Khanna Savita, Roy Sashwati, Slivka Andrew, Craft Tara K S, Chaki Soma, Rink Cameron, Notestine Margaret A, DeVries A Courtney, Parinandi Narasimham L, Sen Chandan K
Department of Surgery, The Ohio State University Medical Center, Columbus, Ohio, USA.
Stroke. 2005 Oct;36(10):2258-64. doi: 10.1161/01.STR.0000181082.70763.22. Epub 2005 Sep 15.
The current work is based on our previous finding that in neuronal cells, nmol/L concentrations of alpha-tocotrienol (TCT), but not alpha-tocopherol (TCP), blocked glutamate-induced death by suppressing early activation of c-Src kinase and 12-lipoxygenase.
The single neuron microinjection technique was used to compare the neuroprotective effects of TCT with that of the more widely known TCP. Stroke-dependent brain tissue damage was studied in 12-Lox-deficient mice and spontaneously hypertensive rats orally supplemented with TCT.
Subattomole quantity of TCT, but not TCP, protected neurons from glutamate challenge. Pharmacological as well as genetic approaches revealed that 12-Lox is rapidly tyrosine phosphorylated in the glutamate-challenged neuron and that this phosphorylation is catalyzed by c-Src. 12-Lox-deficient mice were more resistant to stroke-induced brain injury than their wild-type controls. Oral supplementation of TCT to spontaneously hypertensive rats led to increased TCT levels in the brain. TCT-supplemented rats showed more protection against stroke-induced injury compared with matched controls. Such protection was associated with lower c-Src activation and 12-Lox phosphorylation at the stroke site.
The natural vitamin E, TCT, acts on key molecular checkpoints to protect against glutamate- and stroke-induced neurodegeneration.
当前的研究基于我们之前的发现，即在神经元细胞中，纳摩尔浓度的α-生育三烯酚（TCT）而非α-生育酚（TCP），可通过抑制c-Src激酶和12-脂氧合酶的早期激活来阻止谷氨酸诱导的细胞死亡。
采用单神经元显微注射技术，比较TCT与更为人熟知的TCP的神经保护作用。在口服补充TCT的12-脂氧合酶缺陷小鼠和自发性高血压大鼠中研究了中风相关的脑组织损伤。
亚阿托摩尔量的TCT而非TCP可保护神经元免受谷氨酸的攻击。药理学及遗传学方法表明，在受到谷氨酸攻击的神经元中，12-脂氧合酶会迅速发生酪氨酸磷酸化，且这种磷酸化由c-Src催化。12-脂氧合酶缺陷小鼠比其野生型对照对中风诱导的脑损伤更具抵抗力。给自发性高血压大鼠口服补充TCT可使脑中TCT水平升高。与匹配的对照组相比，补充TCT的大鼠对中风诱导的损伤表现出更强的保护作用。这种保护作用与中风部位较低的c-Src激活和12-脂氧合酶磷酸化有关。
天然维生素E，即TCT，作用于关键分子检查点，以预防谷氨酸和中风诱导的神经退行性变。
