Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, People's Republic of China.
Free Radic Biol Med. 2010 Feb 15;48(4):597-608. doi: 10.1016/j.freeradbiomed.2009.12.004. Epub 2009 Dec 23.
Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Reactive oxygen species (ROS) are crucial to Ca(2+)-mediated effects of glutamate receptor activation leading to neuronal degeneration. Tetramethylpyrazine (TMP) is a principal ingredient of Ligusticum wallichi Franchat (a Chinese herb), used for treatment of cardiovascular and cerebrovascular ischemic diseases. However, its protection against oxidative brain injury associated with excessive activation of glutamate receptors is unknown. In this study, we demonstrate TMP neuroprotection against kainate-induced excitotoxicity in vitro and in vivo. We found that TMP could partly alleviate kainate-induced status epilepticus in rats and prevented and rescued neuronal loss in the hippocampal CA3 but not the CA1 region. The partial prevention and rescue of neuronal loss by TMP were attributable to the preservation of the structural and functional integrity of mitochondria, evidenced by maintaining the mitochondrial membrane potential, ATP production, and complex I and III activities. Stabilization of mitochondrial function was linked to the observation that TMP could function as a reductant/antioxidant to quench ROS, block lipid peroxidation, and protect enzymatic antioxidants such as glutathione peroxidase and glutathione reductase. These results suggest that TMP may protect against oxidative brain injury by stabilization of mitochondrial function through quenching of ROS.
线粒体是细胞死亡的关键调节者，是神经退行性变的一个关键特征。活性氧（ROS）对于谷氨酸受体激活导致神经元变性的 Ca(2+)-介导效应至关重要。川芎嗪（TMP）是藁本（一种中药）的主要成分，用于治疗心脑血管缺血性疾病。然而，其对与谷氨酸受体过度激活相关的氧化脑损伤的保护作用尚不清楚。在这项研究中，我们证明了 TMP 对体外和体内海人酸诱导的兴奋性毒性具有神经保护作用。我们发现 TMP 可以部分缓解大鼠海人酸诱导的癫痫持续状态，并防止和挽救海马 CA3 区而不是 CA1 区的神经元丢失。TMP 对神经元丢失的部分预防和挽救归因于线粒体结构和功能完整性的保存，这表现在保持线粒体膜电位、ATP 产生以及复合物 I 和 III 的活性。线粒体功能的稳定与以下观察结果有关，即 TMP 可以作为还原剂/抗氧化剂来淬灭 ROS、阻止脂质过氧化，并保护谷胱甘肽过氧化物酶和谷胱甘肽还原酶等酶抗氧化剂。这些结果表明，TMP 通过淬灭 ROS 稳定线粒体功能可能对氧化脑损伤具有保护作用。
