Neuroprotective and Anti-inflammatory Dual-Phenotypic Drug Screening Strategies
Xuehui Liu, Hong-Yuan Liu, Jing Gu, Mouxin Huang, Qin Ouyang · ACS Chemical Neuroscience · 2025
Abstract Traditional drug development, which predominantly focuses on single target/phenotype evaluation, often fails to achieve optimal therapeutic outcomes in multifactorial and multitarget conditions like ischemia-reperfusion injury. In this viewpoint, we highlight a novel dual-phenotypic drug screening strategy targeting neuronal protective and anti-inflammatory effects for treatment of ischemia-reperfusion injury. This strategy involves the utilization of primary neuron treated with oxygen-glucose deprivation/reoxygenation (OGD/R), lipopolysaccharide (LPS)-activated microglial models and coculture systems or brain organoids as in vitro models, as well as mouse middle cerebral artery occlusion/reperfusion (MCAO/R) models for in vivo evaluation. The dual-phenotypic drug screening strategies marks a paradigm shift from single-factorial approach to a system biology-based integrated methodology, offering significant advantages for developing therapies for the complex multifactorial disease ischemia-reperfusion injury.