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.
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