Improvement of Ferroptosis and Cognitive Function Impairment in Alzheimer's Disease Rats by Ditan Decoction via the JNK/p53 Signaling Pathway

OBJECTIVE  To investigate the effect of Ditan Decoction on ameliorated ferroptosis and cognitive dysfunction in rats with Alzheimer's disease by regulating the JNK/p53 signaling pathway.

METHODS  Sixty SPF-level male SD rats were randomly divided into control group, model group, donepezil group(positive control group, 0.00045 g·kg⁻¹) and Ditan Decoction low-dose, medium-dose, high-dose(2.137, 4.275, 8.550 g·kg⁻¹) groups with 10 rats in each group. Each group of rats was injected with β-amyloid protein(Aβ)_25-35 into the hippocampus to established the model except for the control group. Continued intragastric for 4 weeks and administered once a day. The escape latency and cross-platform times in each group were detected by Morris water maze test. The pathomorphological changes in the hippocampus were observed by Hematoxylin-eosin(HE) staining. The ultrastructural changes of mitochondria in rat hippocampal tissues was used to observed by transmission electron microscopy. The level of reactive oxygen species(ROS) in hippocampal tissue was detected by Flow cytometry. The content of superoxide dismutase(SOD), glutathione(GSH) and malondialdehyde(MDA) in hippocampal tissue of rat were detected by biochemical method. The protein and mRNA relative expression levels of c-Jun amino-terminal kinase(JNK), p53, solute carrier family 7 member 11(SLC7A1), glutathione peroxidase(GPX4), ferritin heavy chain(FTH1) and cyclooxygenase-2(COX-2) in hippocampus was detected by Western blotting and Real-time quantitative polymerase chain reaction(qPCR).

RESULTS  Compared with the model group, the intervention of Ditan Decoction improved the learning and spatial memory abilities of model rats significantly(P<0.05 or P<0.01), alleviated pathological and morphological damage of hippocampal tissue, reduced mitochondrial damage, increased the level of SOD and GSH and reduced the level of MDA and ROS(P<0.05 or P<0.01), down-regulated the expression of JNK, p53, COX-2 proteins and mRNA(P<0.05 or P<0.01), up-regulated the expression of SLC7A11, GPX4, FTH1 protein and mRNA simultaneously(P<0.05 or P<0.01).

CONCLUSION  The mechanism of Ditan Decoction improves cognitive impairment in AD rats may be related to inhibited the JNK/p53 signaling pathway and further inhibited the ferroptosis.