Apolipoprotein E mimetic peptide, CN-105, improves outcomes in ischemic stroke.

Published online

Journal Article

OBJECTIVE: 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. METHODS: 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 100 μL 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. RESULTS: 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. INTERPRETATION: 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.

Full Text

Duke Authors

Cited Authors

  • Tu, TM; Kolls, BJ; Soderblom, EJ; Cantillana, V; Ferrell, PD; Moseley, MA; Wang, H; Dawson, HN; Laskowitz, DT

Published Date

  • April 2017

Published In

Volume / Issue

  • 4 / 4

Start / End Page

  • 246 - 265

PubMed ID

  • 28382306

Pubmed Central ID

  • 28382306

International Standard Serial Number (ISSN)

  • 2328-9503

Digital Object Identifier (DOI)

  • 10.1002/acn3.399

Language

  • eng

Conference Location

  • United States