Shengli Quan,Jinhua Li,Shuxian Ding,Xingjie Zhuo,Yuanxiao Yang,Qin Li
Background Parkinson's disease is a progressive neurodegenerative disorder of the brain, that commonly leads to motor dysfunction and dementia. Artemether is a semi - synthetic derivative of artemisinin, which is extracted from the traditional Chinese herb Artemisia annua. And it is widely used in the treatment of malaria. Recent studies have shown that it exhibits significant neuroprotective effects and holds potential for the treatment of neurodegenerative diseases. However, its effects and mechanisms in the context of Parkinson 's disease remain unclear. Objective To explore Artemether's neuroprotective effects and mechanisms in 6-OHDA-induced PD models. Methods Network pharmacology and molecular docking were used to predict potential pathways and targets of Artemether against Parkinson's disease. PD models were established using 6-OHDA-induced PC12 cells and C57BL/6 mice to assess Artemether's effects and mechanisms. Results Through network pharmacological analysis and molecular docking verification, it was found that Artemether against Parkinson 's disease was related to apoptosis-related signaling pathways, and Artemether had good spontaneous binding activity with key targets PI3K, Akt, GSK-3β, and Bcl-2. Furthermore, the related experimental results showed that Artemether could increase the cell viability of PC12 cells induced by 6-OHDA, reduce intracellular ROS level, increase mitochondrial membrane potential and decrease apoptosis. In addition, Artemether improved motor dysfunction and cognitive dysfunction in Parkinson 's disease mice, and increased the expression of dopamine neurons in both the Substantia Nigra and Striatum. Conclusion Artemether exerted neuroprotective effects in Parkinson 's disease models in vitro and in vivo induced by 6-OHDA through the PI3K/Akt/GSK-3β signaling pathway.
Low-density lipoprotein receptor-related protein 1 (LRP1) and tau play an important role in developing Alzheimer's disease. This study aimed to explore the involvement of LRP1 in microtubule dynamic and depressive-like behavior in a depressive-like rat model. It also investigated whether fluoxetine blocked the change induced by chronic unpredictable mild stress (CUMS). Sprague–Dawley rats (200–250 g) were exposed to CUMS and fluoxetine for 4 weeks respectively. The body weight was determined, and behavior tests, including sucrose preference test, forced swimming test and open field test were performed. Western blot analysis was conducted to determine the protein levels of LRP1, tubulin, Acet-tub, Tyr-tub and PI3K/Akt/GSK-3β. Real-time quantitative polymerase chain reaction was used for mRNA expression levels of LRP1. Immunohistochemical staining was applied for LRP1 and immunofluorescence staining for the co-location of p-tau (404,262) and Acet-tub. The CUMS group presented a decreased body weight and depressive-like behavior, which was improved by fluoxetine. The protein and mRNA expression levels of LRP1 were elevated in the CUMS group. The levels of Acet-tub increased following CUMS, accompanied by elevated levels of p-tau (404,262). The binding of p-tau and Acet-tub significantly decreased in depressive-like rats, and fluoxetine attenuated microtubule instability. Finally, the inhibition of CUMS-induced PI3K/Akt activated GSK-3β, and fluoxetine reversed the change in the signaling pathway. Hence, LRP1 might impair the microtubule dynamics accompanied by depressive-like behavior via the PI3K/ Akt /GSK3β pathway in adult depressive-like rats, and hippocampal LRP1 might be involved in the development of depression.
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