Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.

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.

• Authors: Beilei Lei, Michael L James, Ji Liu, Guanen Zhou, Talaignair N Venkatraman, Christopher D Lascola, Shawn K Acheson, Laura G Dubois, Daniel T Laskowitz, Haichen Wang
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 34834 (10 07 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27713572 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Apolipoproteins E
• Neuroprotective Agents
• Oligopeptides

Topics

• Animals
• Apolipoproteins E (chemistry)
• Brain Edema (drug therapy)
• CA3 Region, Hippocampal (drug effects, pathology)
• Cell Survival (drug effects)
• Cerebral Hemorrhage (diagnostic imaging, drug therapy, pathology)
• Disease Models, Animal
• Male
• Mice, Inbred C57BL
• Neurons (drug effects, pathology)
• Neuroprotective Agents (pharmacokinetics, pharmacology)
• Oligopeptides (chemistry, pharmacokinetics, pharmacology)
• Rotarod Performance Test