Vascular dementia (VaD), a cognitive impairment resulting from cerebrovascular issues, could be mitigated by Epimedium. This study investigates Epimedium's efficacy in VaD management through a systematic review, network pharmacology, molecular docking, and molecular dynamic simulations (MDS). Comprehensive literature searches were conducted across various databases. Epimedium's pharmacological properties were analyzed using the TCMSP database. Integration with the Aging Atlas database enabled the identification of shared targets between Epimedium and VaD. A protein-protein interaction (PPI) network was constructed, and central targets' topological attributes were analyzed using Cytoscape 3.9.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using “ClusterProfiler” R package. The interactions between Epimedium and central targets were assessed by Molecular docking and MDS. Epimedium and its 23 bioactive components counteracted oxidative stress, neuroinflammation, and neuronal damage, thereby attenuating cognitive deterioration in VaD. A total of 78 common targets were identified, with 22 being significantly related to aging. Enrichment analysis identified 1769 GO terms and 139 KEGG pathways, highlighting the AGE-RAGE signaling pathway. Molecular docking revealed that 23 bioactive components, except Linoleyl acetate, effectively interacted with top central targets (JUN, MAPK14, IL6, FOS, TNF). MDS demonstrated that flavonoids Icariin, Kaempferol, Luteolin, and Quercetin formed stable complexes with RAGE. The study identifies RAGE as a novel therapeutic target for Epimedium in the mitigation of VaD via its anti-inflammatory properties.

Vascular dementia (VaD), a cognitive impairment resulting from cerebrovascular issues, could be mitigated by Epimedium. This study investigates Epimedium's efficacy in VaD management through a systematic review, network pharmacology, molecular docking, and molecular dynamic simulations (MDS). Comprehensive literature searches were conducted across various databases. Epimedium's pharmacological properties were analyzed using the TCMSP database. Integration with the Aging Atlas database enabled the identification of shared targets between Epimedium and VaD. A protein-protein interaction (PPI) network was constructed, and central targets' topological attributes were analyzed using Cytoscape 3.9.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using “ClusterProfiler” R package. The interactions between Epimedium and central targets were assessed by Molecular docking and MDS. Epimedium and its 23 bioactive components counteracted oxidative stress, neuroinflammation, and neuronal damage, thereby attenuating cognitive deterioration in VaD. A total of 78 common targets were identified, with 22 being significantly related to aging. Enrichment analysis identified 1769 GO terms and 139 KEGG pathways, highlighting the AGE-RAGE signaling pathway. Molecular docking revealed that 23 bioactive components, except Linoleyl acetate, effectively interacted with top central targets (JUN, MAPK14, IL6, FOS, TNF). MDS demonstrated that flavonoids Icariin, Kaempferol, Luteolin, and Quercetin formed stable complexes with RAGE. The study identifies RAGE as a novel therapeutic target for Epimedium in the mitigation of VaD via its anti-inflammatory properties.

Vascular dementia (VaD) ranks as the second most prevalent form of dementia and poses a considerable global health challenge. Icariin has been recognized for its robust neuroprotective effects in combating VaD. Nonetheless, the underlying mechanisms have not been fully elucidated. An integrated approach involving network pharmacology, molecular docking, and molecular dynamics simulations (MDS) was employed to systematically investigate the potential pharmacological actions of Icariin in counteracting VaD. The AGE/RAGE pathway was identified as a promising anti-inflammatory pathway. A chronic cerebral hypoperfusion mouse model was utilized to establish VaD. Both Icariin and FP S-ZM1 (a RAGE inhibitor) were administered through oral gavage and intraperitoneal injection, respectively. The Morris water maze (MWZ) was used to evaluate cognitive functions. Moreover, immunofluorescence, RT-qP CR, and Western blot analyses were carried out to evaluate the effects of FP S-ZM1 on neuroinflammation. Network analysis identified 14 crucial targets and highlighted the AGE-RAGE signaling cascade in diabetic complications as the foremost KEGG pathway with potential anti-neuroinflammatory property. MDS results suggested a stable binding of the RAGE-Icariin complex. Remarkably, Icariin was found to effectively mitigate cognitive deficits in VaD mice, which was correlated with the upregulation of the P I3K/AKT pathway and downregulation of the JNK/cJUN signaling cascade. Critically, co-administration of FP S-ZM1 enhanced Icariin’s ameliorative effects on cognitive deficits, owing to bolstered anti-neuroinflammatory action. This study unveils the potential of Icariin in alleviating cognitive dysfunction and neuroinflammation in VaD, which may be attributed to the modulation of the AGE/RAGE pathway. Communicated by Ramaswamy H. Sarma

Vascular dementia (VaD) ranks as the second most prevalent form of dementia and poses a considerable global health challenge. Icariin has been recognized for its robust neuroprotective effects in combating VaD. Nonetheless, the underlying mechanisms have not been fully elucidated. An integrated approach involving network pharmacology, molecular docking, and molecular dynamics simulations (MDS) was employed to systematically investigate the potential pharmacological actions of Icariin in counteracting VaD. The AGE/RAGE pathway was identified as a promising anti-inflammatory pathway. A chronic cerebral hypoperfusion mouse model was utilized to establish VaD. Both Icariin and FP S-ZM1 (a RAGE inhibitor) were administered through oral gavage and intraperitoneal injection, respectively. The Morris water maze (MWZ) was used to evaluate cognitive functions. Moreover, immunofluorescence, RT-qP CR, and Western blot analyses were carried out to evaluate the effects of FP S-ZM1 on neuroinflammation. Network analysis identified 14 crucial targets and highlighted the AGE-RAGE signaling cascade in diabetic complications as the foremost KEGG pathway with potential anti-neuroinflammatory property. MDS results suggested a stable binding of the RAGE-Icariin complex. Remarkably, Icariin was found to effectively mitigate cognitive deficits in VaD mice, which was correlated with the upregulation of the P I3K/AKT pathway and downregulation of the JNK/cJUN signaling cascade. Critically, co-administration of FP S-ZM1 enhanced Icariin’s ameliorative effects on cognitive deficits, owing to bolstered anti-neuroinflammatory action. This study unveils the potential of Icariin in alleviating cognitive dysfunction and neuroinflammation in VaD, which may be attributed to the modulation of the AGE/RAGE pathway. Communicated by Ramaswamy H. Sarma