Khanna Savita, Roy Sashwati, Ryu Hoon, Bahadduri Praveen, Swaan Peter W, Ratan Rajiv R, Sen Chandan K
Laboratory of Molecular Medicine, Department of Surgery, Dorothy M. Davis Heart and lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
J Biol Chem. 2003 Oct 31;278(44):43508-15. doi: 10.1074/jbc.M307075200. Epub 2003 Aug 13.
Vitamin E is a generic term for tocopherols and tocotrienols. This work is based on our striking evidence that, in neuronal cells, nanomolar concentrations of alpha-tocotrienol, but not alpha-tocopherol, block glutamate-induced death by suppressing early activation of c-Src kinase (Sen, C. K., Khanna, S., Roy, S., and Packer, L. (2000) J. Biol. Chem. 275, 13049-13055). This study on HT4 and immature primary cortical neurons suggests a central role of 12-lipoxygenase (12-LOX) in executing glutamate-induced neurodegeneration. BL15, an inhibitor of 12-LOX, prevented glutamate-induced neurotoxicity. Moreover, neurons isolated from 12-LOX-deficient mice were observed to be resistant to glutamate-induced death. In the presence of nanomolar alpha-tocotrienol, neurons were resistant to glutamate-, homocysteine-, and l-buthionine sulfoximine-induced toxicity. Long-term time-lapse imaging studies revealed that neurons and their axo-dendritic network are fairly motile under standard culture conditions. Such motility was arrested in response to glutamate challenge. Tocotrienol-treated primary neurons maintained healthy growth and motility even in the presence of excess glutamate. The study of 12-LOX activity and metabolism revealed that this key mediator of glutamate-induced neurodegeneration is subject to control by the nutrient alpha-tocotrienol. In silico docking studies indicated that alpha-tocotrienol may hinder the access of arachidonic acid to the catalytic site of 12-LOX by binding to the opening of a solvent cavity close to the active site. These findings lend further support to alpha-tocotrienol as a potent neuroprotective form of vitamin E.
维生素E是生育酚和生育三烯酚的统称。这项工作基于我们引人注目的证据：在神经元细胞中，纳摩尔浓度的α-生育三烯酚而非α-生育酚，通过抑制c-Src激酶的早期激活来阻止谷氨酸诱导的细胞死亡（森，C.K.，坎纳，S.，罗伊，S.，和帕克，L.（2000年）《生物化学杂志》275卷，13049 - 13055页）。这项对HT4和未成熟原代皮层神经元的研究表明12 - 脂氧合酶（12-LOX）在执行谷氨酸诱导的神经退行性变中起核心作用。12-LOX的抑制剂BL15可预防谷氨酸诱导的神经毒性。此外，观察到从12-LOX缺陷小鼠分离出的神经元对谷氨酸诱导的死亡具有抗性。在存在纳摩尔浓度α-生育三烯酚的情况下，神经元对谷氨酸、同型半胱氨酸和L-丁硫氨酸亚砜胺诱导的毒性具有抗性。长期的延时成像研究表明，在标准培养条件下，神经元及其轴突 - 树突网络具有相当的运动性。这种运动性在谷氨酸刺激下会停止。生育三烯酚处理的原代神经元即使在存在过量谷氨酸的情况下仍能保持健康生长和运动性。对12-LOX活性和代谢的研究表明，这种谷氨酸诱导的神经退行性变的关键介质受营养物质α-生育三烯酚的调控。计算机模拟对接研究表明，α-生育三烯酚可能通过结合靠近活性位点的溶剂腔开口来阻碍花生四烯酸进入12-LOX的催化位点。这些发现进一步支持了α-生育三烯酚作为维生素E的一种强效神经保护形式。
