Pandya Jignesh D, Pauly James R, Nukala Vidya N, Sebastian Andrea H, Day Kristen M, Korde Amit S, Maragos William F, Hall Edward D, Sullivan Patrick G
Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40536-0305, USA.
J Neurotrauma. 2007 May;24(5):798-811. doi: 10.1089/neu.2006.3673.
Following experimental traumatic brain injury (TBI), a rapid and significant necrosis occurs at the site of injury which coincides with significant mitochondrial dysfunction. The present study is driven by the hypothesis that TBI-induced glutamate release increases mitochondrial Ca(2+)cycling/overload, ultimately leading to mitochondrial dysfunction. Based on this premise, mitochondrial uncoupling during the acute phases of TBI-induced excitotoxicity should reduce mitochondrial Ca(2+) uptake (cycling) and reactive oxygen species (ROS) production since both are mitochondrial membrane potential dependent. In the present study, we utilized a cortical impact model of TBI to assess the potential use of mitochondrial uncouplers (2,4-DNP, FCCP) as a neuroprotective therapy. Young adult male rats were intraperitoneally administered vehicle (DMSO), 2,4-DNP (5 mg/kg), or FCCP (2.5 mg/kg) at 5 min post-injury. All animals treated with the uncouplers demonstrated a significant reduction in the amount of cortical damage and behavioral improvement following TBI. In addition, mitochondria isolated from the injured cortex at 3 or 6 h post-injury demonstrated that treatment with the uncouplers significantly improved several parameters of mitochondrial bioenergetics. These results demonstrate that post-injury treatment with mitochondrial uncouplers significantly (p < 0.01) increases cortical tissue sparing ( approximately 12%) and significantly (p< 0.01) improves behavioral outcome following TBI. The mechanism of neuroprotection most likely involves the maintenance of mitochondrial homeostasis by reducing mitochondrial Ca(2+) loading and subsequent mitochondrial dysfunction. These results further implicate mitochondrial dysfunction as an early event in the pathophysiology of TBI and that targeting acute mitochondrial events can result in long-term neuroprotection and improve behavioral outcome following brain injury.
实验性创伤性脑损伤（TBI）后，损伤部位会迅速发生显著坏死，这与明显的线粒体功能障碍同时出现。本研究基于这样的假设：TBI诱导的谷氨酸释放会增加线粒体Ca(2+)循环/过载，最终导致线粒体功能障碍。基于这一前提，在TBI诱导的兴奋性毒性急性期的线粒体解偶联应减少线粒体Ca(2+)摄取（循环）和活性氧（ROS）生成，因为两者均依赖线粒体膜电位。在本研究中，我们利用TBI的皮质撞击模型来评估线粒体解偶联剂（2,4-二硝基苯酚，FCCP）作为神经保护疗法的潜在用途。成年雄性幼鼠在受伤后5分钟腹腔注射溶媒（二甲基亚砜）、2,4-二硝基苯酚（5毫克/千克）或FCCP（2.5毫克/千克）。所有用解偶联剂治疗的动物在TBI后均表现出皮质损伤量显著减少和行为改善。此外，在受伤后3或6小时从损伤皮质分离的线粒体表明，用解偶联剂治疗显著改善了线粒体生物能量学的几个参数。这些结果表明，损伤后用线粒体解偶联剂治疗显著（p < 0.01）增加了皮质组织保留（约12%），并显著（p< 0.01）改善了TBI后的行为结果。神经保护机制很可能涉及通过减少线粒体Ca(2+)负荷和随后的线粒体功能障碍来维持线粒体稳态。这些结果进一步表明线粒体功能障碍是TBI病理生理学中的早期事件，针对急性线粒体事件可导致长期神经保护并改善脑损伤后的行为结果。
