Zhongguo quanke yixue (Jan 2024)
Modulation of Iron Death by Poric Acid through Nrf2/SLC7A11/GPX4 Signal Pathway in the Improvement of Cognitive Impairment of Alzheimer's Disease Rats
Abstract
Background Alzheimer's disease (AD) is a common and irreversible neurodegenerative brain disease that severely affects the quality of life and survival of patients, while there is still a lack of effective treatments to delay or stop disease progression. Traditional Chinese medicine (TCM) and its active ingredients have important potential in the prevention and treatment of AD. Objective To investigate the effects of poric acid (PA) on cognitive impairment and nuclear factor E2-related factor 2 (Nrf2) /solute carrier family 7A11 (SLC7A11) /glutathione peroxidase 4 (GPX4) signaling pathway in AD rats. Methods Seventy-five male SPF grade SD rats aged 6 to 8 weeks were divided into the control group (Control group), AD Model group (Model group), PA treatment group (PA group) and PA+Nrf2 inhibitor group (PA+ML385 group) by random number table method to prepare AD rat model from January to September, 2022. After successful modeling 50 mg/kg PA was intraperitoneally injected into the PA group, 50 mg/kg PA and 30 mg/kg ML385 was intraperitoneally injected into the PA+ML385 group, and 0.9% sodium chloride solution was intraperitoneally injected into the Control group and Model group. The Morris water maze experiment was performed 24 h after the last dose, and the positioning navigation experiment was carried out on days 2, 4 and 6 to record the time when the rats arrived at the platform (escape latency). The platform was removed on day 7, and the duration of the rats staying on the platform and the number of times they crossed the platform within 120 s were recorded. The pathological changes of hippocampal neurons in each group were observed after Nissl staining. Iron deposition was detected by Prussian blue staining, GPX4 expression and GSH, MDA and Fe2+ contents were detected by immunofluorescence staining. The protein expression levels of Nrf2, SLC7A11 and GPX4 in rat hippocampus were detected by Western blotting. Results The escape latency of the Model group was higher than that of the Control group and PA group, and escape latency of the PA+ML385 group was higher than that of the PA group at 2, 4 and 6 days after the last administration. The platform residence time and platform crossing times in the Model group were lower than those in the Control group and PA group, and those in the PA+ML385 group were lower than those in PA group, and the difference was statistically significant (P<0.05). The results of Nissl staining showed severe neuronal necrosis, nucleus shrinkage and decreased number of Nissl bodies in the Model group, decreased neuronal necrosis with tight arrangement and increased number of Nissl bodies in the PA group, significantly increased neuronal damage and decreased the number of Nissl bodies in the PA+ML385 group. The Prussian blue staining results showed that iron deposition in the Model group was higher than that in the Control group, iron deposition in the PA group was lower than that in the Model group, and iron deposition in the PA+ML385 was higher than that in the PA group. The results of immunofluorescence staining showed that green fluorescence was weakened and GPX4 positive cells were reduced in the Model group, green fluorescence was enhanced and GPX4 positive cells were increased in the PA group compared with the Model group, and GPX4 positive cells were decreased in the PA+ML385 group compared with the PA group. GSH in the Model group was lower than that in the Control group and PA group, GSH in the PA+ML385 group was lower than that in the PA group. MDA and Fe2+ in the Model group were higher than those in the Control group and PA group, and those in the PA+ML385 group were higher that the PA group, and the differences were statistically significant (P<0.05). The relative expression levels of Nrf2, SLC7A11 and GPX4 in the Model group were lower than those in the Control group and PA group, and those in the PA+ML385 group were lower than those in the PA group, and the differences were statistically significant (P<0.05) . Conclusion PA can improve the cognitive impairment of AD rats, and its mechanism may be related to the inhibition of iron death by activating Nrf2/SLC7A11/GPX4 signal pathway.
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