Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Hepato and nephrotoxicity are important drawbacks of cisplatin. The objective of this study is to evaluate the ability of ambroxol in two different doses (35 & 70 mg/kg, i.p.) to protect liver and kidney from damage induced by a single dose of cisplatin (10 mg/kg, i.p.) in comparison to N- acetylcysteine (250 mg/kg, i.p.). Oxidative stress, Inflammatory and apoptotic biomarkers were investigated to show the influence of ambroxol on hepato and nephrotoxicity. Ambroxol decreased the elevated activity of liver enzymes (ALT and AST) and kidney function tests (BUN and creatinine). Ambroxol mitigated cisplatin inflammatory damage by inhibition of tumor necrosis factor-Ü, interleukin-1Ý, nuclear factor kappa-B and elevation of nuclear factor erythroid 2-related factor 2 (Nrf2). Moreover, ambroxol inhibited oxidative damage indicated by reduction of malondialdehyde and replenished the store of reduced glutathione likely by upregulating glutathione reductase and superoxide dismutase. Elevation of phosphorylated c- Jun N-terminal kinases (p-JNK) and phosphorylated extracellular signal-regulated kinases (p-ERK) were attenuated by ambroxol associated with a decrease of the expression of caspase-3. These results were consistent with the histopathological results. These results recommend ambroxol to be co-administered with cisplatin in cancer patients to ameliorate liver and kidney damage and this was confirmed by MTT assay

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