McEwen Melanie L, Sullivan Patrick G, Springer Joe E
Department of Physical Medicine & Rehabilitation, University of Kentucky Medical Center, Lexington, Kentucky 40536-0298, USA.
J Neurotrauma. 2007 Apr;24(4):613-24. doi: 10.1089/neu.2006.9969.
Trauma to the spinal cord causes a cascade of secondary events, such as mitochondrial dysfunction, which disrupts cellular functions and ultimately leads to cell death. Cyclosporin A (CsA) is a potent immunosuppressant that promotes mitochondrial function by inhibiting mitochondrial permeability transition (mPT). Clinical trials examining CsA in traumatic brain injury are currently under-way, but CsA is potentially neurotoxic. NIM811 is a non-immunosuppressive CsA derivative that inhibits mPT at nanomolar concentrations and with significantly less cytotoxicity than CsA. In the present study, we investigated the effects of NIM811 treatment on mitochondrial bioenergetics and the production of reactive oxygen species following spinal cord injury (SCI) in rats. Rats were pretreated with NIM811 or vehicle, and after 15 min the rats received a "mild/moderate" spinal cord contusion. After 24 h, the spinal cords were rapidly removed and synaptosomal mitochondria were isolated. NIM811 pretreatment significantly improved mitochondrial respiratory control ratios, and the maximal electron transport capacity of complex I and II, as well as their ATP-producing capacity. Consistent with the improvements in mitochondrial function, NIM811 pretreatment significantly decreased free radical production in isolated mitochondria. These studies are the first to demonstrate the therapeutic potential of CsA derivatives in a model of SCI, and support the need for continued investigation of compounds like NIM811 as an acute treatment for human SCI.
脊髓损伤会引发一系列继发性事件，如线粒体功能障碍，这会破坏细胞功能并最终导致细胞死亡。环孢素A（CsA）是一种强效免疫抑制剂，可通过抑制线粒体通透性转换（mPT）来促进线粒体功能。目前正在进行关于CsA治疗创伤性脑损伤的临床试验，但CsA具有潜在的神经毒性。NIM811是一种非免疫抑制性的CsA衍生物，能在纳摩尔浓度下抑制mPT，且细胞毒性明显低于CsA。在本研究中，我们调查了NIM811治疗对大鼠脊髓损伤（SCI）后线粒体生物能量学和活性氧产生的影响。大鼠预先接受NIM811或赋形剂处理，15分钟后，大鼠接受“轻度/中度”脊髓挫伤。24小时后，迅速取出脊髓并分离突触体线粒体。NIM811预处理显著改善了线粒体呼吸控制率、复合体I和II的最大电子传递能力及其ATP产生能力。与线粒体功能的改善一致，NIM811预处理显著降低了分离线粒体中的自由基产生。这些研究首次证明了CsA衍生物在SCI模型中的治疗潜力，并支持继续研究像NIM811这样的化合物作为人类SCI急性治疗方法的必要性。
