Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization.

Antonietta Rossi,Fiorentina Roviezzo,Raffaele Capasso,Rossella Bilancia,Armando Ialenti,Maria A Riemma,Carla Cicala,Angelo A Izzo,Jordan K Zjawiony,Elisabetta Caiazzo,Ester Pagano

doi:10.3389/fphar.2016.00525

Abstract

Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice were sensitized with s.c. injection of ovalbumin (OVA) on days 1 and 8. Sensitized mice received on days 9 and 12 on the shaved dorsal surface air administration to induce the development of the air-pouches. On day 15 animals were challenged by injection of OVA into the air-pouch. Salvinorin A, administered (10 mg/kg) before each allergen exposure, significantly reduced OVA-induced LT increase in the air pouch. This effect was coupled to a reduction in cell recruitment and Th2 cytokine production. In another set of experiments, mice were sensitized with OVA and both bronchial reactivity and pulmonary inflammation were assessed. Salvinorin A abrogated bronchial hyperreactivity and interleukin (IL)-13 production, without effect on pulmonary inflammation. Indeed cell infiltration and peribronchial edema were still present following diterpenoid treatment. Similarly, pulmonary IL-4 and plasmatic IgE levels were not modulated. Conversely, Salvinorin A significantly reduced LTC4 production in the lung of sensitized mice. Finally mast cell activity was evaluated by means of toluidine blue staining. Data obtained evidenced that Salvinorin A significantly inhibited mast cell degranulation in the lung. Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation. In conclusion Salvinorin A could represent a promising candidate for drug development in allergic diseases such as asthma.

Highlights

The plant Salvia divinorum, that occurs naturally in Mexico, has been used for centuries to facilitate spiritual experiences in religious rituals as well as employed by shamans for the cure of various disorders, including those characterized by having an inflammatory/allergic component (Vortherms and Roth, 2006; Mahendran et al, 2016)
Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation
Systemic exposure to allergens results in both the production of IgE against multiple antigen epitopes of several different antigens and the development of long-term changes in the involved tissues, including changes in mast cell number, tissue distribution (with mast cells in the epithelium and Recent studies in animal models have revealed that Salvinorin A exerts a number of pharmacological actions of potential therapeutic interest which are not solely limited to the central nervous system (Butelman and Kreek, 2015)

Summary

Introduction

The plant Salvia divinorum, that occurs naturally in Mexico, has been used for centuries to facilitate spiritual experiences in religious rituals as well as employed by shamans for the cure of various disorders, including those characterized by having an inflammatory/allergic component (Vortherms and Roth, 2006; Mahendran et al, 2016). In addition Salvinorin A has demonstrated to exert anti-inflammatory actions (Aviello et al, 2011; Rossi et al, 2016). We have demonstrated that its anti-inflammatory properties, at least in part, were related to ability to inhibit leukotriene (LT) biosynthesis (Rossi et al, 2016)

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Results

Conclusion