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.
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.
|Tully, Melissa; Tang, Jonathan; Zheng, Lingxing et al. (2018) Systemic Acrolein Elevations in Mice With Experimental Autoimmune Encephalomyelitis and Patients With Multiple Sclerosis. Front Neurol 9:420|
|Ambaw, Abeje; Zheng, Lingxing; Tambe, Mitali A et al. (2018) Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: Implications for Parkinson's disease. Mol Cell Neurosci 88:70-82|
|Ordaz, Josue D; Wu, Wei; Xu, Xiao-Ming (2017) Optogenetics and its application in neural degeneration and regeneration. Neural Regen Res 12:1197-1209|
|Tian, Ran; Shi, Riyi (2017) Dimercaprol is an acrolein scavenger that mitigates acrolein-mediated PC-12 cells toxicity and reduces acrolein in rat following spinal cord injury. J Neurochem 141:708-720|
|Chen, Chen; Zhang, Yi Ping; Sun, Yan et al. (2017) An In Vivo Duo-color Method for Imaging Vascular Dynamics Following Contusive Spinal Cord Injury. J Vis Exp :|
|Wu, Xiangbing; Zhang, Yi Ping; Qu, Wenrui et al. (2017) A Tissue Displacement-based Contusive Spinal Cord Injury Model in Mice. J Vis Exp :|
|Wu, Xiangbing; Walker, Chandler L; Lu, Qingbo et al. (2017) RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation. Mol Neurobiol 54:6885-6895|
|Wu, Xiangbing; Xu, Xiao-Ming (2016) RhoA/Rho kinase in spinal cord injury. Neural Regen Res 11:23-7|
|Walls, Michael K; Race, Nicholas; Zheng, Lingxing et al. (2016) Structural and biochemical abnormalities in the absence of acute deficits in mild primary blast-induced head trauma. J Neurosurg 124:675-86|
|Gianaris, Alexander; Liu, Nai-Kui; Wang, Xiao-Fei et al. (2016) Unilateral microinjection of acrolein into thoracic spinal cord produces acute and chronic injury and functional deficits. Neuroscience 326:84-94|
Showing the most recent 10 out of 33 publications