Thesis (Ph.D.) – Cairo University. Faculty of Pharmacy. Department of Pharmacology & Toxicology.

Includes bibliographical references.

Aim: Mangiferin (MF), a xanthonoid from Mangifera indica, possesses anti-inflammatory, immunomodulatory, and potent antioxidant effects; however, its protective effect against multiple organ dysfunction syndrome has not been fully clarified. The study was designed to assess the possible mechanism of action of MF20 and its nano-formulation (NMF10) against mesenteric I/R model. Main Methods: Male Wister rats were randomly allocated into 6 groups (n= 6); in the first group, rats received saline and the SMA was manipulated only to serve as the sham-operated group. In the 5 other groups rats were subjected to I/R, which was induced by clamping the superior mesenteric artery for 30 minutes followed by declamping for 60 minutes. group 2 was donated as the untreated I/R control and animals received saline only, while in groups 3 and 4, animals were pre-treated with MF (20 mg/kg, i.p) or NMF (10mg/kg, i.p), for 3 days before I/R, while rats in groups 5 and 6 received the two blockers; viz., methyllycaconitine (MLA) and atropine (Sigma-Aldrich Chemical Company, MO, USA) 30 min before NMF10 for 3 days. MF20 was dissolved in the vehicle (2% DMSO in saline), while NMF10 were sonicated well before administration. Atropine and methyllycaconitine (MLA) were diluted with 0.9% saline prior to the experiment. Key findings: The mechanistic studies revealed that MF20 protected the 3 organs studied, viz., liver, kidney and intestine partly via increasing the content of β-catenin and PPAR-γ along with decreasing that of GSK-3β and the phosphorylated NF-қB-p65. MF20 and NMF10 antioxidant effect was evidenced by increasing contents of total antioxidant capacity and GST, besides normalizing that of MDA and increasing m-RNA levels of NRF-2 and HO-1. Regarding the anti-inflammatory effect, MF20 reduced IL-1β and IL-6, effects that were mirrored on the tissue contents of MPO and MMP-9. Moreover, MF20 and NMF10 possessed anti-apoptotic character evidenced by elevating Bcl-2 content and reducing that of caspase-3. In the serum, intestinal I/R increased the activity of ALT, AST, creatinine, and creatine kinase. In all the measured parameters, NMF10 showed promise over MF20, however, these protective effects were deterred by the presence of atropine but not MLA. Significance: The intimated protective mechanisms of MF20 and NMF10 against MODS progression are mediated, partially, by modulation of oxidative stress, inflammation, and apoptosis possibly via the involvement of Wnt/β-catenin/NF-қβ/ PPAR-γ and NRF-2/HO-1 signaling pathways with contribution of muscarinic receptors.

Text in English, abstracts in English and Arabic.