Unrevealing possible mechanism of Riluzole, Salsalate and Nimodipine in Alzheimer's disease: multi-target network pharmacological perspective.

BACKGROUND: Riluzole (RLZ), a benzothiazole, maintains glutamatergic homeostasis, salsalate (SLS) a NSAIDs suppresses NF-κB, and Nimodipine (NMD) blocks of calcium channels, addressing Alzheimer’s Diseases (AD) related excitotoxic, inflammatory, metabolic, and neurological disorders etc. has mapped drug-target-disease interactions and examined mechanism of RLZ, SLS, and NMD on AD. AIM: This study aims to employ network pharmacology approach to investigate the possible therapeutic mechanism of RLZ, SLS, and NMD in AD. MATERIALS AND METHODS: Developed a PPI network to find the main therapeutic targets of RLZ, SLS, and NMD against AD. Got canonical SMILES (Simplified Molecular Input Line Entry System) from PubChem and used several databases (SwissTargetPrediction, DisGeNET, STRING, DAVID, ShinyGO, ADMETlab 3.0, MolSoft, ProTox 3.0) to find AD-associated genes, pharmacokinetic/toxicity features, and to do functional enrichment. DrugBank, Lexicomp, DailyMed, and Medscape to analyse DDIs. RESULTS: RLZ, SLS, and NMD share 25 targets with AD and share KEGG pathways like “Alzheimer’s disease”, “neurodegeneration multiple diseases”, “insulin-resistance”, etc. with hub genes like CASP3, STAT3, APP, GSK3B, ACE, NOS3, MAPT, IGF1R, ACHE, and PPARA. RLZ primarily targeted nuclear and membrane receptors with high blood-brain barrier penetration, SLS targeted oxidoreductases and inflammatory/tau targets with a broad safety margin, and NMD targeted G-protein coupled receptors and calcium/vascular nodes despite a complex transporter-CYP interactome. DDI analysis showed moderate interactions between the NMD and SLS according to DrugBank and other 3 data base shown no significant interaction. CONCLUSIONS: RLZ, SLS, and NMD target multiple pathogenic pathways to regulate AD. Combining RLZ, SLS, and NMD may reduce excitotoxicity, neuroinflammation, metabolic dysfunction, and vascular injury in AD, suggesting promise for additional in-vivo and clinical trials.