Zeman Richard J, Wen Xialing, Ouyang Nengtai, Brown Abraham M, Etlinger Joseph D
Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA.
MotoGen Inc., Mount Kisco, New York, USA.
Neurotrauma Rep. 2021 Sep 14;2(1):411-423. doi: 10.1089/neur.2021.0018. eCollection 2021.
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.
脊髓挫伤会导致轴突束沃勒变性，从而引发不可逆的瘫痪。挫伤会因血栓形成和血管痉挛导致灌注缺失，进而引起脊髓缺血。在包括心脏和大脑在内的多种组织中，缺血会激活多元醇途径的酶——醛糖还原酶（AR）和山梨醇脱氢酶（SDH），这些酶在反应中将葡萄糖转化为山梨醇和果糖，从而导致氧化应激和组织损伤。我们试图确定这种被称为糖毒性的途径的激活是否会导致脊髓挫伤后组织损伤。我们测试了单独使用AR抑制剂（索比尼尔或ARI - 809）、SDH抑制剂（CP - 470711）、超氧化物歧化酶模拟物（替莫泊尔）或索比尼尔与替莫泊尔联合使用的效果。在大鼠脊髓挫伤的标准模型中，每种治疗方法均显著提高了运动功能恢复并减少了脊髓组织的损失。挫伤后，山梨醇的组织水平和轴突AR（AKR1B10）表达增加，这与多元醇途径的激活一致。索比尼尔治疗抑制了上述变化，还减少了轴突肿胀和损失，这是沃勒变性的特征。替莫泊尔治疗诱导的运动功能恢复在程度上与之相似，但与索比尼尔无相加作用，这表明活性氧（ROS）具有共同的作用机制。外源性诱导高血糖进一步增加了损伤诱导的轴突肿胀，这与糖毒性一致。出乎意料的是，挫伤增加了脊髓中葡萄糖的水平，而葡萄糖是多元醇途径的主要底物。这些结果支持了脊髓挫伤后脊髓葡萄糖升高和多元醇途径导致组织糖毒性的作用，这种糖毒性会导致ROS介导的轴突变性。
