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bioRxiv · 10.1101/2020.10.15.339184

Neuroprotective pentapeptide, CN-105, improves outcomes in translational models of intracerebral hemorrhage

Wang, H.·Faw, T. D.·Lin, Y.·Huang, S.·Venkatraman, T. N.·Cantillana, V.·Lascola, C. D.·James, M. L.·Laskowitz, D. T.
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Abstract

BackgroundIntracerebral hemorrhage (ICH) is a devastating form of cerebrovascular disease for which there are no approved pharmacological interventions that improve outcomes. Apolipoprotein E (apoE) has emerged as a promising therapeutic target given its neuroprotective properties and ability to modify neuroinflammatory responses. We developed a 5-amino acid peptide, CN-105, that mimics the polar face of the apoE helical domain involved in receptor interactions, readily crosses the blood-brain barrier, and improves outcomes in well-established preclinical ICH models. In the current study, we investigated the therapeutic potential of CN-105 in translational ICH models that account for hypertensive comorbidity, sex, species, and age. MethodsIn three separate experiments, we delivered three intravenous doses of CN-105 (up to 0.20 mg/kg) or vehicle to hypertensive male BPH/2J mice, spontaneously hypertensive female rats, or 11-month old male mice within 24-hours of ICH. Neuropathological and neurobehavioral outcomes were determined over 3, 7, and 9 days, respectively. ResultsIn spontaneously hypertensive male mice, there was a significant dose-dependent effect of CN-105 on vestibulomotor function at 0.05 and 0.20 mg/kg doses (p < 0.05; 95% CI: 0.91 - 153.70 and p < 0.001; 95% CI: 49.54 - 205.62), while 0.20 mg/kg also improved neuroseverity scores (p < 0.05; 95% CI: 0.27 - 11.00) and reduced ipsilateral brain edema (p < 0.05; 95% CI: -0.037 - -0.001). In spontaneously hypertensive female rats, CN-105 (0.05 mg/kg) had a significant effect on vestibulomotor function (p < 0.01; {eta}2 = 0.093) and neuroseverity scores (p < 0.05; {eta}2 = 0.083), and reduced contralateral edema expansion (p < 0.01; 95% CI: -1.41 - -0.39). In 11-month old male mice, CN-105 had a significant effect on vestibulomotor function (p < 0.001; {eta}2 = 0.111) but not neuroseverity scores (p > 0.05; {eta}2 = 0.034). ConclusionsAcute treatment with CN-105 improves outcomes in translational ICH models independent of sex, species, age, or hypertensive comorbidity.

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Wang, H., Faw, T. D., Lin, Y., Huang, S., Venkatraman, T. N., Cantillana, V., Lascola, C. D., James, M. L., Laskowitz, D. T.. 2020-10-15. Neuroprotective pentapeptide, CN-105, improves outcomes in translational models of intracerebral hemorrhage. https://doi.org/10.1101/2020.10.15.339184

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