Investigation on therapeutic potentials of inducing ischemic tolerance against ischemic neuronal damage in the spinal cord

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Paraplegia is a serious complication caused by spinal cord ischemia during thoracoabdominal aneurysm surgery. Preventive and therapeutic measures are not established. Accumulated data show that central nervous system acquires tolerance against ischemic insult when the neuronal tissues are exposed to non-lethal stress before it is subjected to lethal insult. In the present study we examined the effects of hyperbaric oxygen (HBO) on neuronal survival after ischemia and the mechanism for ischemic tolerance.We used ischemic model in rats and rabbits. Preconditioning with HBO was performed at 2.5〜3.5 ATA (1h/day for 5days). Sequential changes of gene expression and of translated protein were evaluated using DNA microarray, Western blotting, and RT-PCR. In the rabbit that received preconditioning with a short period of ischemia, HSP-70 was detected in the cytoplasm in the motor neurons in the spinal cord. In rats, genes of glutathione peroxidase and hypoxia inducible factor-1 (HIF-1) were detected in the spinal cord. When the animals were subjected to 8-min forebrain ischemia following HBO treatment, neuronal death in the hippocampal CA1 was markedly curtailed, the amelioration being most prominent at 12 hour after HBO. Cluster analysis of the genomic response demonstrated expressions of p75 neurotrophin receptor (p75NTR) and CCAAT-enhancer binding protein δ(C/EBPδ). These changes were confirmed also with RT-PCR and Western blotting.The results suggest that the signal transduction related to nerve growth factor receptor and inflammatory/immune response is involved in ischemic tolerance in the central nervous system. Modulation of these related genes may provide new therapeutic strategy against ischemic damage in the central nervous system.