Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40536-0305, USA.
J Neurotrauma. 2011 Feb;28(2):311-8. doi: 10.1089/neu.2010.1646. Epub 2011 Feb 2.
Mitochondrial dysfunction plays a pivotal role in secondary cell death mechanisms following traumatic brain injury (TBI). Several reports have demonstrated that inhibition of the mitochondrial permeability transition pore with the immunosuppressant drug cyclosporine A (CsA) is efficacious. Accordingly, CsA is being moved forward into late-stage clinical trials for the treatment of moderate and severe TBI. However, several unknowns exist concerning the optimal therapeutic window for administering CsA at the proposed dosages to be used in human studies. The present study utilized a moderate (1.75 mm) unilateral controlled cortical impact model of TBI to determine the most efficacious therapeutic window for initiating CsA therapy. Rats were administered an IP dose of CsA (20 mg/kg) or vehicle at 1, 3, 4, 5, 6, and 8 h post-injury. Immediately following the initial IP dose, osmotic mini-pumps were implanted at these time points to deliver 10 mg/kg/d of CsA or vehicle. Seventy-two hours following the initiation of treatment the pumps were removed to stop CsA administration. Quantitative analysis of cortical tissue sparing 7 days post-injury revealed that CsA treatment initiated at any of the post-injury initiation times out to 8 h resulted in significantly less cortical damage compared to animals receiving vehicle treatment. However, earlier treatment begun in the first 3 h was significantly more protective than that begun at 4 and 8 h. Treatment initiated at 1 h post-injury (∼68% decrease) was not significantly different than that seen at 3 h (∼46% decrease), but resulted in significantly greater cortical tissue sparing compared to CsA treatment initiated at least 4 h post-injury (28% decrease). Together these results illustrate the importance of initiating therapeutic interventions such as CsA as soon as possible following TBI, preferably within 4 h post-injury, to achieve the best possible neuroprotective effect. However, the drug appears to retain some protective efficacy even when initiated as late as 8 h post-injury.
线粒体功能障碍在创伤性脑损伤（TBI）后的继发性细胞死亡机制中起关键作用。有几项报告表明，用免疫抑制剂环孢素 A（CsA）抑制线粒体通透性转换孔是有效的。因此，CsA 正在进入治疗中度和重度 TBI 的后期临床试验。然而，对于拟在人体研究中使用的建议剂量下给予 CsA 的最佳治疗窗，存在一些未知因素。本研究利用中度（1.75 毫米）单侧皮质撞击 TBI 模型，确定开始 CsA 治疗的最有效治疗窗。大鼠在损伤后 1、3、4、5、6 和 8 小时分别给予腹腔注射 CsA（20mg/kg）或载体。在初次腹腔注射后立即，在这些时间点植入渗透微型泵，以输送 10mg/kg/d 的 CsA 或载体。在开始治疗 72 小时后，取出泵以停止 CsA 给药。损伤后 7 天皮质组织保留的定量分析表明，与接受载体治疗的动物相比，在损伤后任何时间点开始治疗，直至 8 小时，CsA 治疗均可显著减少皮质损伤。然而，在第 3 小时之前开始的更早治疗比在 4 小时和 8 小时开始的治疗更具保护作用。在损伤后 1 小时开始治疗（减少约 68%）与在第 3 小时开始治疗（减少约 46%）无显著差异，但与至少在 4 小时后开始 CsA 治疗（减少 28%）相比，可显著增加皮质组织保留。这些结果表明，在 TBI 后尽快启动治疗干预，如 CsA，尽早在损伤后 4 小时内，以获得最佳的神经保护效果非常重要。然而，即使在损伤后 8 小时开始给药，该药物似乎仍保留一些保护效果。
