The role of mitochondrial dysfunction in the delayed onset motor neuron death after transient cord ischemia

线粒体功能障碍在短暂性脊髓缺血后迟发性运动神经元死亡中的作用

基本信息

批准号：
15591633
负责人：
MATSUMOTO Mishiya
金额：
$ 2.24万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

The purpose of the present study was to determine whether mitochondrial dysfunction plays an important role in the mechanism of delayed onset paraplegia after transient spinal cord ischemia. Because cyclosporin A has been reported to preserve mitochondrial integrity in the ischemic condition, we investigated the effects of cyclosporin A on the hind limb motor function and histopathology in rabbits. In our preliminary study, cyclosporin A was found to increase blood glucose concentrations. Therefore, we also investigated an interaction between cyclosporin A and insulin.At 96 h after reperfusion, all animals without treatments could not jump, whereas all animals treated with cyclosporin A (10 mg/kg/day X 3 days) and insulin (0.3 - 0.4 U/kg) maintained normal hindlimb motor function. Two-thirds of animals treated with insulin only maintained normal hindlimb motor function, whereas all animals treated with cyclosporin A only could not jump. These results suggest that insulin protects against ischemic spinal cord injury and that the combination of cyclosporin A and insulin tends to further improve neurological recovery.Insulin has been reported to cause both up-regulation of Bcl-XL and down-regulation of Bax, leading to preservation of mitochondrial integrity. Cyclosporin A has been reported to inhibit the activity of calcineurin and to block the mitochondrial permeability transition pore. Therefore, it seems likely that insulin and cyclosporin synergistically protect against ischemic spinal cord injury.In conclusion, mitochondrial dysfunction may be involved in the development of delayed onset paraplegia after transient spinal cord ischemia.

本研究的目的是确定线粒体功能障碍是否在短暂性脊髓缺血后延迟发作截瘫的机制中起重要作用。由于据报道环孢菌素A在缺血状态下保持线粒体完整性，因此我们研究了环孢菌素A对兔子中后肢运动功能和组织病理学的影响。在我们的初步研究中，发现环孢菌素A会增加血糖浓度。因此，我们还研究了环孢菌素A和胰岛素之间的相互作用。在再灌注后96小时，所有未经治疗的动物都无法跳跃，而所有用环孢菌素A治疗的动物A（10 mg/kg/kg/kg/kg/kg/kg/kg/kg 3天）和胰岛素（0.3-0-0-0-0 -u/kg）（0.3-0.4 u/kg）维持正常的印度障碍limblimb运动功能。用胰岛素治疗的动物中有三分之二仅保持正常的后肢运动功能，而所有用环孢菌素治疗的动物只能跳跃。这些结果表明，胰岛素可以预防缺血性脊髓损伤，而环孢菌素A和胰岛素的组合倾向于进一步改善神经系统恢复。据报道，胰岛素既导致BCL-XL的上调和BAX的下调，从而导致线粒体完整性的保存。据报道，环孢菌素A抑制钙调蛋白的活性并阻断线粒体通透性过渡孔。因此，胰岛素和环孢菌素似乎可以协同预防缺血性脊髓损伤。总而言，线粒体功能障碍可能与短暂性脊髓脊髓局部缺血后延迟发作截瘫的发展有关。