Year: 2017
Type: article
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: L 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.
DOI: 10.1002/acn3.399
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
OpenAlex ID: W2593726173