Integrated network pharmacology, metabolomics, and microbiome studies to reveal the therapeutic effects of Anacyclus pyrethrum in PD-MCI mice.

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BackgroundAnacyclus pyrethrum (l.) DC has potential value in treating Parkinson's disease (PD)-mild cognitive impairment (MCI), manifesting as impaired memory, attention, executive function, and language. However, the specific targets and modes of action of A. pyrethrum remain unclear.PurposeThe aim of this study was to identify the active components of A. pyrethrum and examine their effectiveness in treating a mouse model of PD-MCI.MethodsWe generated ethanol extracts of A. pyrethrum root (EEAP) and identified its active components and related targets using UHPLC-MS/MS and network pharmacology.The PD-MCI model was induced via intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). After following continuous administration of EEAP,Altered learning or memory, as well as anxiety, were tested using the morris water maze, eight-arm radial arm maze (RAM), and open-field test,elevated plus-maze. Brain histopathology and ultrastructural changes were examined using brightfield microscopy, and electron microscopy, respectively. Furthermore, protein expression was assessed using western blotting.Stool samples were used for metabolomics analysis by UHPLC-MS/MS and for 16S rDNA sequencing to determine the compositional changes of the gut microbiota.We conducted a short-chain fatty acid targeted metabolomics experiment to study their role in the gut-brain axis in PD-MCI.ResultsUsing UPLC-MS-MS, 126 compounds were identified from A. pyrethrum samples.After searching the databases and literature reports, 31 active components and 544 drug-disease targets were screened. Biological processes and molecular functions, such as energy channels, cell signaling, and metabolism, were discovered through GO analysis. The water maze experiment showed that the average swimming distance and escape latency of mice in EEAP groups decreased. The eight-arm maze experiment showed that model had a much higher number of errors related to working memory than the control mice. In the open field experiment, compared with the control group, the mice in the EEAP group exhibited an increase in the average movement speed and total movement distance, along with a decrease in the residence time.In the elevated plus maze, the control had less anxiety than the Model. Donepezil/Levodopa(D/l) mitigated anxiety-like behavior, and EEAP (100-400 mg/kg) showed a dose-dependent increase in open-arm metrics, suggesting it may ease anxiety in mice.Hippocampal tissue of mice treated with different doses of EEAP showed intact cellular layers and the hematoxylin-eosin-stained cones were slightly better;cells were arranged neatly; their morphology was normal, and were distributed uniformly. Electron microscopy revealed that the nuclear membrane, chromatin, and nucleoli were clearly demarcated in the hippocampus of mice treated with different doses of EEAP, contrary to that in the model group. In brain extracts of the EEAP group, lighter thinner bands for amyloid precursor protein (APP) and Aβ were observed compared to those in the model group. In model mice, APP and Aβ protein expression was higher than in the blank group, as shown by stronger bands. In EEAP-treated mice, the bands were weaker, indicating reduced expression. In the model group had lower Bcl-2 and higher Bax levels. EEAP treatment increased Bcl-2 and decreased Bax expression.Compared to the control group, the model showed substantially low glutathione peroxidase (GSH-Px),superoxide dismutase(SOD),catalase (CAT)activity (p 1, p ConclusionEEAP holds great promise as a potential therapeutic agent for PD-MCI, exerting its effects through multiple mechanisms, including regulating protein expression, modulating the fecal metabolic profile, and reshaping the gut microbiota and its metabolites.

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