Chrysophanol exerts neuroprotective effects via interfering with endoplasmic reticulum stress apoptotic pathways in cell and animal models of Alzheimer's disease
Chrysophanol exerts neuroprotective effects via interfering with endoplasmic reticulum stress apoptotic pathways in cell and animal models of Alzheimer's disease
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大黄酚通过干扰阿尔茨海默病细胞和动物模型中的内质网应激凋亡途径发挥神经保护作用
DOI：
10.1093/jpp/rgab148
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发表时间：
2021-11-13
影响因子：
3.3
通讯作者：
Cai, Biao
中科院分区：
文献类型：
--
作者：
Li, Xinquan;Cheng, Yaxun;Cai, Biao
目的大黄酚（CHR）又称大黄根茎，是中药的重要成分。由于其抗炎作用，它已被广泛研究为许多疾病的潜在治疗方法。然而，很少有研究表明CHR在阿尔茨海默病（AD）的细胞和动物模型中具有潜在的治疗作用。因此，我们的目的是研究CHR是否可以作为AD患者的潜在治疗方法，并进一步揭示其潜在机制。越来越多的研究表明，内质网（ER）钙（Ca2+）稳态在阿尔茨海默病的发病机制中起着核心作用。此外，内质网应激（ERS）的增加促进了神经元的凋亡，过度的氧化应激是内质网应激的诱导剂。因此，我们认为ers介导的细胞凋亡可能是AD的病因之一。方法观察CHR对AD大鼠和AD细胞模型的神经保护作用，并探讨其可能的机制。主要发现：CHR可减轻神经元损伤。在AD细胞模型中，CHR显著抑制A β(25-35)诱导的神经元损伤，减少凋亡细胞数量，提高细胞存活率。Western blot结果显示，CHR处理后caspases 3、9和12的表达降低，CHR也影响ERS信号通路。此外，CHR通过抑制GRP78信号传导，降低了AD细胞模型中促凋亡蛋白的高表达。进一步研究表明，过表达的蛋白激酶R （PKR）样内质网激酶（PERK）抑制了CHR对PERK的调节作用，削弱了CHR对AD细胞模型的神经保护作用。结论本研究揭示了CHR在AD治疗中通过调节ERS发挥神经保护作用的新机制。
Objectives Chrysophanol (CHR), also well-known as Rhei radix et rhizome, is a crucial component in traditional Chinese medicine. It has been widely studied as a potential treatment for many diseases due to its anti-inflammatory effects. However, there are very few studies to establish the potential therapeutic effect of CHR in cell and animal models of Alzheimer's disease (AD). Therefore, we aim to investigate whether CHR could be used as a potential therapeutic approach to patients with AD and further disclose the underlying mechanism. Increasing studies have shown that endoplasmic reticulum (ER) calcium (Ca2+) homeostasis emerges as a central player in AD pathogenesis. Moreover, augmentation of ER stress (ERS) promotes neuronal apoptosis, and excessive oxidative stress is an inducer of ERS. Therefore, we believe that ERS-mediated apoptosis may be one of the causes of AD.Methods This study examined the neuroprotective effects of CHR on AD rats and AD cell models and explored its potential mechanism.Key findings CHR could reduce the damage of neurons. In AD cell models, CHR significantly inhibited A beta(25-35)-induced neuronal damage, reduced the number of apoptotic cells and improved cell survival rate. Western blot showed that the expression of caspases 3, 9 and 12 was decreased after CHR treatment, and CHR also affected the ERS signalling pathway. In addition, the higher expression of pro-apoptotic proteins in the AD cell model was reduced after CHR treatment by inhibiting GRP78 signalling. Further studies have shown that overexpressed protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) inhibited the regulatory effect of CHR on PERK and weakened the neuroprotective effect of CHR on the AD cell model.Conclusions This study revealed a novel mechanism through which CHR plays a neuroprotective role by regulating ERS when it comes to the therapy of AD.