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

Abstract

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.

• Authors: Tian Ming Tu, Brad J Kolls, Erik J Soderblom, Viviana Cantillana, Paul Durham Ferrell, M Arthur Moseley, Haichen Wang, Hana N Dawson, Daniel T Laskowitz
• Journal: Annals of clinical and translational neurology (Ann Clin Transl Neurol) Vol. 4 Issue 4 Pg. 246-265 (04 2017) ISSN: 2328-9503 [Print] United States
• PMID: 28382306 (Publication Type: Journal Article)