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Master's Dissertation
DOI
https://doi.org/10.11606/D.17.2020.tde-04102019-103415
Document
Author
Full name
Francisco Isaac Fernandes Gomes
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2019
Supervisor
Committee
Cunha, Thiago Mattar (President)
Alves, Sandra Yasuyo Fukada
Cunha, Joice Maria da
Lucas, Guilherme de Araujo
Title in Portuguese
Papel da via succinato/GPR91 no desenvolvimento da dor neuropática induzida por paclitaxel
Keywords in Portuguese
Dor neuropática
GPR91
Paclitaxel
Puimioterapia
Succinato
Abstract in Portuguese
Paclitaxel é um quimioterápico amplamente empregado no tratamento de tumores sólidos, mas a neuropatia periférica é um efeito adverso dose-limitante e uma causa comum de interrupção do tratamento oncológico. Paradoxalmente, neurônios são suscetíveis ao paclitaxel apesar de não serem células em divisão. Degeneração axonal e demielinização se correlacionam com os sintomas clínicos que persistem além da descontinuação do tratamento. A patogênese da neuropatia induzida por paclitaxel não está totalmente elucidada. Ademais, a neuropatia periférica induzida por paclitaxel pode causar alterações metabólicas no sistema nociceptivo e intermediários do ciclo do ácido cítrico, como o succinato, podem se acumular nessas condições e transduzir sinais através da ativação de GPR91. Resultados mostram que animas GPR91-/- são menos propensos a desenvolverem hipersensibilidade mecânica e térmica durante neuropatia periférica induzida por paclitaxel. Diante dessas informações, propomos no presente projeto avaliar os mecanismos pelos quais o receptor GRP91 participa do desenvolvimento da dor crônica de origem neuropática induzida por paclitaxel utilizando ferramentas farmacológicas e genéticas em modelos murinos. O esclarecimento do papel funcional deste receptor adicionaria um conceito inédito na área de pesquisa de dores crônicas, sugerindo um novo alvo terapêutico para o campo da analgesia
Title in English
Role of succinate/GPR91 pathway in the development of paclitaxelinduced peripheral neuropathic pain
Keywords in English
Chemotherapy
GPR91
Neuropathic pain
Paclitaxel
Succinate
Abstract in English
Paclitaxel is a chemotherapeutic agent widely employed in the treatment of solid tumors, but the ensuing peripheral neuropathy is a dose-limiting side-effect and a common cause of treatment interruption. Paradoxically, neurons are susceptible to paclitaxel albeit they are not dividing cells. Axonal degeneration and demyelination correlate with clinical symptoms that persist well beyond treatment cessation. The pathogenesis of paclitaxelinduced neuropathic pain is not fully elucidated. Additionally, paclitaxel-induced neuropathy can cause metabolic changes in the nociceptive system and the levels of citric acid cycle intermediates such as succinate can rise in such conditions and this metabolite can transduce signals through GPR91 activation. Preliminary results from our group show that GPR91-/- mice are less prone to develop mechanical and thermal hypersensitivity during paclitaxel-induced peripheral neuropathy. Knowing such information, this research project aims to evaluate the mechanisms through which GPR91 is involved in the development of paclitaxel-induced neuropathic pain by using pharmacological and genetic tools in experimental murine models. Clarifying the functional role of this receptor would add an unprecedented concept in the chronic pain field of study, suggesting a novel therapeutic target for studies on analgesia
 
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Publishing Date
2020-04-29
 
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