Status epilepticus (SE) in man and rodents can produce cognitive deficits and trigger a series of molecular and cellular events that eventually culminate in the appearance of spontaneous seizures, i.e., epilepsy. An early event in this process is the transient opening of the blood-brain barrier with consequent exchange of cells and proteins between blood and brain interstitium. Our hypothesis, supported by preliminary evidence, is that neuronal cyclooxygenase 2 (COX2) induction by status epilepticus controls the breakdown of the blood-brain barrier.
Specific aims are (1) to determine whether the induction of COX2 in principal forebrain neurons in both rodent models of SE triggers a neuroinflammatory cascade that causes opening of the blood-brain barrier, peripheral leukocyte infiltration, microglial activation, and eventually epilepsy;and (2) To test the hypothesis that EP2 receptor activation on astrocytes or endothelial cells regulates albumin leakage and leukocyte infiltration across the blood-brain barrier. A comparison of the pilocarpine and kainate SE models will be done to minimize model-specific conclusions.
Aim 1 will be pursued by comparing the intensity of inflammatory events following SE in wildtype mice and mice with conditional deletion of the COX2 gene limited to principal forebrain neurons. The expectation is that the broad neuroinflammatory consequences of SE will be attenuated in the COX2 cKO mouse.
The second aim will be pursued by a) measuring the effect of prostaglandin receptor agonists and antagonists on the leakiness of an in vitro blood-brain barrier, and b) determining whether the neuroinflammatory consequences of SE described in aim 1 are attenuated by systemically applied EP2 antagonists.

Public Health Relevance

Status epilepticus, defined as seizures with duration 30 minutes or longer, has high mortality and is a major health concern. Status epilepticus triggers a massive inflammatory reaction in the brain that is partly responsible for morbidity. This project is designed to identify novel drug-like chemicals that can prevent the brain damage associated with status epilepticus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS074169-02
Application #
8319322
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2011-08-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$193,750
Indirect Cost
$68,750
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Varvel, Nicholas H; Neher, Jonas J; Bosch, Andrea et al. (2016) Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc Natl Acad Sci U S A 113:E5665-74
Varvel, Nicholas H; Jiang, Jianxiong; Dingledine, Raymond (2015) Candidate drug targets for prevention or modification of epilepsy. Annu Rev Pharmacol Toxicol 55:229-47
Jiang, Jianxiong; Yang, Myung-soon; Quan, Yi et al. (2015) Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus. Neurobiol Dis 76:126-36
Fu, Yujiao; Yang, Myung-Soon; Jiang, Jianxiong et al. (2015) EP2 Receptor Signaling Regulates Microglia Death. Mol Pharmacol 88:161-70
Vezzani, Annamaria; Dingledine, Raymond; Rossetti, Andrea O (2015) Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application. Expert Rev Neurother 15:1081-92
Dingledine, Ray; Varvel, Nicholas H; Dudek, F Edward (2014) When and how do seizures kill neurons, and is cell death relevant to epileptogenesis? Adv Exp Med Biol 813:109-22
Rojas, Asheebo; Jiang, Jianxiong; Ganesh, Thota et al. (2014) Cyclooxygenase-2 in epilepsy. Epilepsia 55:17-25
Quan, Yi; Jiang, Jianxiong; Dingledine, Ray (2013) EP2 receptor signaling pathways regulate classical activation of microglia. J Biol Chem 288:9293-302
Jiang, Jianxiong; Quan, Yi; Ganesh, Thota et al. (2013) Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation. Proc Natl Acad Sci U S A 110:3591-6
Jiang, Jianxiong; Dingledine, Ray (2013) Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. Trends Pharmacol Sci 34:413-23

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