Physical trauma is only part of the problem in spinal cord injury (SCI): in the days and weeks following damage, oxidative stress plays a critical role in SCI pathology. Despite years of research, conventional strategies aiming to scavenge transient free radicals have not demonstrated any clinical efficacy at curtailing oxidative stress. Evidence indicates that an aldehyde byproduct of lipid peroxidation-acrolein-is elevated following SCI, and that this species is directly toxic to neural tissues, with a much longer half-lfe than the better known reactive oxygen species. Therefore, we hypothesize that acrolein is a key factor in perpetuating oxidative stress following SCI, and thus constitutes a more effective target for therapeutic treatments. We further hypothesize that suppression of acrolein may significantly reduce neuronal damage and enhance functional recovery following SCI. Having demonstrated ample support in vitro and ex vivo, we are now poised to test this hypothesis in vivo through animal models of SCI, an indispensible next step to implicate acrolein as a key factor in SCI. The objective of this application is to ascertain the role of acrolein in post-traumatic pathogenesis in a live animal model of SCI. We will use an established rat spinal cord contusion injury model with three specific aims. First, we seek to quantify the levels of acrolein for multipe severities of injury using high performance liquid chromatography and immunoblotting methods, and correlate those levels with pathological changes in SCI in vivo. Secondly, we will assess the role of acrolein in causing SCI independent of physical trauma by directly injecting varying concentrations of acrolein to the spinal cord of uninjured rats. This experiment will provide crucial evidence to implicate acrolein in secondary injury mechanisms of SCI. Finally, we will evaluate the effectiveness of acrolein binding as therapeutic strategy using two known acrolein scavengers, hydralazine and phenelezine in rat SCI in vivo. The expected outcomes of the proposed work are that we will establish acrolein as an endogenous toxin following spinal cord trauma and a critical factor in secondary expansion of lesions in SCI. By demonstrating that acrolein is a novel, effective target for therapeutic intervention, we expect that existing pharmaceutics can be rapidly translated to clinical therapy for SCI victims, and that new and existing compounds will be investigated for their potential as acrolein scavenging treatments. Such therapeutic strategies could benefit not only spinal cord injury, but also patients with other diseases associated with oxidative stress.

Public Health Relevance

This project is seeking to determine if acrolein plays a key role in spinal cord injury (SCI) in vivo. Following quantification in SCI, acrolein will be examine for its role in secondary injury and anti-acrolein therapy will be tested for enhancing recovery in SCI. Success in this study will establish acrolein as a novel target for therapeutic intervention i SCI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS073636-03S1
Application #
8890974
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jakeman, Lyn B
Project Start
2012-02-15
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Purdue University
Department
Other Basic Sciences
Type
Schools of Veterinary Medicine
DUNS #
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
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