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

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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.