title: Class I PI3K inhibitor ZSTK474 mediates a shift in microglial/macrophage phenotype and inhibits inflammatory response in mice with cerebral ischemia/reperfusion injury.
abstract: Microglia/macrophages play a critical role in the inflammatory and immune processes of cerebral ischemia/reperfusion injury. Since microglia/macrophages can reversibly shift their phenotype toward either a "detrimental" or a "restorative" state in the injured central nervous system (CNS), compounds mediate that shift which could inhibit inflammation and restore the ability to alleviate cerebral ischemia/reperfusion injury would have therapeutic potential.
  
  
  
  Transient middle cerebral artery occlusion was induced in male C57BL/6 mice. Mice were randomly separated into a sham-operated group, a control group, and a ZSTK474-treated group. We investigated the effect of ZSTK474 by assessing neurological deficits, infarct volume, and histopathological changes. We then determined the potential mechanism by immunofluorescent staining, quantitative real-time polymerase chain reaction (PCR), and Western blot analysis. The Tukey's test or Mann-Whitney U test was used to compare differences among the groups.
  
  
  
  ZSTK474 alleviated neurological deficits and reduced infarct volume in the cerebral ischemia/reperfusion injury model. Presumably, ZSTK474 shifted the phenotype of microglia/macrophages to a restorative state, since this treatment decreased the secretion of pro-inflammatory factors and advanced the secretion of anti-inflammatory factors. These neuroprotective properties of ZSTK474 may be mediated by the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway.
  
  
  
  ZSTK474 can mediate a shift in microglia/macrophage phenotype and inhibit the inflammatory response in cerebral ischemia reperfusion injury of mice. These effects appeared to ensue via the PI3K/AKT/mTORC1 pathway. Therefore, ZSTK474 may represent a therapeutic intervention with potential for circumventing the catastrophic aftermath of ischemic stroke.
authors.affiliation: Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Department of Neurology, Baotou Central Hospital, Baotou, Inner Mongolia, 014000, China.
authors.forename: Po
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
authors.forename: Yating
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
authors.forename: Daojing
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
authors.forename: Ranran
authors.initials: R
authors.lastname: Han
authors.affiliation: Genome Analysis Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300000, China.
authors.forename: Guiyou
authors.initials: G
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Dexin
authors.initials: D
authors.lastname: Kong
authors.affiliation: Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China. hjw@tmu.edu.cn.|Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China. hjw@tmu.edu.cn.
authors.forename: Junwei
authors.initials: J
authors.lastname: Hao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D015703:Antigens, CD / Q000378:metabolism; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002545:Brain Ischemia / Q000150:complications*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury; D015398:Signal Transduction / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D014227:Triazines; C510150:ZSTK474; D052247:Nitric Oxide Synthase Type II
keywords: Cerebral ischemia reperfusion injury; Inflammation; Microglia/macrophages; PI3K/AKT/mTORC1 pathway; ZSTK474