Threshold depolarization intervals for ischemic tolerance vs. expression of hsp72 and immediate early genes in gerbils.

1998 Fiscal Year Final Research Report Summary

• Project/Area Number: 08457359
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: NIIGATA UNIVERSITY
• Principal Investigator: ABE Hiroshi NIIGATA UNIVERSITY MEDECAL HOSPITAL,ASSISTANT, 医学部附属病院, 助手 (60240769)
• Co-Investigator(Kenkyū-buntansha): MORII Ken NIIGATA UNIVERSITY MEDECAL HOSPITAL,ASSISTANT, 医学部附属病院, 助手 (20230089)
• Project Period (FY): 1996 – 1998
• Keywords: cerebral ischemia / ischemic tolerance / immediate early gene / heat shock protein / DC potential / depolarization

Research Abstract

Brief ischemia can induce tolerance to later more severe ischemia, but reported effects are highly variable. It has been suggested that changes in gene expression may contribute to ischemic tolerance, but relationships are difficult to test without a quantitatively reproducible model. Anoxic depolarization is a classical indicator of energy failure during ischemia. In this study we have used DC potential recording to precisely define the interval of postischemic depolarization necessary to achieve reproducible tolerance induction in hippocampi of anesthetized gerbils, and have compared this threshold with that required for induction of hsp72, as well as the immediate early gene products of c-fos, junB, junD and c-jun.
Depolarization of 6.5 min or longer produced maximum CAL neuron loss. Maximum tolerance effect was achieved by the ischemic insult of depolarization interval controlled between 2.5 to 3.5 min. No detectable hsp72 expression was seen in CA1 within 1h recirculation after ischemic insults that induce maximum tolerance, but hsp72 induction increased as the depolarization interval reached the threshold for neuronal injury. In contrast to hsp72, c-fos, junB, junD, and c-jun all showed increased expression in the depolarization range associated with ischemic tolerance.
We have established a highly reproducible ischemic tolerance model in the gerbil by carefully monitoring the interval of ischemic depolarization during each insult. We have demonstrated that the threshold depolarization required to induce tolerance was comparable to those for induction of transcription factor mRNAs of the Fos and Jun families, suggesting that complex cascades of target gene expression contribute to mechanisms of induced neuronal protection, while hsp72 mRNA was strongly induced only after more severe insults that approached for neuronal injury.