Analysis of the Molecular Mechanism of Punicalagin in the Treatment of Alzheimer’s Disease by Computer-Aided Drug Research Technology

Abstract

The objective of this work is to explore the effect and potential mechanism of Punicalagin (Pun) in managing Alzheimer’s disease (AD) based on computer-aided drug technology. The following methods were used: the intersection genes of Pun and AD were retrieved from the database and subjected to PPI analysis, GO, and KEGG enrichment analyses. Preliminary verification was performed by molecular docking, molecular dynamics (MD) simulation, and combined free energy calculation. The motor coordination and balance ability, anxiety degree, spatial learning, and memory ability of mice were measured by a rotating rod fatigue instrument, elevated cross maze, and Y maze, respectively. The amyloid β protein (Aβ) in the hippocampus was examined by immunohistochemistry, and the phosphorylation of serine at position 404 of the tau protein (Tau-pS404) was examined by western blot in the mouse brain. The PPI network of Pun showed that the intersection genes were closely related and enriched in muscle cell proliferation and the response to lipopolysaccharide. Results of molecular docking, MD simulations, and MM-GBSA demonstrated that Pun was closely bound to the target protein. Pun could improve the cognitive function of AD mice, as well as reduce Aβ1‑42 deposition and Tau phosphorylation in the brain (P < 0.05, P < 0.01). It can be concluded that Pun holds great promise in improving the cognitive function of AD mice. Mechanistically, Pun potentially acts on ALB, AKT1, SRC, EGFR, CASP3, and IGF-1 targets and mediates proteoglycan, lipid, and atherosclerosis in cancer, so as to reduce the accumulation of neurotoxic proteins in the brain.

Molecular docking study involving bioactive natural compounds against SARS-CoV-2 proteins

“…The majority of bioactive compounds found in pomegranate, namely phytobiotics, flavonoids and anthocyanins, are from its peel. These substances possess therapeutic properties, including anti-inflammatory, antioxidant, hypoglycemic and antimicrobial effects (Grabež et al, 2020;Lansky & Newman, 2007;Saeed et al, 2018;Xu et al, 2022).…”

Therapeutic considerations of bioactive compounds in Alzheimer's disease and Parkinson's disease: Dissecting the molecular pathways

“…However, the toxicity profile of punicalagin still largely remains to be studied as few studies reported nephrotoxicity and liver toxicity exerted by punicalagin while other studies reported a lack of any toxic effect by the molecule Cerdá, Llorach, et al, 2003). Studies suggest the effective dose of punicalagin ranges from 12 to 50 mg/kg oral treatment on a daily basis (Xu et al, 2022) et al, 2022). Sesamol was also found to potentially inhibit Aβ aggregations, suppress neuroinflammation, reduce neuronal and synaptic damage and improve memory and cognition in AD mice (Liu et al, 2021).…”

“…Punicalagin is a phenolic compound belonging to the group ellagitannin and is one of the active components of pomegranate Punica granatum . Although possessing low bioavailability (Cerdá, Cerón, et al, 2003; Cerdá, Llorach, et al, 2003; Venusova et al, 2021), the neuroprotective efficacies of punicalagin have been reported in AD and PD studies (Rojanathammanee et al, 2013; Xu et al, 2022). However, the toxicity profile of punicalagin still largely remains to be studied as few studies reported nephrotoxicity and liver toxicity exerted by punicalagin while other studies reported a lack of any toxic effect by the molecule (Cerdá, Cerón, et al, 2003; Cerdá, Llorach, et al, 2003).…”

“…However, the toxicity profile of punicalagin still largely remains to be studied as few studies reported nephrotoxicity and liver toxicity exerted by punicalagin while other studies reported a lack of any toxic effect by the molecule (Cerdá, Cerón, et al, 2003; Cerdá, Llorach, et al, 2003). Studies suggest the effective dose of punicalagin ranges from 12 to 50 mg/kg oral treatment on a daily basis (Xu et al, 2022). A study reported the anti‐inflammatory effects and amelioration of Aβ aggregations in the brain of AD mice, along with behavioural improvement upon treatment with pomegranate juice.…”

“…The same study demonstrated the antiinflammatory effects exerted by the bioactive component of the extract, that is, punicalagin in murine microglial cell culture thus indicating the therapeutic efficacy of the molecule (Rojanathammanee et al, 2013). Another study reported that punicalagin treatment was found to improve memory and cognition, and inhibit Aβ aggregations and tau phosphorylation in the brain of an AD mouse model (Xu et al, 2022). In the 6‐OHDA treated SH‐SY5Y cell model of PD, punicalagin treatment was found to ameliorate ROS production, enhance antioxidant enzyme activity, reduce mitochondrial dysfunction, downregulate NFKB activity and IL‐1β production and increase the viability and survivability of the cells (Chu & Han, 2018).…”