Immune system modulatory effects of stigmasterol in murine models
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Date
2018-11
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KNUST
Abstract
ABSTRACT
Stigmasterol, a naturally occurring steroid alcohol belongs to a class of plant-derived compounds known as phytosterols. The therapeutic potential of stigmasterol in selected innate and adaptive immune responses, disease models of allergy as well as its immunotoxicity was assessed. The effects of stigmasterol on lipopolysaccharide (LPS)-induced febrile response, inflammatory cell proliferation, multiple organ damage and mortality were investigated. The anti-allergic potential of stigmasterol was assessed in immunogenic and non-immunogenic mast cell degranulation and in models of local and systemic mast cell-mediated responses. The suppressive effects of stigmasterol on compound 48/80-induced pruritus, 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation and its modulatory effects on chronic allergen-induced airway inflammation were also studied. The effects of stigmasterol on indices of general and immune system toxicity were also investigated. Stigmasterol at 10 - 100 mg/kg reduced LPS-induced fever response by 39.93 ± 10.52 % - 77.27 ± 6.25%. Lung and liver histopathology showed stigmasterol controlled LPS-induced organ damage. Stigmasterol at 50 and 100 mg/kg significantly protected mice from LPS-induced mortality. Stigmasterol suppressed active cutaneous anaphylactic reaction, recording 44.74 ± 10.62% - 52.38 ± 7.87% inhibition of concentration of extravasated Evans blue dye at 10 – 100 mg/kg. Pretreatment of mesenteric tissue mast cells with 0.04 – 0.16 μg/ml of stigmasterol reduced ovalbumin-induced and C48/80-induced degranulation by 39.00 ± 3.92% - 22.90 ± 4.60% and 47.60 ± 3.37% - 24.5 ± 2.79% respectively. Stigmasterol offered significant protection from C48/80-induced systemic anaphylaxis. Survival rates of 16.66%, 33.33% and 66.67% were recorded in mice at 10, 50 and 100 mg/kg respectively. Stigmasterol at 50 and 100 mg/kg significantly inhibited compound 48/80-induced scratching behaviour by 34.89 ± 6.41% and 36.00 ± 2.21% respectively, relative to control. Skin histopathology of injected sites showed stigmasterol reduced mast cell proliferation and degranulation associated with C48/80-induced pruritus. Again, stigmasterol controlled inflammatory features such as ear skin oedema, neutrophilia, overexpression of serum TNFα and skin histopathological changes induced by topical TPA application. Stigmasterol exerted significant suppressive effects on ovalbumin-induced airway inflammatory damage. Stigmasterol reduced proliferation of circulating eosinophils, lymphocytes and monocytes while reducing peribronchiolar, perivascular and alveolar infiltration of inflammatory cells. Histopathology revealed a preserved lung architecture and reduced collagen deposition, an index of lung remodeling, in stigmasterol-treated guinea pigs. Expression of serum vascular cell adhesion molecule-1 (VCAM-1) and ovalbumin specific Immunoglobulin E (OVA sIgE) elicited by ovalbumin sensitization and challenge was significantly controlled in stigmasterol-treated guinea pigs. In the toxicity study, no mortality was observed in stigmasterol-treated rats. Stigmasterol did not suppress peripheral leukocyte count, T cell-mediated delayed-type hypersensitivity responses, lymphoid organ weights and spleen cellularity. Histopathology of selected lymphoid organs showed limited deleterious effects on lymphoid tissues of stigmasterol-treated rats. Taken together, stigmasterol proved effective in inhibiting key innate and adaptive immune responses. These immune-modulating properties and limited harmful effects on the immune system suggest stigmasterol holds great therapeutic potential in the development of new drugs for immune system diseases.
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A Thesis submitted to the Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences in partial fulfilment of the requirements for the degree of DOCTOR OF PHILOSOPHY IN PHARMACOLOGY