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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591633/
• 关键词: Spinal cord ischemia; Mitochondria; Cyclosporin A; Delayed onset motor dysfunct; Rabbit; 遅発性運動神経障害; 遅発生運動神経障害

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迟发性截瘫的机制中发挥重要作用。由于环孢菌素 A 据报道可在缺血条件下保持线粒体完整性，因此我们研究了环孢菌素 A 对兔子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。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（10 mg/kg/天 X 3 天）和胰岛素（0.3 - 0.4 U/kg）维持正常的后肢运动功能。三分之二接受胰岛素治疗的动物仅维持正常的后肢运动功能，而所有接受环孢菌素A治疗的动物仅不能跳跃。这些结果表明，胰岛素可以预防缺血性脊髓损伤，环孢素 A 和胰岛素的组合往往会进一步改善神经功能恢复。据报道，胰岛素会导致 Bcl-XL 上调和 Bax 下调，从而导致保持线粒体完整性。据报道，环孢素 A 可以抑制钙调神经磷酸酶的活性并阻断线粒体通透性转换孔。因此，胰岛素和环孢菌素似乎可以协同保护缺血性脊髓损伤。 总之，线粒体功能障碍可能参与短暂性脊髓缺血后迟发性截瘫的发生。