The Main Alkaloids in Uncaria rhynchophylla and Their Anti-Alzheimer’s Disease Mechanism Determined by a Network Pharmacology Approach

Abstract

Alzheimer’s disease (AD) is a growing concern in modern society, and effective drugs for its treatment are lacking. Uncaria rhynchophylla (UR) and its main alkaloids have been studied to treat neurodegenerative diseases such as AD. This study aimed to uncover the key components and mechanism of the anti-AD effect of UR alkaloids through a network pharmacology approach. The analysis identified 10 alkaloids from UR based on HPLC that corresponded to 90 anti-AD targets. A potential alkaloid target-AD target network indicated that corynoxine, corynantheine, isorhynchophylline, dihydrocorynatheine, and isocorynoxeine are likely to become key components for AD treatment. KEGG pathway enrichment analysis revealed the Alzheimers disease (hsa05010) was the pathway most significantly enriched in alkaloids against AD. Further analysis revealed that 28 out of 90 targets were significantly correlated with Aβ and tau pathology. These targets were validated using a Gene Expression Omnibus (GEO) dataset. Molecular docking studies were carried out to verify the binding of corynoxine and corynantheine to core targets related to Aβ and tau pathology. In addition, the cholinergic synapse (hsa04725) and dopaminergic synapse (hsa04728) pathways were significantly enriched. Our findings indicate that UR alkaloids directly exert an AD treatment effect by acting on multiple pathological processes in AD.

Recent Advances in the Anti-Inflammatory Activity of Plant-Derived Alkaloid Rhynchophylline in Neurological and Cardiovascular Diseases

“…Rhy rescued hippocampal synaptic dysfunction in AD and acts as an inhibitor of ephrin type A-receptor 4-precursor (EphA4) tyrosine kinase [ 68 ]. Oral administration of Rhy reduced EphA4 activity in APP/PS1 transgenic mice as well as restored impaired recurrent potentiation in the hippocampus, substantiating the beneficial effects of Rhy on synaptic dysfunction in AD [ 69 ]. Although Rhy is very effective in reducing the pathogenesis of AD, it has certain limitations such as reduced solubility and poor bioavailability in brain tissue, and low permeability across the blood–brain barrier [ 70 , 71 ].…”

Comparison of the chemical constituents and anti-Alzheimer’s disease effects of Uncaria rhynchophylla and Uncaria tomentosa

“…# p < 0.05 and ## p < 0.01 compared with the sham control group. *p < 0.05 and **p < 0.01 compared with the STZ control group chemical components for the treatment of AD [32][33][34]. Among these alkaloids, rhynchophylline (RN), isorhynchophylline (IRN), corynoxeine (CX), and isocorynoxeine (ICX) have been extensively studied, while other alkaloids derived from these Uncaria species have not been systematically studied yet [27,35].…”

“…RN was also found to improve the Aβ 1-42 -induced spatial cognitive impairments in rats [38] and suppress the Aβ-induced enhancement of spontaneous discharges in the hippocampal CA1 region of rats [39], suggesting that RN has neuroprotective effects on AD. It has been reported that 5 alkaloids in U. rhynchophylla including IRN and ICX are likely to be vital components for AD treatment in a potential alkaloid target-AD target network using a network pharmacology approach [33]. RN, IRN CX, and ICX are representative indole alkaloids from U. rhynchophylla and U. tomentosa.…”

Therapeutic Mechanism and Key Alkaloids of Uncaria rhynchophylla in Alzheimer’s Disease From the Perspective of Pathophysiological Processes

“…Only GO terms in the category biological process were considered in this study. Top 20 GO biological processes and KEGG pathways sorted by the p value were visualized using an online tool ( http://www.bioinformatics.com.cn/ ) ( Zeng et al, 2021c ). We used the pathview software Microsoft Office Powerpoint (version 2019, Microsoft, Seattle, WA) to superimpose the UR targets involved in the Alzheimer disease pathway (hsa05010) and corresponding alkaloids on KEGG pathway map.…”