Implicações do envelhecimento na neuropatia induzida por oxaliplatina: 7-cloro-4-(fenilseleno)quinolina como estratégia terapêutica

Abstract

Given the complexity of the effects induced by oxaliplatin and the lack of effective treatment, especially for the elderly, studies that contribute to the understanding of the mechanisms involved in oxaliplatin-induced peripheral neuropathy (NPIO) and that identify new pharmacological targets are becoming increasingly relevant for the development of effective and safe therapies for all ages. In this context, 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) stands out, a quinoline derivative containing selenium, that has been widely studied, as it has promising antioxidant and neuroprotective effects. Therefore, the set of factors mentioned led us to investigate the action of 4-PSQ in an NPIO model at different ages. In this sense, the 1st stage of this study showed that, despite the efficient defenses of the central nervous system (CNS), after exposure to oxaliplatin, there is an accumulation of platinum in the spinal cord of mice, which increases the knowledge about its toxicity. Furthermore, it has been proposed that the accumulation of platinum in the spinal cord can cause oxidative damage to neurons and impair mitochondrial function. In addition, 4- PSQ reduced the neuropathic pain underlying NPIO. In the 2nd stage of the study, a significant correlation was shown between anxious behavior and cognitive impairment, comorbidities associated with NPIO. Also, the administration of oxaliplatin caused an increase in plasma corticosterone levels and inhibition of the enzyme Na+ , K+ - ATPase. 4-PSQ reversed comorbidities and its pharmacological effects seem to be mainly due to the modulation of the enzyme Na+ , K+ - ATPase. In the 3rd stage of the study, it was demonstrated for the first time that acute NPIO was exacerbated by aging through increased oxidative damage and modulation of Na+ , K+ - ATPase. The 4-PSQ reversed the damage caused by oxaliplatin, especially for those aggravated by aging. In the 4th stage of the study, it was shown for the first time that chronic NPIO was exacerbated by aging. Changes in bioelement concentration, oxidative status, and neuroprotection and neuroplasticity pathways seem to contribute to NPIO. Platinum deposition was first identified in the brain of mice exposed to oxaliplatin, regardless of age. In the 5th stage of the study, it was demonstrated that 4-PSQ reversed chronic NPIO and its comorbidities. The pharmacological action of 4-PSQ in this experimental model seems to involve the modulation of the enzymes Na+, K+ - ATPase and acetylcholinesterase and, mainly, the promotion of redox balance. In the 6th stage of the study, the pharmacological and antioxidant potential of 4-PSQ stood out in a cancer pain model. This study is innovative, providing a perspective on the impact of aging on NPIO and evidence on the effects of 4-PSQ.