Fructus mume total flavonoids exert neuroprotective effects involving miR-143-3p and CaMKKβ/AMPK/mTOR signaling in experimental models of Parkinson’s disease

Background Parkinson’s disease (PD) is a common neurodegenerative disorder in the elderly. Dysregulated mitophagy contributes to neuronal damage in PD. Fructus mume total flavonoids (FMF), a flavonoid-enriched extract prepared from Fructus mume, have shown neuroprotective effects in experimental models of PD. However, the underlying molecular mechanisms remain incompletely understood. Therefore, this study investigated whether the neuroprotective effects of FMF in rat models of PD were associated with mitophagy and explored the potential underlying mechanisms. Methods A rat model of PD was established by stereotaxic injection of 6-OHDA into the substantia nigra pars compacta (SNpc) and ventral tegmental area. HE staining, Nissl staining, TUNEL staining, immunohistochemistry staining and Western blotting were used to evaluate the effects of FMF and the autophagy inhibitor 3-methyladenine (3-MA) on neuronal injury and mitophagy in the SNpc. Additionally, an in vitro PD model was established by treating SH-SY5Y cells with MPP + to investigate the molecular mechanisms underlying the neuroprotective effects of FMF. Results FMF treatment significantly increased the number of Nissl bodies and reduced neuronal apoptosis in the SNpc of PD rats. FMF also increased the expression of tyrosine hydroxylase, LC3-II, Beclin 1, p62, PINK1, Parkin and TOM20, while reducing α-synuclein accumulation in the SNpc. RT-qPCR analysis showed that FMF significantly upregulated miR-143-3p expression in both the SNpc of PD rats and MPP + -treated SH-SY5Y cells. Additionally, FMF promoted cell proliferation and the expression of mitophagy-related proteins and reduced apoptosis in MPP + -treated SH-SY5Y cells, whereas miR-143-3p inhibitor significantly weakened these pharmacological effects of FMF in MPP + -treated SH-SY5Y cells. Dual-luciferase reporter assays suggested a potential interaction between miR-143-3p and the CaMKKβ 3′UTR. Pharmacological inhibition of the CaMKKβ/AMPK/mTOR signaling pathway also weakened the pharmacological effects of FMF in MPP + -treated SH-SY5Y cells, and co-treatment with the miR-143-3p inhibitor further weakened the pharmacological effects of FMF. Conclusion These findings suggested that FMF may exert neuroprotective effects in experimental models of PD, potentially involving miR-143-3p, CaMKKβ/AMPK/mTOR signaling and mitophagy-associated processes. These findings would provide new mechanistic insights into the neuroprotective effects of FMF and support the potential therapeutic application of FM and its flavonoids in PD.