Cognitive improving actions of tofacitinib in a mouse model of Alzheimer disease involving TNF-α, IL-6, PI3K-Akt and GSK-3β signalling pathway

DeepDrug: An Expert-led Domain-specific AI-Driven Drug-Repurposing Mechanism for Selecting the Lead Combination of Drugs for Alzheimer’s Disease

“…Doxercalciferol, a vitamin D analog, protects neurons against inflammation and oxidative stress 66 . The clinical relevance of these drugs in AD treatment is also supported by their involvement in various stages of AD drug discovery, including literature review 50 , epidemiological study 67 , animal models 48,65 , and human clinical trial (Phase II) 68 , highlighting their potential effectiveness in treating AD.…”

“…All these drugs are potentially relevant candidates for AD treatment based on evidence from previous literature. Specifically, the top drug, Tofacitinib, was identified as one of the top repurposed drugs in AIdriven AD drug-repurposing research, 47 subsequently tested in mouse models 48 . Among the top five drugs, three were Janus kinase (JAK) inhibitors, which can potentially reduce neuroinflammation, an important factor in AD pathology 49 .…”

“…Doxercalciferol is a Vitamin D analog triggering neuronal protection actions against inflammatory and oxidative stress 66 . Moreover, the relevance of these five drug candidates in AD pathology has been demonstrated by their individual involvements in different stages of AD drug discovery; whilst a cited review highlighted the use of Niraparib for AD drug-repurposing 50 , an epidemiological study linked Doxercalciferol to reduced AD risk, based on observational medical records data 67 and animal models that used Tofacitinib and Empagliflozin to treat AD in mice 48,65 , an interventional human clinical trial (Phase II) investigated the effectiveness of Baricitinib on AD treatment 68 . Figure 3 visualizes the lead five-drug combination in the embedding space of the signed directed biomedical graph to understand how the lead combination can work together for AD treatment.…”

“…The top 15 drug candidates identified by DeepDrug (see Table1in "Results") are consistent with prior biological and clinical knowledge. Tofacitinib, a top candidate, was previously highlighted in AI-driven AD research and tested in mice models47,48 . Three of the top five drugs are JAK inhibitors, which can reduce neuroinflammation contributing to AD pathology49 .…”