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.
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..
|Ganesh, Thota; Jiang, Jianxiong; Dingledine, Ray (2014) Development of second generation EP2 antagonists with high selectivity. Eur J Med Chem 82:521-35|
|Ganesh, Thota (2014) Prostanoid receptor EP2 as a therapeutic target. J Med Chem 57:4454-65|
|Rojas, Asheebo; Gueorguieva, Paoula; Lelutiu, Nadia et al. (2014) The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus. Neurobiol Dis 70:74-89|
|Rojas, Asheebo; Jiang, Jianxiong; Ganesh, Thota et al. (2014) Cyclooxygenase-2 in epilepsy. Epilepsia 55:17-25|
|Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon et al. (2014) Lead optimization studies of cinnamic amide EP2 antagonists. J Med Chem 57:4173-84|
|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|
|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) Role of prostaglandin receptor EP2 in the regulations of cancer cell proliferation, invasion, and inflammation. J Pharmacol Exp Ther 344:360-7|
|Vezzani, Annamaria; Friedman, Alon; Dingledine, Raymond J (2013) The role of inflammation in epileptogenesis. Neuropharmacology 69:16-24|
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