EFFECT OF METHANOL LEAF EXTRACT OF Clerodendrum splendens ON DOXORUBICIN-INDUCED AND HYPERLIPIDEMIC CARDIOTOXICITY IN DIABETIC MALE WISTAR RATS.

Abstract

There is a higher prevalence of cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) characterized with unusual risk factors such as high values of triglycerides, low density lipoprotein (LDL), total cholesterol (TCHOL), and low value of High Density Lipoproteins (HDL), including glucose intolerance and insulin resistance. This study was systematically conducted to investigate the intersecting mechanisms in which bioactive components in methanolic leaf extract of Clerodendrum splendens (MLECS) mitigated CVD and T2DM etiologies. The polyphenolic components in MLECS were characterized by HPLC device. The concentration dependent in vitro antioxidant (FRAP, DPPH, ABTS, NO, O2-and OH radicals scavenging activities, metal chelating and Inhibitions of β-carotene bleaching (ß-CB) and Fe2+ induced lipid peroxidation), anti-diabetes (inhibitions of alpha glucosidase and alpha amylase) and ACE-1 inhibiting activities of MLECS were determined. The LD50, and acute, sub-chronic and chronic toxicity tests in a dose dependent manner (mg/kg BWT) were determined on MLECS using Wistar rats. Thereafter, biochemical indices and histological examinations were evaluated to determine the oxidative (GPx, SOD, GST, GSH, NP-SH, MDA and catalase) and functional status of the liver (activities of ALP, ALT, AST and GGT) and kidney (urine total protein, creatinine clearance rate and blood urea nitrogen), Furthermore, the effect of varying doses of MLECS on the serum lipid profile (TCHOL, HDL, TAG, LDL and VLDL) were also determined. Cardioprotective effects of MLECS were investigated against doxorubicin (15 mg/kg BWT) induced cardiotoxicity and 4-week high fat diet (HFD) induced hypercholesterolemia. The investigation into the anti-diabetes effects of MLECS on T2DM induced by 4-week pre-exposure to HFD and single low dose (35 mg/kg BWT) of streptozotocin (STZ) was determined. The biochemical and histological changes as a result of MLECS treatments on the cardiac and pancreatic systems were determined; cardiofunctional indices (concentrations of troponin-1, Iron, calcium and ascorbic acid; and activities of LDH, CK- MB, AST, ALT and G6PDH), pancreatotoxic indices (concentrations of blood insulin and fasting blood glucose) and oxidative stress (activities of GPx, SOD, GST and catalase and the concentrations of GSH, NP-SH and MDA). In addition, the dose-dependent effects of MLECS on cardiac and pancreatic apoptosis (caspase-3), proinflammatory cytokines (TNF-α, IL1β and IL-6), inflammatory enzymes (myeloperoxidase and xanthine oxidase) and lipid profile (TCHOL, HDL, TAG, LDL, VLDL used for the calculation of atherogenic and coronary risk indices). The results revealed in vitro concentration dependent antioxidant, anti-diabetic and ACE-1 inhibition effects of MLECS. The results also revealed that MLECS mitigated the effects of T2DM on cardiac functions through the modulation of LDH and CK-MB. The cardiac and pancreatic antioxidant status were elevated by MLECS treatments, and showed a complete down-regulation of apoptotic and inflammation pathways as reflected in their indices. MLECS treatment demonstrated anti-diabetes effects by correcting hyperinsulinemia through significantly reduced circulatory insulin and increased absorption of glucose, thus inhibiting the formation of advanced glycation end-products (AGE). MLECS ameliorated DOX-induced cardiotoxicity and HFD-induced hypercholesterolemia by appropriately adjusting the cardiofunctional indices and elevating the depleted antioxidant status vis a vis apoptosis and inflammation. Cardiovascular indices such as atherogenic index and coefficient and coronary risk index were modulated appropriately by MLECS resulting in inferred improved cardiac function in the Wistar rats. There is an established intersection between T2DM and cardiovascular dysfunctions by modulation of key enzymic and non-enzymic factors of cardiac and pancreatic functions through increased in metabolic derangements. The methanolic leaf extract of Clerodendrum splendens can thus be used as a potential therapeutic natural intervention in preventing and treating the diseases arising from diabetes and cardiac dysfunction.