Antioxidant therapies for traumatic brain injury.
Antioxidant therapies for traumatic brain injury.
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DOI：
10.1016/j.nurt.2009.10.021
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Mustafa AG
中科院分区：
文献类型：
--
作者：
Hall ED;Vaishnav RA;Mustafa AG
自由基诱导的氧化损伤反应，特别是膜脂过氧化反应（LP）是临床前创伤性脑损伤模型中最有效的继发性损伤机制之一。除了破坏膜磷脂结构外，LP还导致含有细胞毒性醛的产物的形成，这些产物与细胞蛋白质结合并损害其正常功能。本文综述了近三十年来抗氧化药物的临床前发现和临床开发的进展，这些抗氧化药物旨在通过不同的机制抑制自由基诱导的LP及其神经毒性后果，包括O2•-清除剂超氧化物歧化酶（SOD）和脂质过氧化抑制剂替拉扎德。此外，还简要介绍了在临床前TBI模型中显示出疗效的各种其他抗氧化剂，如LP抑制剂U83836E、白藜芦醇、姜黄素、OPC-14177和硫辛酸；铁螯合剂去铁胺和含氮氧化物的抗氧化剂如α-苯基叔丁基硝基酮和丹酚。一种相对较新的抗氧化机制策略是针对急性TBI的“羰基清除”化合物清除具有高度神经毒性的醛类LP副产物。最后，我们提出，中断创伤后氧化性脑损伤最有效的方法可能是联合使用机械互补抗氧化剂，同时清除LP启动自由基，抑制LP传播，最后清除神经毒性LP副产物。
Free radical-induced oxidative damage reactions, and membrane lipid peroxidation (LP) in particular, are one of the best validated secondary injury mechanisms in preclinical traumatic brain injury models. In addition to the disruption of the membrane phospholipid architecture, LP results in the formation of cytotoxic aldehyde-containing products that bind to cellular proteins and impair their normal functions. This article reviews the progress over the past three decades in regards to the preclinical discovery and attempted clinical development of antioxidant drugs designed to inhibit free radical-induced LP and its neurotoxic consequences via different mechanisms including the O2•- scavenger superoxide dismutase (SOD) and the lipid peroxidation inhibitor tirilazad. In addition, various other antioxidant agents that have been shown to have efficacy in preclinical TBI models are briefly presented such as the LP inhibitors U83836E, resveratrol, curcumin, OPC-14177 and lipoic acid; the iron chelator deferoxamine and the nitroxide-containing antioxidants such as α-phenyl-tert-butyl nitrone and tempol. A relatively new antioxidant mechanistic strategy for acute TBI is aimed at the scavenging of aldehydic LP by-products that are highly neurotoxic with “carbonyl scavenging” compounds. Finally, it is proposed that the most effective approach to interrupt posttraumatic oxidative brain damage after TBI might involve the combined treatment with mechanistically-complementary antioxidants that simultaneously scavenge LP-initiating free radicals, inhibit LP propagation and lastly remove neurotoxic LP byproducts.
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