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/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) in order 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. Treatment with D1 resulted in activation of Nrf2 and 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 GRP78, an ER chaperone protein, and inhibited hyperoxidation of peroxiredoxin 2 (PRX2), a molecule that in it 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.

Transcription factors Hsf1 and Nrf2 engage in crosstalk for cytoprotection

“…Whether HSP25/27 accumulation can activate Nrf2 either directly or indirectly is presently not known. closely-related cyclohexanone derivative (named compound A1) [37], both of which contain electrophilic a,bunsaturated carbonyl groups, the mildly electrophilic sulforaphane analog sulfoxythiocarbamate alkyne [36], and pro-electrophilic oxidizable diphenols [73]. In line with the diverse cytoprotective functions of Hsf1-and Nrf2-dependent proteins, numerous studies have described the protective effects of all of these inducers in various cell culture and animal models of chronic disease, including neurodegenerative and cardiovascular disease, as well as cancer.…”

The Interplay Between Peroxiredoxin-2 and Nuclear Factor-Erythroid 2 Is Important in Limiting Oxidative Mediated Dysfunction in β-Thalassemic Erythropoiesis

“…Recently, we reported that Prx2 expression is up-regulated during both murine and human β-thalassemic erythropoiesis, suggesting a potential functional role for Prx2 to serve as the stress-response cytoprotective system in pathological erythropoiesis (8,13,21,33,34). In other cell models, Prx2 expression has been reported to be under the control of different transcriptional factors such as Nrf2 (45), Foxo3a (37), STAT3 (47), and NF-kB (49).…”

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

“…We showed that CA up-regulates endogenous antioxidant phase II enzymes via the NRF2 transcriptional pathway. Moreover, this pathway is largely responsible for the mechanism of CA action because silencing Nrf2 significantly abrogated the protective effect (30,(40)(41)(42)(43). Here, we wanted to determine if CA could provide neuroprotection in the Mef2d +/− mice model of LIRD (44).…”