Neuroprotective Compounds through Induction of Heat Shock Proteins

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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 (desi … More gnated 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. Furthermore, NRF2 was translocatd into nuclei by D1 but HSF-1 was already in nuclei in control cells, thus activating NRF2-and HSF-1.responsive transcriptional elements. 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. Less