Neuroprotective role of hydralazine in rat spinal cord injury-attenuation of acrolein-mediated damage

Authors

  • Jonghyuck Park,

    1. Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
    2. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
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  • Lingxing Zheng,

    1. Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
    2. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
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  • Andrew Marquis,

    1. Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
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  • Michael Walls,

    1. Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
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  • Brad Duerstock,

    1. Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
    2. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
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  • Amber Pond,

    1. Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
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  • Sasha Vega-Alvarez,

    1. Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
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  • He Wang,

    1. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
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  • Zheng Ouyang,

    1. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
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  • Riyi Shi

    Corresponding author
    1. Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
    2. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
    • Address correspondence and reprint requests to Riyi Shi, Department of Basic Medical Sciences, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA. E-mail: riyi@purdue.edu

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Abstract

Acrolein, an α,β-unsaturated aldehyde and a reactive product of lipid peroxidation, has been suggested as a key factor in neural post-traumatic secondary injury in spinal cord injury (SCI), mainly based on in vitro and ex vivo evidence. Here, we demonstrate an increase of acrolein up to 300%; the elevation lasted at least 2 weeks in a rat SCI model. More importantly, hydralazine, a known acrolein scavenger can provide neuroprotection when applied systemically. Besides effectively reducing acrolein, hydralazine treatment also resulted in significant amelioration of tissue damage, motor deficits, and neuropathic pain. This effect was further supported by demonstrating the ability of hydralazine to reach spinal cord tissue at a therapeutic level following intraperitoneal application. This suggests that hydralazine is an effective neuroprotective agent not only in vitro, but in a live animal model of SCI as well. Finally, the role of acrolein in SCI was further validated by the fact that acrolein injection into the spinal cord caused significant SCI-like tissue damage and motor deficits. Taken together, available evidence strongly suggests a critical causal role of acrolein in the pathogenesis of spinal cord trauma. Since acrolein has been linked to a variety of illness and conditions, we believe that acrolein-scavenging measures have the potential to be expanded significantly ensuring a broad impact on human health.

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The pathological role of acrolein in spinal cord injury (SCI) is demonstrated through its prolonged elevation and subsequent reduction by hydralazine, an acrolein scavenger, which leads to amelioration of tissue damage, motor deficits, and neuropathic pain. Acrolein injection into the spinal cord caused similar SCI pathologies that further support its role as an effective therapeutic target in SCI.

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