Abstract

Presently, no pharmacological treatments have been demonstrated to improve long-term functional outcomes following intracerebral hemorrhage (ICH). Clinical evidence associates apolipoprotein E (apoE) genotype with ICH incidence and outcome. While apoE modifies neuroinflammatory responses through its adaptive role in glial downregulation, intact apoE holoprotein is too large to cross the blood-brain barrier (BBB). Therefore, we developed a 5-amino acid peptide – CN-105 – that mimics the polar face of the apoE helical domain involved in receptor interactions. In the current study, we investigated the therapeutic potential of CN-105 in a mouse model of ICH. Three doses of CN-105 (0.05 mg/kg) was administered by tail vein injection within 24 hours after ICH induction. Functional assessment showed durable improvement in vestibulomotor performance after CN-105 treatment, as quantified by increased Rotarod latencies on Days 1–5 post-ICH, and long-term improvement in neurocognitive performance, as quantified by reduced Morris water maze latencies on Days 29–32 post-ICH. Further, brain water content was significantly reduced, neuroinflammation was decreased and hippocampal CA3 neuronal survival was increased, although hemorrhage volume was not affected by CN-105. We concluded, therefore, that pentapeptide CN-105 improved short- and long-term neurobehavioral outcomes in a murine model of ICH, suggesting therapeutic potential for patients with acute ICH.

Highlights

  • Primary intracerebral hemorrhage (ICH) affects as many as 80,000 people every year in the United States alone

  • Hemorrhage volume was not changed after CN-105 treatment

  • Brain inflammatory responses mediate the development of cerebral edema, intracranial hypertension, and secondary neuronal injury

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Summary

Introduction

Primary intracerebral hemorrhage (ICH) affects as many as 80,000 people every year in the United States alone. In several preclinical models of acute brain injury, including ICH, exogenous apoE-mimetic peptides improved functional and histological outcomes when administered intravenously after injury[8,9,10,11,12,13,14,15]. These peptides are well tolerated, cross into the CNS compartment after intravenous administration, and reduce neuroinflammation after acute brain injury[14,16,17]. We hypothesized that intravenous administration of CN-105 in this model reduces cerebral edema, increases neuronal survival, and improves vestibulomotor and cognitive performance after experimental ICH

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