The long-term goal of this research program is to elucidate the role of the prostanoid-synthesizing enzyme cyclooxygenase-2 (COX-2) in ischemic brain injury. Studies during the previous funding period have provided evidence that COX-2 is one of the factors by which the inflammatory process involving the ischemic brain (post-ischemic inflammation) contributes to the late progression of focal cerebral ischemic damage. These findings have indicated that COX-2 participates in the late stages of ischemic brain injury. Other evidence however suggests additional mechanisms by which COX-2 could contribute to ischemic brain injury. In particular, COX-2-derived prostanoids are potent constrictors of cerebral blood vessels and participate in pathogenic processes linked to the activation of glutamate receptors. Considering that cerebral blood flow and activation of glutamate receptors play a critical role in the initiation of ischemic damage, these data raise the possibility that COX-2 could also be involved in early events of the ischemic cascade. Therefore, in this renewal application we will continue to pursue our long-term goal by testing the hypothesis that COX-2, in addition to its role in post-ischemic inflammation, is also involved in the mechanisms initiating ischemic brain injury. As a starting point, we will focus on the role of COX-2 in critical hemodynamic changes that occur during ischemia-reperfusion and in glutamate receptor-mediated cytotoxicity. In the proposed experiment, we will use molecular and biochemical approaches, as well as methods to assess hemodynamic, histological, and neurological outcome after cerebral ischemia. Focal cerebral ischemia will be produced by transient occlusion of the middle cerebral artery in mice. The brain damage resulting from focal microinjection of N-methyl-D-aspartate or kainate in neocortex will also be investigated. The role of COX-2 will be examined using both pharmacological inhibition of COX-2, and COX-2-deficient mice. The role of COX-2 derived reactive oxygen species will be examined using mice over expressing the antioxidant superoxide dismutase. While the proposed studies will expand our understanding of the involvement of COX-2 in ischemic brain injury, they will also provide the rational basis for new neuroprotective strategies for human stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS035806-06
Application #
6562685
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (02))
Program Officer
Jacobs, Tom P
Project Start
1997-03-01
Project End
2005-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
6
Fiscal Year
2002
Total Cost
$381,375
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Shimamura, Munehisa; Zhou, Ping; Casolla, Barbara et al. (2013) Prostaglandin E2 type 1 receptors contribute to neuronal apoptosis after transient forebrain ischemia. J Cereb Blood Flow Metab 33:1207-14
Anrather, Josef; Gallo, Eduardo F; Kawano, Takayuki et al. (2011) Purinergic signaling induces cyclooxygenase-1-dependent prostanoid synthesis in microglia: roles in the outcome of excitotoxic brain injury. PLoS One 6:e25916
Iadecola, Costantino; Anrather, Josef (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796-808
Iadecola, Costantino; Anrather, Josef (2011) Stroke research at a crossroad: asking the brain for directions. Nat Neurosci 14:1363-8
Leng, Lewis Z; Fink, Matthew E; Iadecola, Costantino (2011) Spreading depolarization: a possible new culprit in the delayed cerebral ischemia of subarachnoid hemorrhage. Arch Neurol 68:31-6
Gallo, Eduardo F; Iadecola, Costantino (2011) Balancing life and death in the ischemic brain: SIK and TORC weigh in. Neuron 69:3-6
Abe, Takato; Shimamura, Munehisa; Jackman, Katherine et al. (2010) Key role of CD36 in Toll-like receptor 2 signaling in cerebral ischemia. Stroke 41:898-904
Felger, Jennifer C; Abe, Takato; Kaunzner, Ulrike W et al. (2010) Brain dendritic cells in ischemic stroke: time course, activation state, and origin. Brain Behav Immun 24:724-37
Yin, Fangfang; Banerjee, Rebecca; Thomas, Bobby et al. (2010) Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 207:117-28
Capone, Carmen; Faraco, Giuseppe; Anrather, Josef et al. (2010) Cyclooxygenase 1-derived prostaglandin E2 and EP1 receptors are required for the cerebrovascular dysfunction induced by angiotensin II. Hypertension 55:911-7

Showing the most recent 10 out of 46 publications