Objective
The mechanism of delayed ischemic spinal cord injury during thoracoabdominal vascular surgery is speculated to be triggered by the apoptosis of spinal motor neuron cells. Recently, it has been shown that activated neutrophil play a central role in ischemia-reperfusion injury of the central nerve system. Moreover, neutrophil elastase might be one of the deteriorating factors of neutrophil caused injury. Therefore, we tested the hypothesis that ONO-5046, which is specific inhibitor of neutrophil elastase, can prevent the delayed ischemic spinal cord injury possibly through apoptosis related signal transduction.
Methods
Rabbit spinal cord ischemia model with a balloon catheter was used in this study. Spinal cord was removed 8 hour, 1, 2, and 7 days after 15 minutes of transient spinal ischemia with or without ONO-5046 administration. Cell damage was analyzed by counting the number of motor neurons. The temporal profile of immunoreactivity of of CPP32 (caspase3), brain-derived neurotrophic factor (BDNF) and phosphorylated extracellular signal-regulated kinase (p-ERK) were also investigated.
Results
In the control group, lower limb function and most motor neurons were preserved until 2 days but were lost at 7 days after reperfusion. In the ONO-5046 treated group, the functional deficits were attenuated and motor neurons were more preserved histologically at 7 days. The induction of caspase3 was significantly reduced by ONO-5046 treatment. Furthermore, the expression of BDNF and p-ERK was prolonged.
Conclusions
The results indicate that ONO-5046 may protect motor neurons from ischemic injury by reducing caspase3 and prolonging the expression of BDNF and p-ERK. ONO-5046 may be a strong candidate for use as a therapeutic agent in the treatment of ischemic spinal cord injury.