Chrysophanol exerts a protective effect against Aβ25-35-induced Alzheimer's disease model through regulating the ROS/TXNIP/NLRP3 pathway

Background: The primary pathogenic factors of Alzheimer's disease (AD) have been identified as oxidative stress, inflammatory damage, and Apoptosis. Chrysophanol (CHR) has a good neuroprotective effect on AD, however, the potential mechanism of CHR remains unclear.

Purpose: In this study, we focused on the ROS/TXNIP/NLRP3 pathway to determine whether CHR regulates oxidative stress and neuroinflammation.

Methods: D-galactose and Aβ_25-35 combination were used to build an in vivo model of AD, and the Y-maze test was used to evaluate the learning and memory function of rats. Morphological changes of neurons in the rat hippocampus were observed using hematoxylin and eosin (HE) staining. AD cell model was established by Aβ_25-35 in PC12 cells. The DCFH-DA test identified Reactive Oxygen Species (ROS). The Apoptosis rate was determined using Hoechst33258 and flow cytometry. In addition, the levels of MDA, LDH, T-SOD, CAT, and GSH in serum, cell, and Cell Culture supernatant were detected by colorimetric method. The protein and mRNA expressions of the targets were detected by Western blot and RT-PCR. Finally, molecular docking was used to further verify the in vivo and in vitro experimental results.

Results: CHR could significantly improve learning and memory impairment, reduce hippocampal neuron damage, and reduce ROS production and Apoptosis in AD rats. CHR could improve the survival rate, and reduce the oxidative stress and Apoptosis in the AD cell model. Moreover, CHR significantly decreased the levels of MDA and LDH, and increased the activities of T-SOD, CAT, and GSH in the AD model. Mechanically, CHR significantly reduced the protein and mRNA expression of TXNIP, NLRP3, Caspase-1, IL-1β, and IL-18, and increase TRX.

Conclusions: CHR exerts neuroprotective effects on the Aβ_25-35-induced AD model mainly by reducing oxidative stress and neuroinflammation, and the mechanism may be related to ROS/TXNIP/NLRP3 signaling pathway.

Alzheimer’s disease; Chrysophanol; NLRP3 pathway; Neuroinflammation; Oxidative stress; ROS; TXNIP.