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Neuroprotective Pentapeptide, CN-105, Improves Outcomes in Translational Models of Intracerebral Hemorrhage

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Abstract

Background

Intracerebral 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 isoform-specific 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.

Methods

In three separate experiments, we delivered three intravenous doses of CN-105 (up to 0.20 mg/kg) or vehicle to hypertensive male BPH/2 J mice, spontaneously hypertensive female rats, or 11-month-old male mice within 24-h of ICH. Neuropathological and neurobehavioral outcomes were determined over 3, 7, and 9 days, respectively.

Results

In 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 to − 0.001). In spontaneously hypertensive female rats, CN-105 (0.05 mg/kg) had a significant effect on vestibulomotor function (p < 0.01; η2  = 0.093) and neuroseverity scores (p < 0.05; η2 = 0.083), and reduced contralateral edema expansion (p < 0.01; 95% CI: − 1.41 to − 0.39). In 11-month-old male mice, CN-105 had a significant effect on vestibulomotor function (p < 0.001; η2 = 0.111) but not neuroseverity scores (p > 0.05; η2 = 0.034).

Conclusions

Acute treatment with CN-105 improves outcomes in translational ICH models independent of sex, species, age, or hypertensive comorbidity.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373:1632–44.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics-2020 update: a report from the American heart association. Circulation. 2020;141:e139–596.

    PubMed  Google Scholar 

  3. McFadyen CA, Zeiler FA, Newcombe V, et al. Apolipoprotein E4 polymorphism and outcomes from traumatic brain injury: a living systematic review and meta-analysis. J Neurotrauma. 2019. https://doi.org/10.1089/neu.2018.6052.

    Article  PubMed  Google Scholar 

  4. Alberts MJ, Graffagnino C, McClenny C, et al. ApoE genotype and survival from intracerebral haemorrhage. Lancet. 1995;346:575.

    Article  CAS  PubMed  Google Scholar 

  5. McCarron MO, Weir CJ, Muir KW, et al. Effect of apolipoprotein E genotype on in-hospital mortality following intracerebral haemorrhage. Acta Neurol Scand. 2003;107:106–9.

    Article  CAS  PubMed  Google Scholar 

  6. James ML, Blessing R, Bennett E, Laskowitz DT. Apolipoprotein E modifies neurological outcome by affecting cerebral edema but not hematoma size after intracerebral hemorrhage in humans. J Stroke Cerebrovasc Dis. 2009;18:144–9.

    Article  PubMed  PubMed Central  Google Scholar 

  7. James ML, Sullivan PM, Lascola CD, Vitek MP, Laskowitz DT. Pharmacogenomic effects of apolipoprotein e on intracerebral hemorrhage. Stroke. 2009;40:632–9.

    Article  CAS  PubMed  Google Scholar 

  8. Lei B, Mace B, Bellows ST, et al. Interaction between sex and apolipoprotein e genetic background in a murine model of intracerebral hemorrhage. Transl Stroke Res. 2012;3:94–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Aono M, Bennett ER, Kim KS, et al. Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures. Neuroscience. 2003;116:437–45.

    Article  CAS  PubMed  Google Scholar 

  10. Laskowitz DT, Thekdi AD, Thekdi SD, et al. Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides. Exp Neurol. 2001;167:74–85.

    Article  CAS  PubMed  Google Scholar 

  11. Lei B, James ML, Liu J, et al. Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage. Sci Rep. 2016;6:34834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Laskowitz DT, Lei B, Dawson HN, et al. The apoE-mimetic peptide, COG1410, improves functional recovery in a murine model of intracerebral hemorrhage. Neurocrit Care. 2012;16:316–26.

    Article  CAS  PubMed  Google Scholar 

  13. Guptill JT, Raja SM, Boakye-Agyeman F, et al. Phase 1 randomized, double-blind, placebo-controlled study to determine the safety, tolerability, and pharmacokinetics of a single escalating dose and repeated doses of CN-105 in healthy adult subjects. J Clin Pharmacol. 2017;57:770–6.

