Cyclosporin A improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats
Cyclosporin A improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats
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DOI：
10.1089/08977150260190429
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发表时间：
2002-07-01
影响因子：
4.2
通讯作者：
Bullock, MR
中科院分区：
文献类型：
--
作者：
Alessandri, B;Rice, AC;Bullock, MR
创伤性脑损伤（TBI）引发复杂的病理生理级联反应，导致细胞死亡。TBI发病机制中的一个主要因素是神经元钙超载，导致线粒体通透性转换孔（MPTP）开放，从而抑制正常的线粒体功能。免疫抑制剂环孢菌素A（CsA）已被证明可以阻断MPTP，并在缺血和TBI中具有神经保护作用。然而，这些对线粒体功能的影响转化为行为终点尚未得到彻底研究。因此，我们测试了一个低的，临床评估，CsA剂量为0.125毫克/公斤（输注3小时）和较高的“已知”神经保护剂量18.75毫克/公斤的脑组织O-2的消耗，运动和认知能力的影响后，侧向液压冲击损伤（FPI）的大鼠。两种浓度的CsA均消除了FPI后5 h盐水处理动物中观察到的O-2消耗（VO 2）减少25%。此外，较低剂量的CsA还改善了急性运动缺陷（FPI后1-5天）和在FPI后11- 1 - 5天的Morris水迷宫测试中的学习和记忆障碍。虽然较高剂量的CsA改善了认知能力，但它恶化了急性运动功能恢复。这些结果表明，CsA诱导的线粒体功能保护（通过组织O-2消耗评估）直接转化为运动和认知行为的改善。
Traumatic brain injury (TBI) triggers a complex pathophysiological cascade, leading to cell death. A major factor in the pathogenesis of TBI is neuronal overloading with calcium, causing the opening of mitochondrial permeability transition pores (MPTP), which consequently inhibit normal mitochondrial function. The immunosuppressant Cyclosporin A (CsA) has been shown to block MPTPs, and to be neuroprotective in ischemia and TBI. However, the translation of these effects on mitochondrial function, into behavioral endpoints has not been investigated thoroughly. Therefore, we tested the effect of a low, clinically evaluated, CsA dose of 0.125 mg/kg (infused for 3 h) and a higher "known" neuroprotective dose of 18.75 mg/kg on brain tissue O-2 consumption, and on motor and cognitive performance following lateral fluid percussion injury (FPI) in rats. CsA at both concentrations abolished the 25% decrease in O-2 consumption (VO2), seen in saline-treated animals at 5 h post-FPI. Furthermore, the lower dose of CsA also ameliorated acute motor deficits (days 1-5 post-FPI) and learning and memory impairments in a Morris water maze test on days 11-15 post-FPI. Although, the higher dose of CsA improved cognitive performance, it worsened acute motor functional recovery. These results suggest, that the CsA-induced preservation of mitochondrial function, as assessed by tissue O-2 consumption, directly translated into improvements in motor and cognitive behavior.