Neuroprotective Compounds through Induction of Heat Shock Proteins

KEAP1/Nrf2通路的激活和继而诱导的第二相抗氧化酶被认为具有神经保护作用。在这里，我们提出了一系列新的亲电化合物，通过这一途径保护神经元。天然产物，如鼠尾草酸(CA)，在迷迭香和鼠尾草中以邻二氢苯二酚的形式大量存在，特别引起人们的注意，因为它们被氧化应激转化为其活性形式(邻苯二酚类)，刺激Keap1/Nrf2转录途径。一旦被激活，这一途径就会导致一系列抗氧化剂第二阶段酶的产生。因此，这种二氢对苯二酚的功能是氧化还原激活的“亲电体”。在这里，我们探索了这样一个概念，即相关的对二氢对苯二酚代表着更有效的生物活性亲电体，可以在不产生毒副作用的情况下诱导第二相酶。我们合成了几种新型对苯二酚型亲电化合物(DESI…D2)，以分析它们的保护机制。DNA芯片、聚合酶链式反应和蛋白质印迹分析表明，化合物D1除了诱导HO-1、NADP(H)奎宁氧化还原酶1和Na+非依赖性半胱氨酸/谷氨酸交换蛋白外，还诱导热休克蛋白(HSP70、HSP27和DNAJ)的表达。此外，在对照细胞中，NRF2被转位到细胞核中，而HSF-1已经在细胞核中，从而激活了NRF2-和HSF-1。通过这种方式，D1保护神经细胞免受氧化和内质网(ER)相关的压力。此外，D1抑制了内质网伴侣蛋白GRP78的诱导，并抑制了过氧化还蛋白2(PRX2)的过度氧化，PRX2是一种处于还原状态的分子，可以防止氧化应激。这些结果表明，D1是一种新的亲电化合物，它同时激活NRF2和HSF-1通路，从而可能提供对氧化和内质网应激的保护。较少

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