A carregar...
Publicação
Via de sinalização Keap1-Nrf2-ARE como alvo terapêutico na modulação do stress oxidativo nas doenças neurodegenerativas
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 899.93 KB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
O stress oxidativo nas várias células integrantes do SNC contribuí significativamente para a fisiopatologia subjacente de diversas doenças neurodegenerativas. Este resulta principalmente da formação de espécies reativas de oxigénio (ROS), resultando num desequilíbrio do estado redox celular.
A principal resposta fisiológica ao desequilíbrio redox é a ativação da via de sinalização celular Keap1-Nrf2-ARE (Kelch-like ECH associated protein 1 - nuclear factor-erythroid-2 related factor 2 – elemento de resposta antioxidante), na qual o factor de transcrição Nrf2 atua como um importante regulador da expressão de genes que codificam para proteínas com ação antioxidante.
Em condições basais a proteína Keap1 atua como um repressor endógeno do Nrf2 promovendo a sua degradação pela via da ubiquitina-proteossoma; e em condições de stress oxidativo dissocia-se do Nrf2 permitindo que este seja translocado para o núcleo, funcionando como um sensor do ambiente redox celular. Em resposta ao stress oxidativo, o Nrf2 promove a transcrição de diversas enzimas envolvidas em reações de biotransformação de fase I, II e III e nos mecanismos anti-oxidantes. A ativação desta via de sinalização permite aos organismos eucariotas contrariar os efeitos nefastos dos agentes oxidantes e outros eletrófilos, que representam as maiores classes de agentes que poderão contribuir para a patogénese das doenças neurodegenerativas e, portanto, tornou-se um alvo atrativo para a prevenção e tratamento de doenças relacionadas com o stress oxidativo. Ao longo dos últimos anos têm sido estudados os diversos componentes integrantes desta via e que teoricamente podem ter um papel neuroprotetor nas doenças neurodegenerativas, sendo por isso, possíveis alvos terapêuticos.
O presente trabalho pretende apresentar uma revisão sobre as moléculas moduladoras do Nrf2 de diferentes classes químicas e farmacologicamente distintas que atualmente se encontram em estudo.
Oxidative stress in the various cells that constitute the CNS contributes to the pathophysiology underlying the various neurodegenerative diseases. This results mainly from the formation of reactive oxygen species (ROS) that determine an imbalance of the cellular redox state. The main physiological response to the redox imbalance is the activation of the Keap1- Nrf2- ARE (Kelch-like ECH associated with protein 1 - Nuclear factor 2 related factor erythroid-2 – Antioxidant response element) cell signaling pathway, in which the transcription factor Nrf2 is an important regulator of the expression of genes that code for proteins with antioxidant action. In basal conditions the Keap1 protein acts as an endogenous Nrf2 repressor, promoting its degradation via the ubiquitin-proteasome pathway and in oxidative stress conditions it dissociates from Nrf2 so that it is translocated to the nucleus, functioning as a sensor of the cellular redox environment. In response to oxidative stress, Nrf2 induces the transcription of several enzymes involved in phase I, II and III biotransformation reactions and antioxidant mechanisms. The activation of this signaling pathway allows eukaryotic organisms to counteract the harmful effects of oxidizing agents and other electrophiles, which contribute to the pathogenesis of neurodegenerative diseases and, therefore, has become an attractive target for prevention and treatment of diseases related to oxidative stress. Over the past few years, the various components of this pathway that have been studied and theoretically may have a neuroprotective role, being therefore, possible therapeutic targets. In this written assay a review of the currently candidate drugs modulators of Nrf2 of several distinct chemical classes is presented.
Oxidative stress in the various cells that constitute the CNS contributes to the pathophysiology underlying the various neurodegenerative diseases. This results mainly from the formation of reactive oxygen species (ROS) that determine an imbalance of the cellular redox state. The main physiological response to the redox imbalance is the activation of the Keap1- Nrf2- ARE (Kelch-like ECH associated with protein 1 - Nuclear factor 2 related factor erythroid-2 – Antioxidant response element) cell signaling pathway, in which the transcription factor Nrf2 is an important regulator of the expression of genes that code for proteins with antioxidant action. In basal conditions the Keap1 protein acts as an endogenous Nrf2 repressor, promoting its degradation via the ubiquitin-proteasome pathway and in oxidative stress conditions it dissociates from Nrf2 so that it is translocated to the nucleus, functioning as a sensor of the cellular redox environment. In response to oxidative stress, Nrf2 induces the transcription of several enzymes involved in phase I, II and III biotransformation reactions and antioxidant mechanisms. The activation of this signaling pathway allows eukaryotic organisms to counteract the harmful effects of oxidizing agents and other electrophiles, which contribute to the pathogenesis of neurodegenerative diseases and, therefore, has become an attractive target for prevention and treatment of diseases related to oxidative stress. Over the past few years, the various components of this pathway that have been studied and theoretically may have a neuroprotective role, being therefore, possible therapeutic targets. In this written assay a review of the currently candidate drugs modulators of Nrf2 of several distinct chemical classes is presented.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Doenças neurodegenerativas Stress oxidativo Via de sinalização Keap1-Nrf2-ARE Mestrado integrado - 2020