Envolvimento da endotelina-1, de receptores (TRPV1 E NMDA) e da substância p na neuropatia sensitiva periférica induzida pelo agente antineoplásico oxaliplatina

Abstract

Introduction: The cumulative neurotoxicity is a toxicity that can result from oxaliplatin-based therapy (OXL), which is the 3rd generation platinum agent with broad spectrum of antitumor activity, including colorectal, ovarian and lung cancer. Neurotoxicity associated with OXL generates a dose-limiting toxicity, chronic, peripheral sensory neuropathy (NSP). Objective: To investigate the involvement of endothelin-1, TRPV1 receptors and NMDA and substance P involved in the pathogenesis of peripheral sensory neuropathy induced by oxaliplatin antineoplastic agent. Methods: Male Swiss mice (20g) were pre-treated with antagonists of endothelin-1 receptors (Bosentan 100mg / kg orally; BQ-123 and BQ-788 30μl, intraplantar) and TRPV1 receptor antagonists (capsazepine, 5mg / kg , IP), antagonist of NK-1 receptor for substance P (apreptanto, 1 mg / kg, IP), and a NMDA receptor antagonist (MK-801, 0.5mg / kg, IP) 30 minutes before administration of OXL (1mg / kg, IV) for 4.5 weeks. Parallel nociceptive tests performed to assess the development of peripheral sensory neuropathy. The hyperalgesia assessed by the tail immersion test (ICT) in cold water (10° C) or warm (43° C) and test Von Frey (HPM). Then it was performed spinal segment, and the dorsal root ganglion immunofluorescence and RT-PCR the Ethics Committee approved the study for Animal Research UFC (Protocol 75/12). Results: The results observed when using the antagonists, as a pretreatment to the use of OXL there was attenuation of the induced hyperalgesia (NSP) OXL. Upon administration of selective antagonists of endothelin in the right paw was significant reduction in paw hyperalgesia in the right (treated) compared to the left paw (control). By analyzing the gene expression of cFos, NK-1 and endothelin B receptor, it was observed that there was significant reduction of expression of the markers in pre-treated bosentan group versus OXL group that showed increased expression for these markers. Conclusion: It was concluded in this study that there is evidence of the role of endothelin-1 receptors (TRPV1 and NMDA) and substance SP in the pathogenesis of NSP induced antineoplastic agent OXL.