Ischemic injury is a common complication in a wide range of surgical procedures. Hypothermia administered during and/or after an ischemic event has proven to be clinically beneficial, and its effects rival or exceed those of other therapeutic strategies. This application describes a novel therapeutic strategy in which brief hypothermic preconditioning is used to induce a delayed form of ischemic tolerance that persists for a few days. Evidence is presented demonstrating that hypothermic preconditioning substantially reduces cerebral infarction elicited by transient focal ischemia, that this tolerance phenomenon is protein synthesis dependent and that it occurs in cells located in the brain parenchyma. The proposed work will characterize therapeutic, cellular and molecular features of hypothermia-induced tolerance by addressing the following specific issues: 1) What are the optimal hypothermic conditions for inducing tolerance? 2) Can hypothermia-induced tolerance complement the protective effects of intraischemic hypothermia? 3) Which cell types contribute to hypothermia-induced tolerance? 4) a. What are the candidate genes for mediating tolerance? b. What cell types express the candidate genes? c. What role do these genes play in ischemic neuroprotection? The ultimate goal of this project is to develop a new therapeutic strategy wherein a simple preconditioning treatment, administered well before surgery, can be used to limit subsequent ischemic injury. A parallel goal is to identify cellular sites and molecular mechanisms responsible for tissue tolerance. In as much as hypothermia is already used safely during human surgery, it is plausible that this new strategy could be implemented rapidly in the clinical setting. Hypothermic preconditioning could provide a low risk approach for improving surgical outcome after virtually any form of invasive surgery, including high-risk neurological and cardiovascular procedures. Moreover, because of the relatively benign nature of hypothermic preconditioning, it will also be possible to refine the search for salient cellular and molecular events responsible for neural tolerance. This approach will ultimately facilitate the development of novel gene-based therapies for limiting ischemic injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS038918-01A1
Application #
6331238
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Jacobs, Tom P
Project Start
2001-06-01
Project End
2004-04-30
Budget Start
2001-06-01
Budget End
2002-04-30
Support Year
1
Fiscal Year
2001
Total Cost
$300,883
Indirect Cost
Name
University of Virginia
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Yunoki, Masatoshi; Nishio, Shinsaku; Ukita, Naoya et al. (2003) Hypothermic preconditioning induces rapid tolerance to focal ischemic injury in the rat. Exp Neurol 181:291-300
Yunoki, Masatoshi; Nishio, Shinsaku; Ukita, Naoya et al. (2002) Characteristics of hypothermic preconditioning influencing the induction of delayed ischemic tolerance. J Neurosurg 97:650-7