Effects Of Small Molecules Targeting The Nrf2/ARE Signaling Pathway In Neuroprotection

Redox homeostasis is the decisive foundation for maintaining various normal physiological functions.However,when redox imbalance occurs in the body,i.e.,the level of reactive oxygen species（ROS）is much higher than the antioxidant capacity,oxidative stress will occur.Studies have shown that oxidative stress is closely related to neurodegenerative disease.Activating the Nrf2/ARE signaling pathway,a core intracellular antioxidant defense mechanism,can upregulation of the antioxidant defense system to protect against oxidative damage,and hence this signaling pathway may be one of the important targets for preventing or delaying neurodegenerative diseases.In this dissertation,we mainly found several small molecules with a better neuroprotective effect on PC12 cells and investigated their potential molecular mechanisms,which can provide theoretical guidance for the discovery and development of Nrf2 activators.The main contents of this dissertation are below:Chapter 1 Firstly,we introduced oxidative stress and neurodegenerative diseases.Secondly,we presented the basic structure and regulations of the Nrf2/ARE signaling pathway.Lastly,we summarized the research progress of Keap1/Nrf2/ARE signaling pathway activators.Chapter 2 A series of 3-benzoyl coumarin compounds were designed and synthesized,and their neuroprotective activities were screened.After screening assay,compounds 13 and 25 showed potential activity in protecting PC12 cells against oxidative damage.In further mechanism studies,we found that compounds 13 and 25could activate the Nrf2/ARE signaling pathway,thus upregulating the antioxidant defense system,attenuating the apoptosis induced by H₂O₂ or 6-OHDA,reducing the intracellular ROS accumulation,and providing neuroprotection to the cells.This work provides some instructions for later studies of coumarin-chalcone hybrid compounds in activating the Nrf2 pathway and exerting neuroprotective effects.Chapter 3 Salvianolic acid C（SAC）is an effective active ingredient in the Chinese medicine Salvia miltiorrhiza,and we investigated the neuroprotective effect of SAC on PC12 cells.Studies found that SAC can promote the nuclear translocation of Nrf2 and induce the transcription and expression of antioxidant genes/detoxification genes downstream of Nrf2,thus exerting cytoprotective effects.Furthermore,SAC possessed a strong antioxidant capacity,which further enhanced the ability of SAC to combat oxidative stress.This work reveals the neuroprotective effect of SAC with its potential mechanism,which adds a certain theoretical basis to the research of the biological activity of SAC.Chapter 4 Summarized the whole dissertation and provide a novel insight into the development of Nrf2 activators in their potential application.