Abstract
Spinal cord contusion injury leads to Wallerian degeneration of axonal tracts, resulting in irreversible paralysis. Contusion injury causes perfusion loss by thrombosis and vasospasm, resulting in spinal cord ischemia. In several tissues, including heart and brain, ischemia activates polyol pathway enzymes—aldose reductase (AR) and sorbitol dehydrogenase (SDH)—that convert glucose to sorbitol and fructose in reactions, causing oxidative stress and tissue loss. We sought to determine whether activation of this pathway, which has been termed glucotoxicity, contributes to tissue loss after spinal cord contusion injury. We tested individual treatments with AR inhibitors (sorbinil or ARI-809), SDH inhibitor (CP-470711), superoxide dismutase mimetic (tempol), or combined sorbinil and tempol. Each treatment significantly increased locomotor recovery and reduced loss of spinal cord tissue in a standard model of spinal cord contusion in rats. Tissue levels of sorbitol and axonal AR (AKR1B10) expression were increased after contusion injury, consistent with activation of the polyol pathway. Sorbinil treatment inhibited the above changes and also decreased axonal swelling and loss, characteristic of Wallerian degeneration. Treatment with tempol induced recovery of locomotor function that was similar in magnitude, but non-additive to sorbinil, suggesting a shared mechanism of action by reactive oxygen species (ROS). Exogenous induction of hyperglycemia further increased injury-induced axonal swelling, consistent with glucotoxicity. Unexpectedly, contusion increased spinal cord levels of glucose, the primary polyol pathway substrate. These results support roles for spinal glucose elevation and tissue glucotoxicity by the polyol pathway after spinal cord contusion injury that results in ROS-mediated axonal degeneration.
Highlights
IntroductionSpinal cord injury (SCI) often leads to Wallerian degeneration and loss of descending and ascending axonal tracts, resulting in irreversible paralysis.[1,2,3] These injuries cause hemorrhage and loss of spinal cord perfusion attributable to causes such as thrombosis and vasospasm,[4] rapidly leading to spinal cord ischemia
Spinal cord injury (SCI) often leads to Wallerian degeneration and loss of descending and ascending axonal tracts, resulting in irreversible paralysis.[1,2,3] These injuries cause hemorrhage and loss of spinal cord perfusion attributable to causes such as thrombosis and vasospasm,[4] rapidly leading to spinal cord ischemia.In several tissues, including brain and heart, ischemia can activate aldose reductase (AR)
To determine whether inhibition of the polyol pathway protects from loss of locomotor function after SCI, groups of rats received spinal cord contusion and were treated with either the AR inhibitors, sorbinil or ARI809, or the sorbitol dehydrogenase (SDH) inhibitor, CP-470711
Summary
Spinal cord injury (SCI) often leads to Wallerian degeneration and loss of descending and ascending axonal tracts, resulting in irreversible paralysis.[1,2,3] These injuries cause hemorrhage and loss of spinal cord perfusion attributable to causes such as thrombosis and vasospasm,[4] rapidly leading to spinal cord ischemia. In several tissues, including brain and heart, ischemia can activate aldose reductase (AR). AR is the ratelimiting enzyme of the polyol pathway that, together with sorbitol dehydrogenase (SDH), sequentially converts glucose to sorbitol and fructose. These enzymatic reactions promote generation of reactive oxygen species (ROS) and reduce oxidative protection, which cause oxidative stress and consequent tissue loss.[5,6] AR and SDH are present in both peripheral nerve a Richard J.
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