Spinal cord injury results in functional deficits that can range from mild to life threatening, but few effective treatments are clinically available. We have observed damage to neuronal cell bodies and axons after traumatic spinal cord injury that is dependent on the severity of the injury. We postulate that this damage is initiated by the mechanical injury and that normal phospholipid homeostasis is disrupted, leading to ongoing damage and ultimately negatively contributes to poor neurological outcome. Our long-term objective is to develop clinically relevant treatments that promote membrane repair following spinal cord injury. The specific objective of this small research program proposal is to assess the effects and mechanisms of plasma membrane repair mediated by citicoline, a membrane stabilizing agent that has been shown to be beneficial in many models of central nervous system disease. The overall hypothesis is that injury-induced membrane damage is detrimental to cell survival and functional outcome, but citicoline treatment can reduce these effects through facilitation of membrane preservation. Specifically, we will use a clinically relevant rodent contusion model to 1) determine a treatment dose of citicoline for spinal cord injury, defined by the ability to reseal compromised plasma membranes in cell bodies and axons and spare tissue, 2) assess possible mechanisms of citicoline-mediated repair, and 3) assess the ability of citicoline to mediate motor recovery. We propose that citicoline leads to membrane resealing by decreasing both lipid peroxidation and phospholipase A2 activity (both of which may contribute to phospholipid breakdown following spinal cord injury) and increasing phospholipid synthesis. These studies are expected to optimize a treatment regimen and begin to determine the mechanisms of membrane damage and repair following spinal cord injury. The proposed studies describe a new research direction and will provide critical data on the effects of targeted membrane repair that will guide future studies. ?
There is a critical need to develop new treatment strategies for spinal cord injury, which results in functional deficits that can range from mild to life threatening. In this exploratory study, we propose to target cell membrane repair as a possible therapy. We have observed membrane damage after traumatic spinal cord injury and hypothesize that phospholipid breakdown contributes to membrane damage and can be restored by adding citicoline, a membrane stabilizing agent. These studies are directly relevant to public health, as they may lead to novel treatment approaches aimed at neuroprotection for traumatic spinal cord injury and possibly other neurological disorders. ? ? ?
| Simon, Crystal M; Sharif, Shan; Tan, Richard P et al. (2009) Spinal cord contusion causes acute plasma membrane damage. J Neurotrauma 26:563-74 |
