulmonary hyperactivity by decreasing the smooth muscle layer hypertrophy and the collagen fiber deposition in the extracellular matrix. The immunomodulatory effect of the alkaloid was due to the decrease of cytokines like IL-5 and IL-17A (type 2 and 3), TSLP (epithelial), and the immunoregulatory cytokine, TGF-ß. These MHTP effects on granulocytes were dependent on the p38/ERK1/2 MAP kinase signaling pathway axis. Indeed, the synthetic alkaloid reduced the frequency of activation of both kinases independent of the NF-κB (p65) pathway indicating that the molecule shut down the intracellular transduction signals underlie the cytokine gene transcription.

MHTP, 2-Methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) phenol, a Synthetic Alkaloid, Induces IFN-γ Production in Murine Model of Ovalbumin-Induced Pulmonary Allergic Inflammation.

MHTP [2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) phenol], a synthetic isoquinolinic alkaloid, presented anti-inflammatory activity in several experimental models of acute inflammation as lipopolysaccharide (LPS)-induced acute lung injury and phlogistic agent-induced edema and presented low preclinical toxicity. The aim of this study was to determine the MHTP effect on ovalbumin (OVA)-induced pulmonary allergic inflammation. In other to realize this study, female BALFB/c mice were sensitized and challenged with OVA (OVA group) and treated with MHTP (MHTP group) by nasal instillation. Inflammatory, allergic, and immunomodulatory parameters such as migration of inflammatory cells to the lung tissue, pulmonary histological analysis, serum level of IgE-allergen specific, cytokine secretion, and lung T cell population characterization were analyzed and the data were considered statistically significant with p < 0.05. OVA-sensitized and OVA-challenged and MHTP (5.0 mg/kg)-treated mice presented reduction on total leukocyte migration into the bronchoalveolar lavage (BALF) dependent of lymphocyte and eosinophil migration (p < 0.001 and p < 0.01) as compared with the OVA group. Flow cytometric analysis showed that MHTP treatment decreased the percentage of granulocytes (p < 0.001) into the BALF and lung tissue histological analyzes demonstrated that the MHTP treatment decreased leukocyte migration and mucus production. In addition, treatment with MHTP decreased the number of CD3+CD4+ T cells independently of CD8+ T cell reduction into the BALF. The treatment also reduced significantly (p < 0.05) the serum level of IgE-OVA specific followed by reduction of IL-4, IL-13, and IL-17 production. Surprisingly, the MHTP treatment increased significantly (p < 0.05) the IFN-γ production in the BALF of these animals. Therefore, the results presented here showed that MHTP treatment, by nasal instillation, in a mouse model of OVA-induced pulmonary allergy has anti-allergic and immunomodulatory effects dependent on a Th1-skewed cytokine production that ameliorate the pulmonary allergic inflammation.