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

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 Aß 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.

Huang-Pu-Tong-Qiao Formula Ameliorates the Hippocampus Apoptosis in Diabetic Cognitive Dysfunction Mice by Activating CREB/BDNF/TrkB Signaling Pathway.

BACKGROUND: Huang-Pu-Tong-Qiao formula (HPTQ), a traditional Chinese medicine (TCM) formula used to improve cognitive impairment. However, the underlying neuroprotective mechanism of HPTQ treated for diabetic cognitive dysfunction (DCD) remains unclear. The purpose of this study was to investigate the neuroprotective mechanism of HPTQ in DCD mice based on molecular docking. METHODS: To investigate the neuroprotective effect of HPTQ in DCD, the Morris water maze (MWM), novel object recognition (NOR) test was used to detect the learning and memory changes of mice; hematoxylin-eosin (HE) staining was used to investigate the damage of hippocampal neurons; the western blot (WB) was used to examine the level of brain-derived neurotrophic factor (BDNF) of hippocampus. To investigate the neuroprotective mechanism of HPTQ in DCD, molecular docking was used to predict the possible target proteins of different active components in HPTQ and then the WB was used to verify the expression of key target proteins in the hippocampus of mice. RESULTS: HPTQ improved the learning and memory ability, hippocampal neuron damage, and the level of BDNF in the hippocampus of the DCD model treated with HFD/STZ for 12 weeks. Besides, the results of molecular docking showed that the main chemical components of HPTQ could be well combined with the targets of Bcl-2-associated X (Bax) and B-cell lymphoma2 (Bcl-2) and caspase-3. The levels of Bax/Bcl-2 protein ratio and caspase-3 increased in the DCD model while the HPTQ inhibited it. In addition, HPTQ restored DCD-induced decline of p-CREB, BDNF, TrkB, and p-Akt in the hippocampus. CONCLUSIONS: These data indicated that HPTQ ameliorates the hippocampus apoptosis in diabetic cognitive dysfunction mice by activating CREB/BDNF/TrkB signaling pathway.