PDF(Pubmed)
Abstract：
Glutathione (GSH) is a major endogenous antioxidant, and its depletion has been observed in several brain diseases including epilepsy. Previous studies in our laboratory have shown that dimercaprol (DMP) can elevate GSH via post-translational activation of glutamate cysteine ligase (GCL), the rate limiting GSH biosynthetic enzyme and inhibit neuroinflammation in vitro. Here we determined 1) the role of cysteamine as a new mechanism by which DMP increases GSH biosynthesis and 2) its ability to inhibit neuroinflammation and neuronal injury in the rat kainate model of epilepsy. DMP depleted cysteamine in a time- and concentration-dependent manner in a cell free system. To guide the in vivo administration of DMP, its pharmacokinetic profile was determined in the plasma, liver, and brain. The results confirmed DMP\'s ability to cross the blood-brain-barrier. Treatment of rats with DMP (30 mg/kg) depleted cysteamine in the liver and hippocampus that was associated with increased GCL activity in these tissues. GSH levels were significantly increased (20 %) in the hippocampus 1 h after 30 mg/kg DMP administration. Following DMP (30 mg/kg) administration once daily, a marked attenuation of GSH depletion was seen in the SE model. SE-induced inflammatory markers including cytokine release, microglial activation, and neuronal death were significantly attenuated in the hippocampus with DMP treatment. Taken together, these results highlight the importance of restoring redox status with rescue of GSH depletion by DMP in post epileptogenic insults.
摘要：
谷胱甘肽（GSH）是一种主要的内源性抗氧化剂，在包括癫痫在内的几种脑部疾病中观察到了它的消耗。我们实验室先前的研究表明，二甲醚（DMP）可以通过翻译后激活谷氨酸半胱氨酸连接酶（GCL）来提高GSH，限速GSH生物合成酶并在体外抑制神经炎症。在这里，我们确定了1）半胱胺作为DMP增加GSH生物合成的新机制的作用，以及2）其在大鼠红藻氨酸癫痫模型中抑制神经炎症和神经元损伤的能力。DMP在无细胞系统中以时间和浓度依赖性方式耗尽半胱胺。为了指导DMP的体内给药，它的药代动力学特征是在血浆中测定的，肝脏,和大脑。结果证实了DMP穿过血脑屏障的能力。在肝脏和海马中用DMP(30mg/kg)耗尽半胱胺处理大鼠,这与这些组织中增加的GCL活性相关。30mg/kgDMP给药后1小时，海马中的GSH水平显着增加（20％）。DMP（30mg/kg）每日一次给药后，在SE模型中观察到GSH耗竭的显著衰减。SE诱导的炎症标志物，包括细胞因子释放，小胶质细胞激活，DMP治疗后海马神经元死亡明显减弱。一起来看,这些结果强调了在癫痫后损伤中通过DMP挽救GSH耗竭来恢复氧化还原状态的重要性.
