The induction and regulation of reactive oxygen species in mammalian spinal cord injury
Abstract
Reactive oxygen species (ROS) and the resultant oxidative stress play a critical role in the pathology of spinal cord injury (SCI). However, the induction and regulation of ROS have not been studied in detail. To address this issue we developed an in vitro SCI model that has been demonstrated to be suitable for studying the mechanisms of ROS generation and evaluating the efficiency of ROS suppressors. Using this and other models we found that acrolein, a byproduct of lipid peroxidation which accumulates after traumatic spinal cord injury, induces neuronal membrane damage in spinal cord tissue in an oxidative stress-dependent manner. Exposure of isolated mitochondria to acrolein resulted in significant oxidative stress, which is likely mediated by a functional compromise of the mitochondrial electron transport system associated with decreased ANT activity. These results suggest that acrolein may serve as a toxin, triggering secondary injury cascades following the initial physical insult to the spinal cord. To suppress oxidative injury we proposed an alternate strategy through membrane repair rather than the conventional antioxidants. We demonstrated that administration of polyethylene glycol (PEG) immediately after spinal cord injury produced a marked decrease in oxidative stress and cell death, as well as an increase in mitochondrial function. However, PEG itself does not possess direct antioxidant activity. Confocal microscopy analysis using fluorescein conjugated PEG revealed that PEG entered the injured cells of the spinal cord, placing the polymer in a position to directly interact with cellular organelles. We found that PEG improves mitochondrial function and reduces cytochrome c release in isolated mitochondria. These results indicate that PEG may exert neuroprotection through direct interaction with mitochondria, in addition to its known ability to rescue neurons and their axons by repairing their plasma membranes.
Degree
Ph.D.
Advisors
Shi, Purdue University.
Subject Area
Neurology
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