Current medical countermeasures to nerve gas exposure such as midazolam and atropine are of doubtful general utility for civilian populations because they must be administered within minutes of an attack to be effective. Therapies that can be administered hours after chemical exposure are needed. Prolonged status epilepticus (SE) induced by the muscarinic agonist, pilocarpine, or the organophosphate, diisopropyl fluorophosphate (DFP), triggers a similar series of cellular events in the brain that prominently includes substantial mortality and selective neuronal degeneration. We have evidence that activation of brain EP2 receptors can be neuroprotective after status epilepticus. Our overarching goal is to develop small molecules that act on specific prostanoid receptors to oppose seizure-induced neurodegeneration. We have recently created the first allosteric potentiators of the EP2 receptor for PGE2 and have shown they are neuroprotective in vitro. The objective of the next project period is to develop these compounds into a practical nerve gas countermeasure. Achieving the objective of developing a novel countermeasure that can be administered hours after exposure to nerve gases will require: a) compelling proof-of-principle studies for EP2-mediated neuroprotection in the pilocarpine and DFP models of brain damage;b) optimizing EP2 allosteric potentiators for brain pharmacokinetics and potency, testing them against pilocarpine, DFP and sarin;c) completing FDA-mandated preclinical safety pharmacology and submitting an IND for use as a countermeasure for nerve gas attack or accidental release. Work will be organized around annual milestones.

Public Health Relevance

Injury of the brain is a major target of nerve gases, and is often associated with long-term disability with unusually high accompanying social and medical costs. We intend to create novel drugs that target inflammation pathways to minimize the brain damage and cognitive deficits that accompany prolonged seizures..

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS058158-09
Application #
8730235
Study Section
Special Emphasis Panel (ZRG1-MDCN-J (50))
Program Officer
Jett, David A
Project Start
2006-09-30
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
9
Fiscal Year
2014
Total Cost
$527,623
Indirect Cost
$187,221
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Dingledine, Raymond; Coulter, Douglas A; Fritsch, Brita et al. (2017) Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models. Sci Data 4:170061
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Hassel, Bjørnar; Elsais, Ahmed; Frøland, Anne-Sofie et al. (2015) Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro. J Neurochem 133:572-81
Ganesh, Thota (2015) Evaluation of WO 2012/177618 A1 and US-2014/0179750 A1: novel small molecule antagonists of prostaglandin-E2 receptor EP2. Expert Opin Ther Pat 25:837-44
Varvel, Nicholas H; Jiang, Jianxiong; Dingledine, Raymond (2015) Candidate drug targets for prevention or modification of epilepsy. Annu Rev Pharmacol Toxicol 55:229-47

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