Toxic levels of glutamate released during ischemia have been implicated in the damage caused by stroke. Unfortunately, drugs that mediate the effect of glutamate have proven ineffective or cause unacceptable side effects. Current research is moving towards investigating a number of neuromessengers involved in glutamate signaling including Zn2+, D-serine and nitric oxide. Developing treatments for stroke based on these neuromessengers has been hampered by our limited understanding of their function in vivo. Currently there are no methods for measuring the dynamics of Zn2+, D-serine and nitric oxide in vivo on a time scale of seconds. We propose designing online capillary electrophoresis-microdialysis assays for Zn2+, D-serine and nitric oxide capable of making measurements every 10 seconds, a 120-fold improvement over existing techniques. These assays will allow a detailed pharmacological study of the function Zn2+, D-serine and nitric oxide play in vivo. Tissue (salamander retina) and single cell models (neuron and gila) will also be studied to compare different levels of complexity. The dynamics of Zn2+, D-serine and nitric oxide will be measured during ischemia and reperfusion for the first time. It is hypothesized that toxic concentrations of Zn2+ and nitric oxide are released during ischemia. Understanding what happens in the brain chemically during ischemia is cdtical considering that most of the damage caused by stroke is thought to be chemical in origin. We will use the high temporal resolution assays for glutamate, Zn2+, D-serine and nitric oxide to test the effect of several proposed preventative stroke treatments. Classes of compounds that will be tested include blood thinners (aspirin, t-PA), anaerobic energy sources (creatine, arginine), antioxidants (vitamins C and E) and metal chelators (EDTA).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS043304-01A1
Application #
6678526
Study Section
Special Emphasis Panel (ZRG1-BECM (01))
Program Officer
Talley, Edmund M
Project Start
2003-06-15
Project End
2007-04-30
Budget Start
2003-06-15
Budget End
2004-04-30
Support Year
1
Fiscal Year
2003
Total Cost
$284,763
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Chemistry
Type
Other Domestic Higher Education
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Graf, Neil J; Bowser, Michael T (2013) Effect of cross sectional geometry on PDMS micro peristaltic pump performance: comparison of SU-8 replica molding vs. micro injection molding. Analyst 138:5791-800
Turgeon, Ryan T; Fonslow, Bryan R; Jing, Meng et al. (2010) Measuring aptamer equilibria using gradient micro free flow electrophoresis. Anal Chem 82:3636-41
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Rosenberg, Dina; Kartvelishvily, Elena; Shleper, Maria et al. (2010) Neuronal release of D-serine: a physiological pathway controlling extracellular D-serine concentration. FASEB J 24:2951-61
Turgeon, Ryan T; Bowser, Michael T (2009) Improving sensitivity in micro-free flow electrophoresis using signal averaging. Electrophoresis 30:1342-8
Turgeon, Ryan T; Bowser, Michael T (2009) Micro free-flow electrophoresis: theory and applications. Anal Bioanal Chem 394:187-98
Fonslow, Bryan R; Bowser, Michael T (2008) Fast electrophoretic separation optimization using gradient micro free-flow electrophoresis. Anal Chem 80:3182-9
Graf, Neil J; Bowser, Michael T (2008) A soft-polymer piezoelectric bimorph cantilever-actuated peristaltic micropump. Lab Chip 8:1664-70
Klinker, Chanda Ciriacks; Bowser, Michael T (2007) 4-fluoro-7-nitro-2,1,3-benzoxadiazole as a fluorogenic labeling reagent for the in vivo analysis of amino acid neurotransmitters using online microdialysis-capillary electrophoresis. Anal Chem 79:8747-54
O'Brien, Kylie B; Bowser, Michael T (2006) Measuring D-serine efflux from mouse cortical brain slices using online microdialysis-capillary electrophoresis. Electrophoresis 27:1949-56

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