The actions of the prostaglandins (PGs) have been suggested to play a significant role in stroke and neurodegenerative disorders. Cyclooxygenase 2 (COX-2) and PG levels increases markedly in neurons following cerebral ischemia. Previous studies in rodent stroke models have shown that COX-2 enzymatic activity promotes neuronal injury and the administration of COX-2 inhibitors reduces infarct volume. We have used transgenic mice overexpressing hCOX-2 selectively in neurons and observed an increased infarct size in the transgenic animals. Mechanisms by which PGs promote neuronal injury in stroke have not been defined. Some PGs have been reported to be toxic while others may be cytoprotective. PGs are likely to act through activation of specific PG receptors. PGs are diffusible signaling lipids whose effects are mediated through a diverse class of G-protein coupled receptors that can have opposing effects on cAMP (such as EP2, EP4, DP1) may promote neuroprotection; whereas, receptor subtypes that either decrease cAMP and signal through phosphoinositude turnover and intracellular calcium increases (such as FP, EP1, EP3 and DP2) will promote injury. Since these receptors have been cloned relatively recently, the development and availability of highly specific agonists/antagonists for in vivo use is still lacking. We will take advantage of newly available, different prostaglandin receptor knockout strain of mice to determine the effect of specific PG receptor gene deletion on neuronal injury from focal cerebral ischemia and delayed selective neuronal injury arising from cardiac arrest. The time course and localization of distinct PGs and PG receptors will be determined. Complementary experiments of oxygen/glucose deprivation and glutamate excitotoxicity will be performed on neuronal and mixed cultures from witdtype and knockouts to better define cellular mechanisms of the specific PG receptors/metabolites in regulating the outcome of ischemic damage.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-BDCN-3 (01))
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Jacobs, Tom P
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Johns Hopkins University
Schools of Medicine
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