Acrolein mediated cellular damage in neuronal trauma and diseases

Acrolein, an alpha, beta - unsaturated aldehyde, is a ubiquitous pollutant that is also produced endogenously through lipid peroxidation. This compound is hundreds of times more reactive than other aldehydes such as 4-hydroxynonenal, is produced at much higher concentrations, and persists in solution for much longer than better known free radicals. It has been implicated in disease states known to involve chronic oxidative stress. In particular, our lab is the first to provide the initial evidence to implicate acrolein in spinal cord injury and multiple sclerosis. We and others have also shown that acrolein may overwhelm the anti-oxidative systems of any cell by depleting glutathione reserves, preventing glutathione regeneration, and inactivating protective enzymes. On the cellular level, we have shown that acrolein exposure can cause neuronal membrane damage, mitochondrial dysfunction, and myelin disruption. Such pathologies can be exacerbated by increased concentrations or duration of exposure, and can occur in normal tissue incubated with injured spinal cord, showing that acrolein can act as a diffusive agent, spreading secondary injury. We have also provided compelling evidence that several chemical species capable of binding and inactivating acrolein can offer significant neuroprotection in neuronal trauma and diseases. Specifically, hydralazine, an FDA-approved drug for hypertension, and phenelzine, an FDA-approved antidepressant, can reduce elevated acrolein concentrations and inhibit acrolein-mediated pathologies in animal models of multiple sclerosis and spinal cord injury. Our work has suggested that acrolein scavenging is a novel effective treatment which is primed for rapid translation to the clinic. Through collaborative efforts with researchers at Department of Neurology and Stark Neuroscience Institute at Indiana University School of Medicine, we are aiming to translate anti-acrolein therapy from a laboratory discovery to novel and effective treatments for reducing neuronal damage, potentially helping millions of multiple sclerosis and spinal cord injury patients. Concomitant investigations in the lab have also been focused on revealing the mechanisms of acrolein-mediated neuronal damage. Such study is expected to indentify Key damaging factors that will inspire innovative therapies that could be synergistically applied with anti-acrolein treatment to achieve greater effect in MS and SCI patients.

Selected publications related to the topic:

Shi, R., Luo, J. and Peasley, M.A. Acrolein inflicts axonal membrane disruption and conduction loss in isolated guinea pig spinal cord. Neuroscience 115: 337-340, 2002.

Luo, J. and Shi, R. Acrolein induces axolemmal disruption, oxidative stress, and mitochondrial impairment in spinal cord tissue. Neurochem. Int. 44: 475-486, 2004.

Luo, J., Uchida, K. and Shi, R. Accumulation of acrolein-protein adducts after traumatic spinal cord injury. Neurochem. Res. 30: 291-295. 2005

Luo, J. and Shi, R. Acrolein induces oxidative stress in brain mitochondria. Neurochem. Intl. 46: 243-252, 2005

Luo, J., Uchida, K. and Shi, R. Accumulation of acrolein-protein adducts after traumatic spinal cord injury. Neurochem. Res. 30: 291-295. 2005

Logan, M.P., Parker S. and Shi R. Glutathion and ascorbic acid enhance recovery of guinea pig spinal cord white matter following ischemia and acrolein exposure. Pathobiology, 72: 171-178. 2005.

Luo, J., Robinson, J. P. and Shi, R. Acrolein-induced cell death in PC 12 cells: role of mitochondria-mediated oxidative stress. Neurochem. Int. 47: 449-457.2005.

Shi, R and Luo, J. The role of acrolein in spinal cord injury (invited review). Applied Neurology: 2: 22-27. 2006.

Liu-Snyder, P., McNally, H. Shi, R. and Borgens, R. B. Acrolein - Mediated Mechanisms of Neuronal Death. J. Neurosci. Res. 84: 209-218. 2006.

Liu-Snyder, P., Borgens, R. B. and Shi, R. Hydralazine rescues PC 12 cells from acrolein-mediated death. J. Neurosci. Res. 84: 219-227. 2006.

Hamann, K., Nehrt, G., Ouyang, H., Duerstock, D. and Shi, R. Hydralazine inhibits compression and acrolein-mediated injuries in ex vivo spinal cord. Journal of Neurochemistry. 104: 708-718. 2008.

Cho, Y., Shi, R., Borgens, R., and Ivanisevic, A. The Functionalized Mesoporous Silica Nanoparticles (MSNs) Based Drug Delivery System to Rescue Acrolein-Mediated Cell Death. Nanomedicine. 3: 507-519. 2008

Hamann, K., Durkes, A., Ouyang, H., Uchida K, Pond, A., and Shi, R. Critical Role of acrolein in secondary injury following ex vivo spinal cord trauma. J. Neurochemistry. 107: 712-721. 2008.

Hamann, K., and Shi, R. Acrolein scavenging: A potential novel mechanism of attenuating oxidative stress following spinal cord injury (invited review). J. Neurochem. 111: 1348-1356. 2009.

Cho*, Y., Shi*, R., and Borgens, R. Chitosan nanoparticle-based neuronal membrane sealing and neuroprotection following acrolein-induced cell injury. Journal of Biological Engineering. 4:2, 2010. (open access: *: equal contribution.

Leung, G., Sun , W., Zheng, L., Brookes, S, Tully, M., and Shi, R. Anti-acrolein treatment improves behavioral outcome and alleviates myelin damage in EAE mouse. Neuroscience. 173: 150-155, 2011.

Shi, Y., Sun, W., McBride, J., Cheng, J. and Shi, R. Acrolein induces myelin damage in mammalian spinal cord. J. Neurochem. 117: 554-564, 2011.

Shi, R., Rickett, T., and Sun, W. Acrolein-mediated injury in nervous system trauma and diseases (invited review). Molecular nutrition and food research. 55: 1320-1331, 2011.