Background Recent evidences highlight role of mitochondria in the development of 5-fluorouracil (5-FU)-induced intestinal toxicity. Mitochondria-targeted antioxidants are well-known for their protective effects in mitochondrial oxidative stress- mediated diseases. In the present study, we investigated protective effect of Mito-TEMPO in 5-FU-induced intestinal toxicity. Methods Mito-TEMPO (0.1 mg/kg b.w.) was administered intraperitoneally to male BALB/c mice for 7 days, followed by co-administration of 5-FU for next 4 days (intraperitoneal 12 mg/kg b.w.). Protective effect of Mito-TEMPO on intestinal toxicity was assessed in terms of histopathological alterations, modulation in inflammatory markers, apoptotic cell death, expression of 8-OhDG, mitochondrial functional status and oxidative stress. Results 5-FU administered animals showed altered intestinal histoarchitecture wherein a shortening and atrophy of the villi was observed. The crypts were disorganized and inflammatory cell infiltration was noted. Mito-TEMPO pre-protected animals demonstrated improved histoarchitecture with normalization of villus height, better organized crypts and reduced inflammatory cell infiltration. The inflammatory markers and myeloperoxidase activity were normalized in mito-TEMPO protected group. A significant reduction in intestinal apoptotic cell death and expression of 8-OhDG was also observed in mito-TEMPO group as compared to 5-FU group. Further, mtROS, mtLPO and mitochondrial antioxidant defense status were improved by mito-TEMPO. Conclusion Mito-TEMPO exerted significant protective effect against 5-FU-induced intestinal toxicity. Therefore, it may be used as an adjuvant in 5-FU chemotherapy.
Purpose The mitochondria-targeted antioxidants (MTAs) are known to offer protection against mitochondrial oxidative stress. The recent evidences support their role in mitigating oxidative stress-induced diseases, including cancer. Therefore, this study investigated cardioprotective potential of mito-TEMPO against 5-FU-induced cardiotoxicity. Methods Mito-TEMPO was administered to male BALB/C mice (intraperitoneally, 0.1 mg/kg b.w. for 7 days) followed by intraperitoneal administration of 5- FU (12 mg/kg b.w. for 4 days). During this period, mito-TEMPO treatment was also continued. The cardioprotective potential of mito-TEMPO was assessed by evaluating cardiac injury markers, extent of non-viable myocardium and histopathological alterations. Mitochondrial functional status and mitochondrial oxidative stress were assessed in cardiac tissue. 8-OHdG expression and apoptotic cell death were assessed using immunohistochemical techniques. Results The level of cardiac injury markers CK-MB and AST were significantly (P ≤ 0.05) decreased in mito-TEMPO pre-protected group which was further reflected in histopathology as decrease in the percentage of non-viable myocardial tissue, disorganization, and loss of myofibrils. Mito-TEMPO ameliorated mtROS, mtLPO and conserved mitochondrial membrane potential. Further, it had significantly (P ≤ 0.05) improved the activity of mitochondrial complexes and mitochondrial enzymes. A significant (P ≤ 0.05) increase in the level of mtGSH, activity of mitochondrial glutathione reductase, glutathione peroxidase, and mitochondrial superoxide dismutase was observed. A decreased expression of 8-OHdG and reduced apoptotic cell death were observed in mito-TEMPO pre-protected group. Conclusion Mito-TEMPO effectively mitigated 5-FU-induced cardiotoxicity by modulating mitochondrial oxidative stress, hence may serve as a protective agent/adjuvant in 5-FU-based combinatorial chemotherapy.
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