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Author Spotlight: Establishing a Reliable Distal MCA Occlusion Model in Mice for Stroke Research
Published on: December 15, 2023
Multi-dimensional data-driven computational drug repurposing strategy for screening novel neuroprotective agents in
Qingqi Meng1, Qing Liu2, Yan Mi1,2
1Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Key Laboratory of Data Analytics and Optimization for Smart Industry, Ministry of Education, Northeastern University, Shenyang, China.
A new computational drug repositioning strategy identified sulbutiamine as a promising neuroprotective agent for ischemic stroke by targeting pyruvate dehydrogenase kinase 2 (PDK2) and enhancing mitochondrial function.
Area of Science:
- Neuroscience
- Pharmacology
- Computational Biology
Background:
- Developing neuroprotective drugs for ischemic stroke is challenging due to biological complexity and misconceptions.
- Existing approaches have limitations in identifying effective neuroprotective agents.
Purpose of the Study:
- To identify novel neuroprotective agents for ischemic stroke using a Multidimensional Data-Driven Computational Drug Repositioning (MDCDR) strategy.
- To validate the efficacy and elucidate the mechanism of action of identified agents.
Main Methods:
- Integrated ischemic stroke transcriptomics with neuronal protection data.
- Employed the Connectivity Map (CMap) database for drug prediction.
- Developed a machine learning model to screen for neuroprotective agents, followed by in vitro and in vivo validation.
Main Results:
- The MDCDR strategy identified 19 potential neuroprotective agents, with sulbutiamine (SUL) showing significant promise.
- Sulbutiamine demonstrated neuroprotective effects in both cell models (OGD/R) and animal models (MCAO/R), improving survival and reducing neurological deficits.
- Mechanistic studies revealed SUL inhibits pyruvate dehydrogenase kinase 2 (PDK2), enhances mitochondrial function, reduces reactive oxygen species (ROS), and suppresses the MAPK signaling pathway.
Conclusions:
- The MDCDR strategy is effective for screening neuroprotective agents for ischemic stroke.
- Sulbutiamine is a promising neuroprotective agent for ischemic stroke, with PDK2 as a key therapeutic target.
- This study provides a new theoretical basis for developing neuroprotective therapies for ischemic stroke.
