Lan Min-Yu, Chang Yung-Yee, Chen Shun-Sheng, Wu Hsiu-Shan, Chen Wei-Hsi, Liu Jia-Shou
Department of Neurology, Chang Gung Memorial Hospital, Kaohsiung, ROC.
Chang Gung Med J. 2005 Feb;28(2):77-84.
3-Nitropropionic acid (3-NP), a mitochondrial toxin, impairs cellular energy generation by inhibiting succinate dehydrogenase. The basis of its neurotoxicity is oxidative stress in the wake of cellular energy failure. alpha-Phenyl-tert-butyl-nitrone (PBN), a spin-trapping agent with free radical-scavenging capability, has shown protective effects in various models of experimental brain insults. The effect of PBN on the 3-NP neurotoxicity paradigm was evaluated in this study.
Two groups of adult male mice receiving daily systemic 3-NP administration were pretreated with PBN or normal saline respectively for 5 days. After the treatment course, motor dysfunction and the volume of cerebral lesions were quantitatively evaluated. Cellular apoptosis and expressions of glial fibrillary acidic protein (GFAP) and cyclooxygenase-2 (COX-2) in the brain were compared between the 2 groups.
All mice treated with normal saline and 3-NP survived but developed mild motor dysfunction. Apoptosis of striatal cells was noted in the absence of destructive cerebral lesions. In contrast, combined treatment with PBN and 3-NP resulted in more severe motor dysfunction and higher mortality in experimental animals. Destructive lesions with cellular necrosis, and enhanced expressions of GFAP and COX-2 were noted in the striatum.
3-NP neurotoxicity was paradoxically accentuated by the combined treatment with PBN and 3-NP. Metabolic clearance of 3-NP is probably impaired by PBN and the increased oxidative stress caused by higher 3-NP levels may exceed the free radical-scavenging ability of PBN. The shift from apoptotic to necrotic changes with increased 3-NP toxicity is in accord with the theory that cellular energy reserves determine the pattern of cellular death.
3-硝基丙酸（3-NP）是一种线粒体毒素，通过抑制琥珀酸脱氢酶损害细胞能量生成。其神经毒性的基础是细胞能量衰竭后的氧化应激。α-苯基叔丁基硝酮（PBN）是一种具有自由基清除能力的自旋捕获剂，已在各种实验性脑损伤模型中显示出保护作用。本研究评估了PBN对3-NP神经毒性模式的影响。
两组成年雄性小鼠每日接受全身3-NP给药，分别用PBN或生理盐水预处理5天。治疗过程结束后，对运动功能障碍和脑损伤体积进行定量评估。比较两组脑内细胞凋亡以及胶质纤维酸性蛋白（GFAP）和环氧合酶-2（COX-2）的表达。
所有接受生理盐水和3-NP治疗的小鼠均存活，但出现轻度运动功能障碍。在无破坏性脑损伤的情况下，观察到纹状体细胞凋亡。相比之下，PBN与3-NP联合治疗导致实验动物出现更严重的运动功能障碍和更高的死亡率。在纹状体中观察到伴有细胞坏死的破坏性损伤，以及GFAP和COX-2表达增强。
PBN与3-NP联合治疗反常地加剧了3-NP的神经毒性。PBN可能损害了3-NP的代谢清除，并且较高的3-NP水平引起的氧化应激增加可能超过了PBN的自由基清除能力。随着3-NP毒性增加，细胞死亡模式从凋亡转变为坏死，这与细胞能量储备决定细胞死亡模式的理论一致。
