Inflammation-related changes are a prominent part of the CNS response to acute injury, infection, and chronic neurodegenerative disease. Numerous studies indicate that attenuation of CNS inflammation may be beneficial in treating CNS disorders, including Alzheimer's disease (AD). Microglia and astrocytes play a significant role in the initiation and maintenance of CNS inflammation by producing a wide-range of inflammation-related gene products. Elaboration of inflammatory responses elicited by both acute and chronic stimuli depends on key molecular players that drive interactions among cells. One of these players is IL-1 beta proinflammatory cytokine strongly implicated in acute CNS inflammation as well as AD. Based on studies of peripheral inflammation, another key player is likely to be prostaglandin E2 (PGE2) produced by the inflammation-responsive protein, cyclooxygenase-2 (COX-2), one of two isoforms of the obligate enzyme for prostaglandin biosynthesis. COX-2 is made in brain and can be induced by IL-1 beta and other proinflammatory cytokines in astrocytes and microglia. Moreover, preliminary studies indicate that selective inhibition of COX-2 attenuates the expression of inflammation-related genes following acute CNS injury. Based on these findings and epidemiological evidence that inhibitors of cyclooxygenase may be beneficial in AD, this competitive renewal focuses on the role of COX-2 in CNS inflammation. The hypothesis that COX-2 derived prostaglandins are required for elaboration of acute as well as chronic local inflammatory responses in the central nervous system will be tested in three different model systems. The first specific aim will characterize direct influences of COX-2 and PGE2 on expression of IL-1 beta responsive genes in primary cultures of human and murine astrocytes. In the second specific aim, the contributions of COX-2 and PGE2 to an acute inflammatory cascade elicited by cortical injection of IL-1 beta will be established. In the third and fmal specific aim, COX-2 specific inhibitors will be employed in double transgenic PS-1/APP mice to ascertain the role of COX-2 in chronic CNS inflammation secondary to Abeta deposition. Together, these studies examine the role of COX-2 and increased prostaglandin production in CNS inflammation and a model of Alzheimer's disease. This work will provide a clearer understanding of the mechanisms by which anti-inflammatory drugs influence AD and may reveal new avenues for therapeutic intervention. Moreover, these studies have relevance to pathological processes occurring in head trauma, stroke, and other neurodegenerative diseases where gliosis and inflammation-related changes take place.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS033553-06
Application #
6132685
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Heemskerk, Jill E
Project Start
2000-04-28
Project End
2003-03-31
Budget Start
2000-04-28
Budget End
2001-03-31
Support Year
6
Fiscal Year
2000
Total Cost
$335,769
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
O'Banion, M Kerry (2010) Prostaglandin E2 synthases in neurologic homeostasis and disease. Prostaglandins Other Lipid Mediat 91:113-7
Matousek, Sarah B; Hein, Amy M; Shaftel, Solomon S et al. (2010) Cyclooxygenase-1 mediates prostaglandin E(2) elevation and contextual memory impairment in a model of sustained hippocampal interleukin-1beta expression. J Neurochem 114:247-58
Maida, Mary E; Hurley, Sean D; Daeschner, Jo Anna et al. (2006) Cytosolic prostaglandin E2 synthase (cPGES) expression is decreased in discrete cortical regions in psychiatric disease. Brain Res 1103:164-72
Moore, Amy H; Olschowka, John A; Williams, Jacqueline P et al. (2005) Regulation of prostaglandin E2 synthesis after brain irradiation. Int J Radiat Oncol Biol Phys 62:267-72
Moore, Amy H; Olschowka, John A; Williams, Jacqueline P et al. (2004) Radiation-induced edema is dependent on cyclooxygenase 2 activity in mouse brain. Radiat Res 161:153-60