    Article  CAS  PubMed  Google Scholar 

  14. Percie du Sert N, Hurst V, Ahluwalia A, et al. The ARRIVE guidelines 20: updated guidelines for reporting animal research. PLOS Biol. 2020;18:e3000410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lei B, Sheng H, Wang H, et al. Intrastriatal injection of autologous blood or clostridial collagenase as murine models of intracerebral hemorrhage. J Vis Exp. 2014. https://doi.org/10.3791/51439.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Laskowitz DT, Wang H, Chen T, et al. Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumatic brain injury murine model. Sci Rep. 2017;7:46461.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hamm RJ, Pike BR, O’Dell DM, Lyeth BG, Jenkins LW. The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J Neurotrauma. 1994;11:187–96.

    Article  CAS  PubMed  Google Scholar 

  18. Garcia JH, Wagner S, Liu KF, Hu XJ. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats statistical validation. Stroke. 1995;26:627–34.

    Article  CAS  PubMed  Google Scholar 

  19. Warner DS, James ML, Laskowitz DT, Wijdicks EF. Translational research in acute central nervous system injury: lessons learned and the future. JAMA Neurol. 2014;71:1311–8.

    Article  PubMed  Google Scholar 

  20. Participants HSAIHR. (2018) Basic and Translational research in intracerebral hemorrhage: limitations, priorities, and recommendations. Stroke 2018;49:1308-14.

  21. Selim M, Hanley D, Steiner T, et al. Recommendations for clinical trials in ICH. Stroke. 2020;51:1333–8.

    Article  PubMed Central  Google Scholar 

  22. Yin C, Ackermann S, Ma Z, et al. ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med. 2019;25:496–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Laskowitz DT, Goel S, Bennett ER, Matthew WD. Apolipoprotein E suppresses glial cell secretion of TNF alpha. J Neuroimmunol. 1997;76:70–4.

    Article  CAS  PubMed  Google Scholar 

  24. Martini SR, Flaherty ML, Brown WM, et al. Risk factors for intracerebral hemorrhage differ according to hemorrhage location. Neurology. 2012;79:2275–82.

    Article  PubMed  PubMed Central  Google Scholar 

  25. James ML, Warner DS, Laskowitz DT. Preclinical models of intracerebral hemorrhage: a translational perspective. Neurocrit Care. 2008;9:139–52.

    Article  PubMed  Google Scholar 

  26. Bhatia PM, Chamberlain R, Luo X, Hartley EW, Divani AA. Elevated blood pressure causes larger hematoma in a rat model of intracerebral hemorrhage. Transl Stroke Res. 2012;3:428–34.

    Article  CAS  PubMed  Google Scholar 

  27. Tu TM, Kolls BJ, Soderblom EJ, et al. Apolipoprotein E mimetic peptide, CN-105, improves outcomes in ischemic stroke. Ann Clin Transl Neurol. 2017;4:246–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Caceres JA, Goldstein JN. Intracranial hemorrhage. Emerg Med Clin North Am. 2012;30:771–94.

    Article  PubMed  PubMed Central  Google Scholar 

  29. James ML, Cox M, Xian Y, et al. Sex and age interactions and differences in outcomes after intracerebral hemorrhage. J Womens Health. 2017;26:380–8.

    Article  Google Scholar 

  30. Hemphill JC 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001;32:891–7.

    Article  PubMed  Google Scholar 

  31. Kuramatsu JB, Sauer R, Mauer C, et al. Correlation of age and haematoma volume in patients with spontaneous lobar intracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 2011;82:144–9.

    Article  PubMed  Google Scholar 

  32. Gong Y, He Y, Gu Y, Keep RF, Xi G, Hua Y. Effects of aging on autophagy after experimental intracerebral hemorrhage. Acta Neurochir Suppl. 2011;111:113–7.

    Article  PubMed  Google Scholar 

  33. Lively S, Schlichter LC. Age-related comparisons of evolution of the inflammatory response after intracerebral hemorrhage in rats. Transl Stroke Res. 2012;3:132–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu J, Zhou G, Kolls BJ, et al. Apolipoprotein E mimetic peptide CN-105 improves outcome in a murine model of SAH. Stroke Vasc Neurol. 2018;3:222–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Norden DM, Muccigrosso MM, Godbout JP. Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology. 2015;96:29–41.

