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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Whittemore, Vicky R
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Emory University
Schools of Medicine
United States
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Rojas, Asheebo; Jiang, Jianxiong; Ganesh, Thota et al. (2014) Cyclooxygenase-2 in epilepsy. Epilepsia 55:17-25
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
Vezzani, Annamaria; Friedman, Alon; Dingledine, Raymond J (2013) The role of inflammation in epileptogenesis. Neuropharmacology 69:16-24
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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) Role of prostaglandin receptor EP2 in the regulations of cancer cell proliferation, invasion, and inflammation. J Pharmacol Exp Ther 344:360-7
Jiang, Jianxiong; Ganesh, Thota; Du, Yuhong et al. (2012) Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2. Proc Natl Acad Sci U S A 109:3149-54