Certain neuron populations are selectively vulnerable to transient intervals of global ischemia, but there is now strong evidence that such vulnerability can be profoundly influenced by previous stimuli. We have developed optimized models of induced ischemic tolerance in gerbil and rat in which the duration of ischemic depolarizations monitored during priming and test insults provides a quantitative index of ischemic severity. In the gerbil model a doubling of the threshold for CA1 neuron loss can be reproducibly achieved for intervals of many days following the priming insult, allowing a wide range of studies to be made in predictably tolerant animals. Proposed experiments will determine the mechanism(s) of induced neuroprotection.
Aim 1. To define changes in known endogenous antioxidant, stress response and cell death pathways in neurons and other cell types that occur during the development of ischemic tolerance.
Aim 2. To determine the physiological correlates of ischemic tolerance in vivo and in hippocampal slices from animals subjected to priming insults that induce neuroprotection.
Aim 3. To identify novel changes in gene expression in tolerant hippocampus using a differential display approach based on polymerase chain reaction methods. These studies will identify components of endogenous, inducible defense mechanisms that protect neurons against transient ischemia, and thereby provide insight into the fundamental processes determining neuron loss and survival after such insults. The results will elucidate successful protection strategies that may be applicable to a wide range of neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032344-07
Application #
6188159
Study Section
Neurology A Study Section (NEUA)
Program Officer
Michel, Mary E
Project Start
1994-09-01
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2003-03-31
Support Year
7
Fiscal Year
2000
Total Cost
$238,069
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Neurology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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Sorimachi, Takatoshi; Nowak Jr, Thaddeus S (2004) Pharmacological manipulations of ATP-dependent potassium channels and adenosine A1 receptors do not impact hippocampal ischemic preconditioning in vivo: evidence in a highly quantitative gerbil model. J Cereb Blood Flow Metab 24:556-63
Abe, H; Nowak Jr, T S (2000) Postischemic temperature as a modulator of the stress response in brain: dissociation of heat shock protein 72 induction from ischemic tolerance after bilateral carotid artery occlusion in the gerbil. Neurosci Lett 295:54-8
Yufu, K; Yaida, Y; Nowak Jr, T S (2000) Localization of oligonucleotides in brain by in situ hybridization. Methods Enzymol 314:238-47
Harrub, J B; Nowak Jr, T S (1998) Cryptic expression of the 70-kDa heat shock protein, hsp72, in gerbil hippocampus after transient ischemia. Neurochem Res 23:703-8

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