Estudo pré-clínico de compostos organocalcogênios como estratégia terapêutica para a toxicidade da oxaliplatina em camundongos

Abstract

Oxaliplatin (OXA), a chemotherapeutic drug widely used in the treatment of colorectal carcinoma, is associated with the development of neurological and renal toxicological conditions. In this context, efforts were directed towards the preclinical study of organochalcogen compounds as therapeutic strategies for the OXA toxicity. Initially, the therapeutic potential of 5 - ((4-methoxyphenyl) thio) benzo[c][1,2,5] thiodiazole (MTDZ) was investigated against peripheral neuropathy and its comorbidities in male and female Swiss mice exposed to OXA. The animals received OXA (10 mg/kg) intraperitoneally, on days 0 and 2 of the experimental protocol. The oral administration of MTDZ (1 mg/kg) was performed on days 2 to 14. OXA caused cognitive impairment, anxiety-like behavior, mechanical and thermal hypersensitivities in mice, with females being more susceptible to thermal sensitivity. MTDZ reversed OXA-induced hypersensitivity, cognitive impairment, and anxiety-like behavior. OXA altered the activity of ion pumps: total ATPase, Na+ K+- ATPase, Ca2+ - ATPase and Mg2+ - ATPase and increased the levels of reactive species (ER) and superoxide dismutase (SOD) activity. MTDZ was able to regulate the homeostasis of total ATPases, Mg2+-ATPase and SOD activity. The results obtained suggest that the organic sulfur compound (MTDZ) is promising for the treatment of neurotoxicity induced by OXA chemotherapy. In the second study, OXA-induced renal toxicity was evaluated in male Swiss mice. At this stage, the relationship between OXA-induced renal oxidative damage and the therapeutic potential of 7-chloro-4-(phenylselanyl) 10 quinoline (4-PSQ) was studied. The mice received either OXA (10 mg/kg) or vehicle intraperitoneally (days 0 and 2). Oral administration of 4-PSQ (1 mg/kg) or vehicle was performed on days 2 to 14. On day 15, animals were euthanized, and kidneys and blood were collected. The results revealed an increase in urea levels and significant renal oxidative damage in mice exposed to OXA. Exposure to chemotherapy increased the activity of SOD, glutathione peroxidase (GPx) and glutathione-S-transferase (GST). OXA caused a reduction in the levels of non protein thiols (NPSH) and inhibition of the activity of the enzymes catalase (CAT) and glutathione reductase (GR). The activity of the enzymes Na+ K+ ATPase and δ-aminolevulinate dehydratase (δ-ALA-D) were inhibited by OXA. 4-PSQ decreased plasma urea levels and renal oxidative damage. SOD, GPx, CAT, GR and Na+ K+- ATPase activities were restored by 4-PSQ. The dataset obtained suggests that 4-PSQ reduces OXA-induced kidney damage in mice, possibly due to its antioxidant potential. Based on the results obtained, it can be concluded that 4-PSQ and MTDZ are promising molecules in the treatment of toxicity induced by OXA.