Cyclooxygenase, the enzyme that catalyzes the production of prostaglandins from arachidonic acid, has long been thought to play a role in exacerbating injury due to cerebral ischemia via its vascular and inflammatory effects. Recently it has been found that the inducible isoform of the enzyme, cyclooxygenase 2 (COX2), is expressed in high levels within neurons. We hypothesize that COX2 activity within the neuron itself promotes cell death after hypoxia/ischemia. The proposed experiments are designed to test whether COX2 activity exacerbates anoxic injury by oxidative stress, production of prostaglandins including the cyclopentenone prostaglandins, or both. The following specific aims are proposed: 1. Test whether COX2 activity exacerbates anoxic injury through production of oxidative stress via peroxidase activity. 2. Test whether COX2 activity exacerbates anoxic injury through production of prostaglandins via cyclooxygenase activity. 3. Test whether 15-deoxy-delta(12,14) -PGJ2 or other prostaglandins activate PPARgamma receptor binding and exacerbate anoxic neuronal death via activation of the PPARgamma receptor. COX2 activity has been implicated in the pathogenesis of stroke and neurodegenerative diseases, including Atzheimer's disease and amyotrophic lateral sclerosis. The current studies will address the mechanisms by which COX2 activity can directly injure neurons and thus could lead to new therapeutic strategies for stroke and neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037459-06
Application #
6749435
Study Section
Brain Disorders and Clinical Neuroscience 5 (BDCN)
Program Officer
Jacobs, Tom P
Project Start
1999-06-01
Project End
2008-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
6
Fiscal Year
2004
Total Cost
$350,887
Indirect Cost
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Tecuatl, Carolina; Herrrera-López, Gabriel; Martín-Ávila, Alejandro et al. (2018) TrkB-mediated activation of the phosphatidylinositol-3-kinase/Akt cascade reduces the damage inflicted by oxygen-glucose deprivation in area CA3 of the rat hippocampus. Eur J Neurosci 47:1096-1109
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Graham, Steven H; Liu, Hao (2017) Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia. Ageing Res Rev 34:30-38
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Shaik, Jafar Sadik B; Miller, Tricia M; Graham, Steven H et al. (2014) Rapid and simultaneous quantitation of prostanoids by UPLC-MS/MS in rat brain. J Chromatogr B Analyt Technol Biomed Life Sci 945-946:207-16
Liu, Hao; Rose, Marie E; Miller, Tricia M et al. (2013) COX2-derived primary and cyclopentenone prostaglandins are increased after asphyxial cardiac arrest. Brain Res 1519:71-7
Liu, Hao; Li, Wenjin; Ahmad, Muzamil et al. (2013) Increased generation of cyclopentenone prostaglandins after brain ischemia and their role in aggregation of ubiquitinated proteins in neurons. Neurotox Res 24:191-204

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