Targeting Nrf2 With Small Molecules For Neuroprotection

Reactive oxygen species(ROS)are produced from various metabolic pathways and enzymatic reactions.At physiological levels,ROS act as important signaling molecules.However,excessive accumulation of ROS leads to oxidative stress,which has deleterious effects on lipids,DNA,and proteins.Human brain contains a high content of polyunsaturated fatty acids and consumes a large amount of oxygen,making it especially vulnerable to oxidative damage.Neurodegenerative diseases,such as Parkinson's disease and Alzheimer's disease,are closely associated with oxidative stress.Accordingly,upregulating the cellular antioxidant defense system is a promising strategy in the prevention or treatment of neurodegeneration.The expression of many antioxidant molecules is predominantly regulated by nuclear factor erythroid 2 related factor 2(Nrf2).Under physiological conditions,Nrf2 is anchored in the cytosol by its suppressor protein,Kelch-like ECH-associated protein 1(Keap1),to facilitate the ubiquitination and proteasome degradation of Nrf2.Under electrophilic/oxidative stress conditions,Nrf2 separates from Keap1 and translocates into the nucleus.With the aid of small Maf proteins,Nrf2 binds to the antioxidant response element(ARE)and initiates the transcription of a set of antioxidant genes.As Nrf2 is a master regulator of the cellular antioxidant response,approaches to activate Nrf2 have gained increasing interest for the treatment of neurodegenerative diseases.Here we report the neuroprotective effect of lipoamide,avenanthramide-2c,dibenzopyrone derivatives,parthenolide,allyl isothiocyanate and IM3829 derivates on PC12 cells,and this action is via the activation of Keap1/Nrf2/ARE signaling pathway.The main contents of this thesis are summarized and classified as follows:1.A brief review of Keap1/Nrf2/ARE signaling pathway and its regulation manners was presented.Meanwhile,we also listed the relationship of this pathway between neurodegenerative disorders and cancers.In addition,recent reported Nrf2 regulators were summarized.2.Lipoamide,parthenolide,allyl isothiocyanate,Aven-2c,and compounds 3,4,6,7(dibenzopyrone derivatives)are from food or Chinese medicine,and they possess multiple pharmacological benefits.We disclosed herein that they are potent agonists of Nrf2 and confer remarkable protection against the hydrogen peroxide-or 6-hydroxydopamine-mediated injuries of PC12 cells.Mechanistic studies revealed that these compounds promoted Nrf2 nuclear translocation and elicited the induction of a series of Nrf2-driven antioxidant molecules,including glutathione,heme oxygenase-1,NAD(P)H:quinone oxidoreductase 1 and thioredoxin reductase.More importantly,genetic silence of Nrf2 abolished the observed cytoprotection,highlighting the importance of Nrf2 in the cytoprotection of these compounds.3.IM3829 is an efficient Nrf2 inhibitor.We designed and synthetized IM3829 derivates,and evaluated their effect on Nrf2.Compound 7 is the most potent Nrf2 activator among these compounds.Subsequently,we evaluated the effect of compound7 on PC12 cells.This compound protected PC12 cells from oxidative damage,induced the Nrf2 activation,and promoted the expression of a set of phase II enzymes.Compound 7 has a novel scaffold for Nrf2 activation,and it might be a potential candidate for the prevention of neurodegenerative diseases.