Dor oncológica em roedores induzidos com vincristina: impactos do envelhecimento, neurodesenvolvimento, dimorfismo sexual e o papel protetor do 4-PSQ

Abstract

Vincristine (VCR) is a chemotherapeutic agent widely used in the treatment of various malignancies. Despite its well-established antitumor efficacy, VCR is directly associated with the development of neurotoxicity, primarily manifested as VCR-induced peripheral neuropathy (VIPN), a debilitating condition that can affect patients across different age groups, including children during critical neurodevelopmental stages. On the other hand, 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) is a promising synthetic compound with recognized antioxidant, anti-inflammatory, and neuroprotective properties. This study was designed to address experimental gaps related to VIPN by investigating both the influence of biological factors, such as aging and sexual dimorphism, and the therapeutic potential of 4-PSQ. Initially, the hypothesis that aging could increase susceptibility to VIPN was tested. Indeed, aged rats showed greater vulnerability, evidenced by Wallerian degeneration, oxidative stress, and alterations in ATPase activity, which are key pathophysiological mechanisms associated with neuropathy development. Subsequently, the study evaluated whether VCR could induce neurocognitive and emotional impairments in male and female mice. The results demonstrated anxiety-like and depressive-like behaviors, along with cognitive deficits, associated with the activation of the Nuclear Factor kappa B (NFκB)/Na+, K+-ATPase signaling pathway. In a third stage, the in vitro antitumor potential of 4-PSQ was explored, revealing significant activity against the proliferation of leukemic cells, in addition to antinociceptive effects in VIPN models in both sexes. Considering the frequent use of VCR in pediatric patients, its impact on neonatal rats was also assessed. For the first time, it was demonstrated that VCR significantly impairs neurodevelopment and physical growth, inducing spinal cord degeneration, oxidative stress, mitochondrial dysfunction (altered mitophagy), and neuronal apoptosis. Finally, the efficacy of 4-PSQ in managing oncological pain associated with VIPN and a sarcoma (S180) model was investigated. The combined treatment with VCR and 4-PSQ not only enhanced antitumor effects but also reduced signs of peripheral neuropathy by modulating the inflammatory profile, peritoneal macrophage response, ATPase activity, and oxidative stress. In conclusion, aging, neurodevelopmental stage, and sexual dimorphism are critical factors influencing susceptibility to VIPN. Moreover, 4-PSQ emerges as a promising strategy by combining antitumor and neuroprotective actions, opening new therapeutic perspectives for managing oncological patients exposed to VCR.