Stroke and Neurovascular Disease Center, Section of Cerebrovascular Disease, Department of Neurology, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan.
National Taipei University of Nursing and Health Science, Taiwan.
Biochem Pharmacol. 2014 Feb 1;87(3):502-14. doi: 10.1016/j.bcp.2013.11.018. Epub 2013 Dec 14.
2-Methoxystypandrone (2-MS), a naphthoquinone, has been shown to display an immunomodulatory effect in a cellular model. To explore whether 2-MS could protect mice against cerebral ischemic/reperfusion (I/R)-induced brain injury, we evaluated 2-MS's protective effects on an acute ischemic stroke by inducing a middle cerebral artery occlusion/reperfusion (MCAO) injury in murine model. Treatment of mice that have undergone I/R injury with 2-MS (10-100 μg/kg, i.v.) at 2 h after MCAO enhanced survival rate and ameliorated neurological deficits, brain infarction, neural dysfunction and massive oxidative stress, due to an enormous production of free radicals and breakdown of blood-brain barrier (BBB) by I/R injury; this primarily occurred with extensive infiltration of CD11b-positive inflammatory cells and upexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and p65 nuclear factor-kappa B (NF-κB). All of these pathological changes were diminished by 2-MS; 2-MS also intensively limited cortical infarction and promoted upexpression of neurodevelopmental genes near peri-infarct cortex and endogenous neurogenesis near subgranular zone of hippocampal dentate gyrus and the subventricular zone, most possibly by inactivation of GSK3β which in turn upregulating β-catenin, Bcl-2 adam11 and adamts20. We conclude that 2-MS blocks inflammatory responses by impairing NF-κB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity; 2-MS also concomitantly promotes neurodevelopmental protein expression and endogenous neurogenesis through inactivation of GSK3β to enhance β-catenin signaling for upexpression of neuroprotective genes and proteins.
2-甲氧基紫檀烷（2-MS），一种萘醌，已被证明在细胞模型中具有免疫调节作用。为了探索 2-MS 是否可以保护小鼠免受脑缺血/再灌注（I / R）引起的脑损伤，我们通过在小鼠模型中诱导大脑中动脉闭塞/再灌注（MCAO）损伤来评估 2-MS 对急性缺血性中风的保护作用。在 MCAO 后 2 小时用 2-MS（10-100μg/kg，静脉内）治疗 I / R 损伤的小鼠，可提高存活率并改善神经功能缺损，脑梗死，神经功能障碍和大量氧化应激，这是由于 I / R 损伤引起的自由基大量产生和血脑屏障（BBB）破裂；这主要与 CD11b 阳性炎症细胞的广泛浸润和诱导型一氧化氮合酶（iNOS），环氧化酶-2 和 p65 核因子-κB（NF-κB）的过度表达有关。所有这些病理变化均被 2-MS 减轻；2-MS 还强烈限制皮质梗死，并促进梗塞周围皮质和海马齿状回颗粒下区和脑室下区的神经发育基因的上调，最有可能通过抑制 GSK3β 来实现，从而上调β-连环蛋白，Bcl-2 adam11 和 adamts20。我们得出结论，2-MS 通过破坏 NF-κB 信号来阻止炎症反应，从而限制炎症和氧化应激以保持 BBB 的完整性；2-MS 还通过抑制 GSK3β 同时促进神经发育蛋白表达和内源性神经发生，从而增强β-连环蛋白信号传导，以上调神经保护基因和蛋白的表达。
