Neuro- and nephroprotective effect of grape seed proanthocyanidin extract against carboplatin and thalidomide through modulation of inflammation, tumor suppressor protein p53, neurotransmitters, oxidative stress and histology

Abstract

The combination of thalidomide and carboplatin is one of the most potent chemotherapeutic strategies for the treatment of cancer. However, limited studies have been conducted on the neurotoxicity and nephrotoxicity of both chemotherapeutic agents. The aim of our study was to assess the toxicity of thalidomide and carboplatin combination on brain and kidney and investigate the protective effect of grape seed proanthocyanidin extract (GSPE). Thalidomide and carboplatin induced up-regulation of the expression of p53, tumor necrosis factor-α and interleukin-6 in brain and kidney. Acetylcholinesterase, dopamine and serotonin were decreased and norepinephrine was increased. Thiobarbituric acid reactive substances, nitric oxide, lipid profile, bilirubin and creatinine were elevated, while antioxidants enzymes (GST, GPX, CAT and SOD), total antioxidant capacity and the levels of glutathione were decreased. A microscopic examination showed shrinkage of capillaries, degeneration with pyknotic nuclei, loss of normal structure and neuronal degeneration. GSPE co-treatment with thalidomide and carboplatin reduced their brain and renal damage, oxidative stress, diminished cytokines, p53, neurotransmitters and biochemical parameters, and inhibited brain and renal cell apoptosis. It can be concluded that, the protective effects of GSPE against thalidomide and carboplatin induced-brain and renal damage was associated with the minimization of oxidative stress. Keywords: Thalidomide, Carboplatin, Grape seed proanthocyanidin extract, Neurotoxicity, Nephrotoxicity