Xanthoangelol Mitigates Neuroinflammation and Hypoxia via MAPK and HIF-1 Signaling Modulation: Network Pharmacology and In-Vivo Approach in a Haloperidol-Induced Model of Parkinson’s Disease

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Abstract Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that is produced by a network of interdependent pathophysiological processes, such as oxidative stress, neuroinflammation, ferroptosis, pyroptosis, apoptosis, autophagic failure, endocrine dysregulation, and aberrant neuronal signalling. Therefore, multitarget pharmacological natural products have potential therapeutic uses in alleviating this heterogeneity of mechanisms. Saposhnikovia divaricata is a common medicinal herb that contains a wide array of bioactive compounds, which have been reported to exhibit antioxidant, anti-inflammatory, and neuroprotective effects. Eight key terpenoids and coumarins: scopoletin, fraxidin, isofraxidin, 5-O-methylvisamminol, deltoin, anomalin, α-pinene, and panaxydol were chosen in this investigation after ADME filtration to evaluate their suitability in AD. We employed integrative network pharmacology, mechanistic target profiling, protein interaction network construction, identification of hub genes, KEGG pathway enrichment for Alzheimer's disease, and in silico docking to systematically elucidate the mechanistic relevance of each compound. Fraxidin, panaxydol, deltoin, and 5-O-methylvisamminol showed the most significant common targets between them and the main regulatory nodes, including AKT1, MTOR, CASP3, MAPK, INS, and NFKB1. Molecular docking made an emphasis on strong ligand protein interactions, and deltoin, panaxydol, and anomalin binding PTGS2 (ΔG -8.03 kcal mol − 1), MTOR (ΔG -7.65 kcal mol − 1), and INS (ΔG -7.74 kcal mol − 1) were found to have a strong binding affinity. Altogether, these data present several S.divaricata constituents as promising multitarget modulators of AD pathophysiology, which gives a solid foundation in terms of the future experimental validation and emphasizes the therapeutic value of coumarins and terpenoids in the modification of neurodegenerative diseases.

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