Abstract

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 vasodilatation 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. The first goal of this project is to determine whether enhancement of extracellular AD function is beneficial in focal cerebral ischemia-reperfusion. The second goal is to study 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 third goal is to develop therapeutic regimens based on optimal enhancement of AD actions in ischemia-reperfusion. During the current granting period, we have fully developed a focal cerebral ischemia-reperfusion 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025545-10
Application #
2609609
Study Section
Neurology A Study Section (NEUA)
Program Officer
Marler, John R
Project Start
1988-04-01
Project End
2000-11-30
Budget Start
1997-12-01
Budget End
2000-11-30
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Chen, Shang-Der; Lee, Jin-Moo; Yang, Ding-I et al. (2002) Combination therapy for ischemic stroke: potential of neuroprotectants plus thrombolytics. Am J Cardiovasc Drugs 2:303-13
Xu, J; Chen, S; Ahmed, S H et al. (2001) Amyloid-beta peptides are cytotoxic to oligodendrocytes. J Neurosci 21:RC118
Xu, J; Chen, S; Ku, G et al. (2001) Amyloid beta peptide-induced cerebral endothelial cell death involves mitochondrial dysfunction and caspase activation. J Cereb Blood Flow Metab 21:702-10
Chen, H; Hu, C J; He, Y Y et al. (2001) Reduction and restoration of mitochondrial dna content after focal cerebral ischemia/reperfusion. Stroke 32:2382-7
Kanellopoulos, G K; Xu, X M; Hsu, C Y et al. (2000) White matter injury in spinal cord ischemia: protection by AMPA/kainate glutamate receptor antagonism. Stroke 31:1945-52
Majid, A; He, Y Y; Gidday, J M et al. (2000) Differences in vulnerability to permanent focal cerebral ischemia among 3 common mouse strains. Stroke 31:2707-14
Ahmed, S H; He, Y Y; Nassief, A et al. (2000) Effects of lipopolysaccharide priming on acute ischemic brain injury. Stroke 31:193-9
Xu, J; He, L; Ahmed, S H et al. (2000) Oxygen-glucose deprivation induces inducible nitric oxide synthase and nitrotyrosine expression in cerebral endothelial cells. Stroke 31:1744-51
Ahmed, S H; Shaikh, A Y; Shaikh, Z et al. (2000) What animal models have taught us about the treatment of acute stroke and brain protection. Curr Atheroscler Rep 2:167-80
Chao, K S; Hsu, J S; Xu, J et al. (1999) Differential effect of cycloheximide on neuronal and glioma cells treated with chemotherapy and radiation. J Neurooncol 45:19-26

Showing the most recent 10 out of 38 publications