Pharmacologic evaluation of protective efficacy of caspase inhibitor, diazoxide for spinal cord protection using aspartate segmental infusion model. -Strategy against paraplegia by reducing mitochondrial-dependent apoptotic pathway

2003 Fiscal Year Final Research Report Summary

• Project/Area Number: 14571276
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Thoracic surgery
• Research Institution: KEIO UNIVERSITY
• Principal Investigator: SHIMIZU Hideyuki Keio University, School of Medicine, Instructor, 医学部, 助手 (50226247)
• Project Period (FY): 2002 – 2003
• Keywords: Aspartate / Delayed onset paraplegia / Diazoxide / Caspase inhibitor / NMDA / Experimental model / Spinal cord protection / Aspartate segmental infusion model

Research Abstract

We evaluated the protective effects of caspase inhibitor, diazoxide on spinal cord neurons using segmental aspartate infusion model under brief ischemia in vivo. New Zealand white rabbits underwent an infrarenal aortic isolation. Group A animals(n=7) received intravenous pretreatment of caspase inhibitor, diazoxide (4mg/kg). Group B animals(n=7) received pretreatment of NMDA antagonist, MK-801(6mg/kg) after the pretreatment similar to group A. Group C animals (n=7) received oral medication of riluzole(100mg/kg/day) preoperatively for ten days adding the pretreatment similar to group A. Group D animals(n=7) received viehcles only as a control of group A. Animals received segmental aspartate(30 mM) infusion for 10 minutes at a rate of 2ml/min. Neurologic status was scored at 12,24 and 48 hours after surgery using Tarlov score. Neurologic status was 3.8±0.9 in group A, 3.4±0.6 in group B, 4.0±0.6 in group C, 0.8±0.6 in group D respectively. Animals in group A showed significantly better neurologic recovery compared with group D (p<0.05). There was no significant difference between the functional scores of group A, group Band groupC respectively. Sections from group D exhibited severe gray matter necrosis in ventral horn. In contrast, group A, group B and group C exhibited mild neuronal change with eosinophilic changes. Diazoxide might ameliorate the spinal cord injury induced by segmental aspartate infusion combined with brief ischemia. Pharmacologic strategy using caspase inhibitor, might be a promising strategy against delayed onset paraplegia associated with aortic surgery reducing aspartate excitotoxicity.