The effect of nicotinamide mononucleotide and troxerutin on doxorubicin-induced hepatotoxicity in rats

Abstract

Doxorubicin is a cytotoxic anthracycline drug used to treat various types of cancer. However, a number of systemic side effects have limited its administration in cancer patients. One of the most important side effects of doxorubicin is hepatotoxicity, which causes liver dysfunction. Nicotinamide mononucleotide (NMN) is essential for mitochondrial activity, and its supplements can compensate for its low concentration in doxorubicin hepatotoxicity and enhance mitochondrial-cellular activity. Troxerutin itself has a wide range of effects in the body, from reducing oxidative stress to affecting many mitochondrial functions. Therefore, it is expected that the combined administration of these two drugs has potential to effectively prevent doxorubicin hepatotoxicity in cancer patients. Methods: In this study, 30 rats were used under standard laboratory conditions. The treatment groups were nicotinamide mononucleotide and troxerutin in combination with doxorubicin, together or alone, at different levels of doses. By passing the specified time, liver histopathological changes were examined by utilizing hematoxylin-eosin staining and light microscopy and serum levels of AST (aspartate aminotransferase) and ALT (alanine aminotransferase) were evaluated using a specific kit and ELISA method. In order to assessing the mitochondrial membrane depolarization, JC-1 staining and fluorometric technique was conducted. Also, mitochondrial ROS (Reactive Oxygen Species) production was evaluated using DCFH-DA staining using fluorometric method, and inflammatory cytokines TNF-α (Tumor Necrosis Factor-α), IL-1β (Interlukine-1β) and IL-6 (Interlukine-6) were assessed by ELISA method. Results: The results of this investigation declared that the administration of NMN and TXR, in combination or alone, in the groups receiving doxorubicin, reduced liver damage at the tissue level of the studied rats. In addition, the results of examining the normal function of mitochondria (membrane potential) and its antioxidant properties (ROS measurement) showed that the groups receiving TXR and NMN simultaneously reduced oxidative stress and increased liver mitochondrial biogenesis more effectively than the other treatment groups. Also, the reduction of liver enzymes AST and ALT and the reduction of inflammatory cytokines (IL-1β, IL-6 and TNF-α) also indicate that this treatment method has a significant effect on liver function and has reduced the level of inflammation.