title: Dual neuroprotective pathways of a pro-electrophilic compound via HSF-1-activated heat-shock proteins and Nrf2-activated phase 2 antioxidant response enzymes.
abstract: Activation of the Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and consequent induction of phase 2 antioxidant enzymes is known to afford neuroprotection. Here, we present a series of novel electrophilic compounds that protect neurons via this pathway. Natural products, such as carnosic acid (CA), are present in high amounts in the herbs rosemary and sage as ortho-dihydroquinones, and have attracted particular attention because they are converted by oxidative stress to their active form (ortho-quinone species) that stimulate the Keap1/Nrf2 transcriptional pathway. Once activated, this pathway leads to the production of a series of antioxidant phase 2 enzymes. Thus, such dihydroquinones function as redox-activated 'pro-electrophiles'. Here, we explored the concept that related para-dihydroquinones represent even more effective bioactive pro-electrophiles for the induction of phase 2 enzymes without producing toxic side effects. We synthesized several novel para-hydroquinone-type pro-electrophilic compounds (designated D1 and D2) to analyze their protective mechanism. DNA microarray, PCR, and western blot analyses showed that compound D1 induced expression of heat-shock proteins (HSPs), including HSP70, HSP27, and DnaJ, in addition to phase 2 enzymes such as hemeoxygenase-1 (HO-1), NADP(H) quinine-oxidoreductase1, and the Na(+)-independent cystine/glutamate exchanger (xCT). Treatment with D1 resulted in activation of Nrf2 and heat-shock transcription factor-1 (HSF-1) transcriptional elements, thus inducing phase 2 enzymes and HSPs, respectively. In this manner, D1 protected neuronal cells from both oxidative and endoplasmic reticulum (ER)-related stress. Additionally, D1 suppressed induction of 78 kDa glucose-regulated protein (GRP78), an ER chaperone protein, and inhibited hyperoxidation of peroxiredoxin 2 (PRX2), a molecule that is in its reduced state can protect from oxidative stress. These results suggest that D1 is a novel pro-electrophilic compound that activates both the Nrf2 and HSF-1 pathways, and may thus offer protection from oxidative and ER stress.
authors: Department of Welfare Engineering, Faculty of Engineering, Iwate University, Morioka, Iwate, Japan. tsatoh@iwate-u.ac.jp
authors: Takumi
authors: T
authors: Satoh
authors: Tayebeh
authors: T
authors: Rezaie
authors: Masaaki
authors: M
authors: Seki
authors: Carmen R
authors: CR
authors: Sunico
authors: Takahito
authors: T
authors: Tabuchi
authors: Tomomi
authors: T
authors: Kitagawa
authors: Mika
authors: M
authors: Yanagitai
authors: Mutsumi
authors: M
authors: Senzaki
authors: Chihiro
authors: C
authors: Kosegawa
authors: Hideharu
authors: H
authors: Taira
authors: Scott R
authors: SR
authors: McKercher
authors: Jennifer K
authors: JK
authors: Hoffman
authors: Gregory P
authors: GP
authors: Roth
authors: Stuart A
authors: SA
authors: Lipton
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism / Q000502:physiology*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011809:Quinones / Q000138:chemical synthesis / Q000494:pharmacology*; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000619706:HSF1 protein, human; C000717247:HSPA5 protein, human; D000076249:Heat Shock Transcription Factors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D018696:Neuroprotective Agents; D011809:Quinones; D014157:Transcription Factors