title: Apolipoprotein E mimetic peptide, CN-105, improves outcomes in ischemic stroke.
abstract: At present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti-inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN-105, in a microglial cell line and murine model of ischemic stroke.
  
  
  
  Ten to 13-week-old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN-105 (0.1 mg/kg) in 100μL volume or vehicle via tail vein injection at various time points. Survival, motor-sensory functional outcomes using rotarod test and 4-limb wire hanging test, infarct volume assessment using 2,3,5-Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor-alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN-105 in ischemic stroke.
  
  
  
  Mice receiving CN-105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN-105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN-105 reduces proinflammatory pathways and lower oxidative stress.
  
  
  
  CN-105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN-105 represents an attractive candidate for clinical translation.
authors.affiliation: Department of Neurology Duke University School of Medicine Durham North Carolina; Department of Neurology National Neuroscience Institute Tan Tock Seng Campus Singapore.
authors.forename: Tian Ming
authors.identifier: 0000-0002-7175-0357
authors.initials: TM
authors.lastname: Tu
authors.affiliation: Department of Neurology Duke University School of Medicine Durham North Carolina.
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Kolls
authors.affiliation: Duke Proteomics Core Facility Center for Genomic and Computational Biology Duke University Durham North Carolina.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Soderblom
authors.affiliation: Department of Neurology Duke University School of Medicine Durham North Carolina.
authors.forename: Viviana
authors.initials: V
authors.lastname: Cantillana
authors.affiliation: Department of Pathology Duke University School of Medicine Durham North Carolina.
authors.forename: Paul Durham
authors.initials: PD
authors.lastname: Ferrell
authors.affiliation: Duke Proteomics Core Facility Center for Genomic and Computational Biology Duke University Durham North Carolina.
authors.forename: M Arthur
authors.initials: MA
authors.lastname: Moseley
authors.affiliation: Department of Neurology Duke University School of Medicine Durham North Carolina.
authors.forename: Haichen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neurology Duke University School of Medicine Durham North Carolina.
authors.forename: Hana N
authors.initials: HN
authors.lastname: Dawson
authors.affiliation: Department of Neurology Duke University School of Medicine Durham North Carolina.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Laskowitz