Abstract：
Spinal cord contusion injury results in Wallerian degeneration of spinal cord axonal tracts, which are necessary for locomotor function. Axonal swelling and loss of axonal density at the contusion site, characteristic of Wallerian degeneration, commence within hours of injury. Tempol, a superoxide dismutase mimetic, was previously shown to reduce the loss of spinal cord white matter and improve locomotor function in an experimental model of spinal cord contusion, suggesting that tempol treatment might inhibit Wallerian degeneration of spinal cord axons. Here, we report that tempol partially inhibits Wallerian degeneration, resulting in improved locomotor recovery. We previously reported that Wallerian degeneration is reduced by inhibitors of aldose reductase (AR), which converts glucose to sorbitol in the polyol pathway. We observed that tempol inhibited sorbitol production in the injured spinal cord to the same extent as the AR inhibitor, sorbinil. Tempol also prevented post-contusion upregulation of AR (AKR1B10) protein expression within degenerating axons, as previously observed for AR inhibitors. Additionally, we hypothesized that tempol inhibits axonal degeneration by preventing loss of the glutathione pool due to polyol pathway activity. Consistent with our hypothesis, tempol treatment resulted in greater glutathione content in the injured spinal cord, which was correlated with increased expression and activity of gamma glutamyl cysteine ligase (γGCL; EC 6.3.2.2), the rate-limiting enzyme for glutathione synthesis. Administration of the γGCL inhibitor buthionine sulfoximine abolished all observed effects of tempol administration. Together, these results support a pathological role for polyol pathway activation in glutathione depletion, resulting in Wallerian degeneration after spinal cord injury (SCI). Interestingly, methylprednisolone, oxandrolone, and clenbuterol, which are known to spare axonal tracts after SCI, were equally effective in inhibiting polyol pathway activation. These results suggest that prevention of AR activation is a common target of many disparate post-SCI interventions.
摘要：
脊髓挫伤导致脊髓轴突束的Wallerian变性,这是运动功能所必需的。挫伤部位轴突肿胀和轴突密度损失，瓦勒变性的特征，在受伤后几小时内开始。Tempol,超氧化物歧化酶模拟物,先前在脊髓挫伤的实验模型中显示出减少脊髓白质的损失并改善运动功能，提示tempol治疗可能抑制脊髓轴突的Wallerian变性。这里,我们报道tempol部分抑制Wallerian变性,从而改善运动恢复。我们以前报道过，醛糖还原酶（AR）抑制剂可以减少Wallerian变性，在多元醇途径中将葡萄糖转化为山梨糖醇。我们观察到tempol抑制受损脊髓中的山梨糖醇产生的程度与AR抑制剂相同，Sorbinil.Tempol还阻止了挫伤后变性轴突内AR（AKR1B10）蛋白表达的上调，如先前观察到的AR抑制剂。此外,我们假设tempol通过防止由于多元醇途径活性导致的谷胱甘肽库的损失来抑制轴突变性。与我们的假设一致，tempol治疗导致受损脊髓中谷胱甘肽含量增加，这与γ-谷氨酰半胱氨酸连接酶（γGCL;EC6.3.2.2）的表达和活性增加有关，谷胱甘肽合成的限速酶。施用γGCL抑制剂丁硫氨酸亚砜胺消除了tempol施用的所有观察到的效果。一起,这些结果支持谷胱甘肽耗竭中多元醇途径活化的病理作用，导致脊髓损伤后的Wallerian变性。有趣的是,甲基强的松龙,oxandrolone,还有瘦肉精,已知在脊髓损伤后备用轴突束，在抑制多元醇途径激活方面同样有效。这些结果表明，预防AR激活是许多不同的SCI后干预措施的共同目标。
