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Prophylactic treatment with CN-105 improves functional outcomes in a murine model of closed head injury

Experimental Brain Research volume 240, pages 2413–2423 (2022)Cite this article

Abstract

The treatment of traumatic brain injury (TBI) in military populations is hindered by underreporting and underdiagnosis. Clinical symptoms and outcomes may be mitigated with an effective pre-injury prophylaxis. This study evaluates whether CN-105, a 5-amino acid apolipoprotein E (ApoE) mimetic peptide previously shown to modify the post-traumatic neuroinflammatory response, would maintain its neuroprotective effects if administered prior to closed-head injury in a clinically relevant murine model. CN-105 was synthesized by Polypeptide Inc. (San Diego, CA) and administered to C57-BL/6 mice intravenously (IV) and/or by intraperitoneal (IP) injection at various time points prior to injury while vehicle treated animals received IV and/or IP normal saline. Animals were randomized following injury and behavioral observations were conducted by investigators blinded to treatment. Vestibulomotor function was assessed using an automated Rotarod (Ugo Basile, Comerio, Italy), and hippocampal microglial activation was assessed using F4/80 immunohistochemical staining in treated and untreated mice 7 days post-TBI. Separate, in vivo assessments of the pharmacokinetics was performed in healthy CD-1. IV CN-105 administered prior to head injury improved vestibulomotor function compared to vehicle control-treated animals. CN-105 co-administered by IP and IV dosing 6 h prior to injury also improved vestibulomotor function up to 28 days following injury. Microglia counted in CN-105 treated specimens were significantly fewer (P = 0.03) than in vehicle specimens. CN-105 improves functional outcomes and reduces hippocampal microglial activation when administered prior to injury and could be adapted as a pre-injury prophylaxis for soldiers at high risk for TBI.

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Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

A2AD:

Anti-access/area denial

ACURO:

Animal Care and Use Review Office

ANOVA:

Analysis of variance

ApoE:

Apolipoprotein E

CNS:

Central nervous system

DoD:

Department of Defense

LRP-1:

Low density lipoprotein receptor-related protein 1

MRT:

Mean plasma residence time

IP:

Intraperitoneal

IPB:

Intelligence preparation of the battlefield

IV:

Intravenous

PBS:

Phosphate buffered saline

RT:

Room temperature

SD:

Standard deviation

T 1/2 :

Terminal elimination half-life

TBI:

Traumatic brain injury

T max :

Time to maximal plasma concentration

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Funding

Study drug was provided by Aegis CN, LLC. This study was supported by contract DOD CDMRP#W81XWH-16-C-0142 “Prophylactic administration of CN-105 confers neuroprotection against acute brain injury”.

Author information

Authors and Affiliations

  1. 3Rd Special Forces Group (A), U.S. Army Special Operations Command, 111 Enduring Freedom Drive (Stop A), Fort Bragg, NC, 28310, USA

    David Van Wyck

  2. Department of Neurology, Duke University School of Medicine, Durham, NC, 27710, USA

    David Van Wyck, Bradley J. Kolls, Haichen Wang, Viviana Cantillana & Daniel T. Laskowitz

  3. Department of Neurobiology, Duke University School of Medicine, Durham, NC, 27710, USA

    Daniel T. Laskowitz

  4. Aegis-CN LLC., 701 W Main Street, Durham, NC, 27701, USA

    Maureen Maughan & Daniel T. Laskowitz

Authors
  1. David Van Wyck
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  2. Bradley J. Kolls
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  3. Haichen Wang
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  4. Viviana Cantillana
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  5. Maureen Maughan
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  6. Daniel T. Laskowitz
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Contributions

DVW played primary role in data analysis, writing of manuscript. HW performed animal experiments and played a role in editing. BJK played a role in data interpretation and editing. VC performed immunohistochemistry and editing of the manuscript. MM reviewed and edited the manuscript final draft. DTL played a role in experimental design, data analysis, writing and drafting.

Corresponding author

Correspondence to David Van Wyck.

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Conflict of interest

The views expressed are solely those of the authors and do not reflect the official policy or position of the US Army, US Navy, US Air Force, the Department of Defense, or the US Government. Dr. Laskowitz is an officer and has equity in Aegis CN, LLC which supplied the study drug. Dr. Wang serves as a consultant for 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.

Ethical approval and consent to participate

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

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Not applicable.

Additional information

Communicated by Bill J Yates.

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Van Wyck, D., Kolls, B.J., Wang, H. et al. Prophylactic treatment with CN-105 improves functional outcomes in a murine model of closed head injury. Exp Brain Res 240, 2413–2423 (2022). https://doi.org/10.1007/s00221-022-06417-4

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