The compounding effect of cerebral ischemia-reperfusion includes: a. massive release of excitatory neurotransmitters and neuronal excitation leading to increased energy demand; and b. post-ischemic vascular changes caused by infiltration of inflammatory cells and endothelial injury. Adenosine (AD) is an endogenous neuroprotective modulator which is released into extracellular space in increased quantity during ischemia. AD may reverse metabolic derangement and preserve vascular integrity in cerebral ischemia-reperfusion. The metabolic effect of AD may include inhibition of neurotransmitter release and suppression of cell excitation leading to reduced metabolic demand. This effect is primarily mediated by A1 receptors. The favorable vascular effects of AD may include vasodilation in ischemic region and inhibition of polymorphonuclear neutrophil (PMN) function and protection of endothelial integrity. The vascular effects of AD are mainly mediated by A2 receptors. We are attempting to determine whether enhancement of extracellular AD function is beneficial in focal cerebral ischemia-reperfusion. We are also studying the mechanism of action of AD focusing on 2 key events that have been implicated in the pathogenesis of ischemic brain injury and that are known to be modulated by AD. The first event is glutamate release. The second event is PMN infiltration and related vascular injury. We will confirm the roles of AD in modulating these 2 events from different angles and characterize the specific receptor type(s) involved in each event. The goal is to develop therapeutic regimens based on optimal enhancement of AD actions in ischemia-reperfusion. During the recent granting period, we have fully developed a focal cerebral ischemia-refusion model in the rat. This model is suitable for preclinical trials of neuroprotective agents. We will employ a rigorously designed trial protocol to identify the most effective regimens affecting AD mechanism.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001638-11
Application #
5223511
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
1996
Total Cost
Indirect Cost
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