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..
|Rojas, Asheebo; Ganesh, Thota; Manji, Zahra et al. (2016) Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats. Neuropharmacology 110:419-30|
|Hassel, BjÃ¸rnar; Elsais, Ahmed; FrÃ¸land, 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|
|Varvel, Nicholas H; Jiang, Jianxiong; Dingledine, Raymond (2015) Candidate drug targets for prevention or modification of epilepsy. Annu Rev Pharmacol Toxicol 55:229-47|
|Rojas, Asheebo; Ganesh, Thota; Lelutiu, Nadia et al. (2015) Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus. Neuropharmacology 93:15-27|
|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|
|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|
|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|
|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|
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