Chrysophanol exerts neuroprotective effects via interfering with endoplasmic reticulum stress apoptotic pathways in cell and animal models of Alzheimer’s disease

Abstract

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 Aβ 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.

ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments

“…Chrysophanol (aka Rhei radix et rhizome) is a natural anthraquinone, which has been utilized in traditional Chinese medicine owing to its potent anti-inflammatory and anti-oxidative stress activities [ 126 ]. Li et al investigated chrysophanol in cell and animal models of AD with Aβ 25−35 depositions and noted beneficial effects of the compound including a reduction of neuronal apoptosis (evidenced by downregulation of CASP3 and 9), downregulation of ER stress markers, and increased cell survival [ 127 ]. In addition to neurons, chrysophanol can act on microglial cells to dampen neuroinflammation [ 126 ].…”

The Tao Hong Si Wu Decoction ameliorates diabetes‐associated cognitive dysfunction by inhibiting the formation of amyloid plaques

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Herbal/Natural Compounds Resist Hallmarks of Brain Aging: From Molecular Mechanisms to Therapeutic Strategies

“…(medicinal and aromatic plants) act on the structure of Aβ 1–42 to prevent Ca 2+ imbalance and neurotoxicity [ 64 ]. A study on phenols from rhubarb, an important component of Chinese herbal medicines, showed that these compounds exert neuroprotective effects in AD by regulating ER stress [ 65 ]. Furthermore, in the central nervous system, Ca 2+ plays an important role in the regulation of electrical activity and neurotransmitter release [ 66 ].…”