    Article  CAS  PubMed  Google Scholar 

  36. Godbout JP, Chen J, Abraham J, et al. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. Faseb J. 2005;19:1329–31.

    Article  CAS  PubMed  Google Scholar 

  37. Roh D, Sun C-H, Murthy S, et al. Hematoma expansion differences in lobar and deep primary intracerebral hemorrhage. Neurocrit Care. 2019;31:40–5.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Roh D, Chang T, Zammit C, et al. Functional coagulation differences between lobar and deep intracerebral hemorrhage detected by rotational thromboelastometry: a pilot study. Neurocrit Care. 2019;31:81–7.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yu AW, Cutcliffe HC, Laskowitz DT, et al. Neuroprotective effect of an apoE mimetic peptide in a gyrencephalic blast animal model. 2018 Military Health System Research Symposium. Kissimmee, FL, USA2018.

  40. Sheng Z, Prorok M, Brown BE, Castellino FJ. N-methyl-D-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein. Neuropharmacology. 2008;55:204–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Guttman M, Prieto JH, Handel TM, Domaille PJ, Komives EA. Structure of the minimal interface between ApoE and LRP. J Mol Biol. 2010;398:306–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Misra UK, Adlakha CL, Gawdi G, McMillian MK, Pizzo SV, Laskowitz DT. Apolipoprotein E and mimetic peptide initiate a calcium-dependent signaling response in macrophages. J Leukoc Biol. 2001;70:677–83.

    CAS  PubMed  Google Scholar 

  43. Croy JE, Brandon T, Komives EA. Two apolipoprotein E mimetic peptides, ApoE(130–149) and ApoE(141–155)2, bind to LRP1. Biochemistry. 2004;43:7328–35.

    Article  CAS  PubMed  Google Scholar 

  44. Pocivavsek A, Mikhailenko I, Strickland DK, Rebeck GW. Microglial low-density lipoprotein receptor-related protein 1 modulates c-Jun N-terminal kinase activation. J Neuroimmunol. 2009;214:25–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was funded by the National Institutes of Health [NINDS 1 R41 NS108821-01 (MLJ, DTL)].

Author information

Authors and Affiliations

  1. Department of Neurology, Duke University, Durham, NC, USA

    Haichen Wang, Yufeng Lin, Shan Huang, Viviana Cantillana, Michael L. James & Daniel T. Laskowitz

  2. Department of Orthopaedic Surgery, Duke University, Durham, NC, USA

    Timothy D. Faw

  3. Department of Neurology, Tianjin First Central Hospital, Tianjin, China

    Yufeng Lin

  4. Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China

    Shan Huang

  5. Department of Radiology, Duke University, Durham, NC, USA

    Talaignair N. Venkatraman & Christopher D. Lascola

  6. Department of Anesthesiology, Duke University, Durham, NC, USA

    Michael L. James & Daniel T. Laskowitz

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  1. Haichen Wang
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Contributions

HW, MLJ and DTL designed the research. HW, YL, SH, VC and TNV performed the research and collected the data. HW, DTL, CDL, VC, TNV, MLJ and TDF analyzed and interpreted the data. TDF, HW, MLJ and DTL wrote the manuscript. HW, TDF and CDL prepared the figures. All authors edited the manuscript and approved the final version.

Corresponding author

Correspondence to Daniel T. Laskowitz.

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Conflict of interest

Dr. Laskowitz is an officer and has equity in Aegis CN, LLC which supplied the study drug. Dr. Wang serves as a consultant for and Dr. James has received grant funding from Aegis CN, LLC. Aegis CN, LLC had no editorial control over the study design, its execution, or the writing of this manuscript. Duke University has equity and an intellectual property stake in CN-105.

Ethics Approval

All experiments were approved by and conducted in accordance with the Duke University Institutional Animal Care and Use Committee.

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Wang, H., Faw, T.D., Lin, Y. et al. Neuroprotective Pentapeptide, CN-105, Improves Outcomes in Translational Models of Intracerebral Hemorrhage. Neurocrit Care 35, 441–450 (2021). https://doi.org/10.1007/s12028-020-01184-y

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  • DOI: https://doi.org/10.1007/s12028-020-01184-y

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