Estudo da disfunção motora associada à neurotoxicidade da oxaliplatina em camundongos

Abstract

Oxaliplatin (OXL) is an antineoplastic agent considered the first line of treatment for metastatic colorectal cancer, however, it has neurotoxicity as a dose-limiting effect, characterized by sensory changes, cognitive deficits and motor dysfunctions. Such effects prejudice both the patient's quality of life and the effectiveness of treatment. Although sensory symptoms are widely explored in scientific research, there are still few studies and little interest in research on OXL-induced motor impairment. In addition to the lack of effective animal models that allow the assessment of motor dysfunctions. In this perspective, this study aims to evaluate the motor dysfunctions caused by the neurotoxicity of OXL in mice with peripheral neuropathy. Peripheral neuropathy was induced in male Swiss mice from the administration of OXL at a dose of 2mg/kg, which was administered twice a week for 4.5 weeks, totaling 9 applications. During the induction of peripheral neuropathy, the open field test was performed weekly from day 1 to day 28 to determine the animal's exploratory activity, the balance beam test to assess balance, gait assessment to determine the animal's sciatic funcional index (SFI). and the apprehension strength and suspension time test to assess muscle strength and endurance. After day 28, sciatic nerves were collected for histopathological evaluation and the spinal cord was also collected for evaluation of oxidative stress by determination of Reduced Glutathione (GSH) and Malondialdehyde (MDA). Regarding the results found, from day 14, OXL reduced both exploratory activity in the open field test and SFI in the gait assessment, despite not having affected the balance of the animals in the balance bar test. From the 7th day onwards, a reduction in muscle strength and endurance was observed in the animals treated with OXL. Regarding the histological analysis of the sciatic nerve, OXL increased the leukocyte infiltrate, the presence of vacuoles, axonal degeneration and edema, corroborating the sciatic dysfunction found in the gait assessment. Among the mechanisms involved in these motor changes, oxidative stress can be highlighted, as it was demonstrated that OXL caused an increase in MDA and a decrease in GSH both in the sciatic nerve and in the spinal cord. Therefore, it can be concluded that the neurotoxicity caused by OXL was responsible for causing a motor impairment in the animals treated with this chemotherapy.