Lucas Jen Hill, Wheeler Debra G, Guan Zhen, Suntres Zacharias, Stokes Bradford T
Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
J Neurotrauma. 2002 Jun;19(6):763-75. doi: 10.1089/08977150260139138.
Lipid peroxidation (LPO) is considered a major factor in damage spread after spinal cord injury (SCI). Therapies that limit LPO after SCI have demonstrated some utility in clinical trials, but more effective treatments are needed. In the present study the effects of augmenting SC levels of the endogenous antioxidant glutathione (GSH) on LPO after SCI were studied in a rat contusion injury model. A significant decrease in GSH occurred 1h after SCI which was paralleled by increases of 123% in malondialdehyde (MDA) and >500% in the 4-hydroxyalkenals (4-HA's), two LPO products. SC irrigation with gamma-glutamylcysteine (GC) preserved GSH and reduced 4-HA's below naive levels but had no effect on MDA. By 24 h after SCI, MDA returned to naive levels but 4-HA's were still elevated. Once again, GC treatment reduced 4-HA's. 4-HA's are much more reactive than MDA and are considered among the most toxic LPO products. These results suggest that (1) conditions after SCI may favor particular branches of the LPO pathway leading to differential LPO product levels, (2) MDA measurement is not by itself an adequate test for the presence or magnitude of LPO after SCI, (3) binding of GSH to 4-HA's may be an important mechanism by which the GSH system confers protection against LPO after SCI, and (4) SC GSH can be augmented after trauma by local irrigation with GC. These results also suggest that GSH augmentation may be an effective strategy for curtailment of LPO-mediated damage in acute phase SCI.
脂质过氧化（LPO）被认为是脊髓损伤（SCI）后损伤扩散的主要因素。在脊髓损伤后限制脂质过氧化的疗法在临床试验中已显示出一定作用，但仍需要更有效的治疗方法。在本研究中，我们在大鼠挫伤性损伤模型中研究了提高内源性抗氧化剂谷胱甘肽（GSH）脊髓水平对脊髓损伤后脂质过氧化的影响。脊髓损伤后1小时，谷胱甘肽显著下降，同时脂质过氧化的两种产物丙二醛（MDA）增加了123%，4-羟基烯醛（4-HA）增加了500%以上。用γ-谷氨酰半胱氨酸（GC）进行脊髓灌注可维持谷胱甘肽水平，并使4-HA降至未损伤时的水平以下，但对丙二醛没有影响。脊髓损伤后24小时，丙二醛恢复到未损伤时的水平，但4-HA仍升高。同样，GC治疗降低了4-HA水平。4-HA比丙二醛更具反应性，被认为是毒性最强的脂质过氧化产物之一。这些结果表明：（1）脊髓损伤后的情况可能有利于脂质过氧化途径的特定分支，导致脂质过氧化产物水平不同；（2）丙二醛测量本身不足以检测脊髓损伤后脂质过氧化的存在或程度；（3）谷胱甘肽与4-HA结合可能是谷胱甘肽系统在脊髓损伤后对抗脂质过氧化的重要保护机制；（4）创伤后可通过局部灌注GC来提高脊髓谷胱甘肽水平。这些结果还表明，提高谷胱甘肽水平可能是减少急性脊髓损伤中脂质过氧化介导损伤的有效策略。
