The role of mitochondrial dysfunction in the delayed onset motor neuron death after transient 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发病机制中起重要作用。由于环孢素A已被报道在缺血条件下保护线粒体的完整性，我们研究了环孢素A对兔后肢运动功能和组织病理学的影响。在我们的初步研究中，发现环孢素A可以提高血糖浓度。因此，我们还研究了环孢素A与胰岛素的相互作用。在再灌注96h，所有未经治疗的动物均不能跳跃，而给予环孢素A(10 mg/kg/d×3天)和胰岛素(0.3~0.4U/kg)的所有动物均维持正常的后肢运动功能。接受胰岛素治疗的动物中，三分之二的动物只维持了正常的后肢运动功能，而只接受环孢素A治疗的所有动物都不能跳跃。这些结果表明，胰岛素对缺血性脊髓损伤有保护作用，环孢素A和胰岛素联合使用有进一步改善神经功能恢复的趋势。已有报道称，胰岛素可导致Bclxl上调和Bax下调，从而保护线粒体的完整性。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，胰岛素和环孢菌素可能对脊髓缺血损伤有协同保护作用。综上所述，线粒体功能障碍可能参与了暂时性脊髓缺血后迟发性截瘫的发生。

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.