Injury of the brain is a major cause of death and morbidity after exposure to nerve agents that activate the muscarinic receptor system, which often causes long term disability with unusually high accompanying social and medical costs. Current countermeasures such as midazolam and atropine are of doubtful utility for civilian populations because they must be administered within minutes of an attack to be effective. Therapies that can be administered hours to days after the attack are needed. Prolonged status epilepticus (SE) induced by the muscarinic agonist, pilocarpine, triggers a similar series of molecular and cellular events in the rodent brain. Cyclooxygenase-2 (cox-2) is induced strongly in principal hippocampal neurons after a seizure. Our overarching goal is to develop small molecules that act on specific prostanoid receptors to oppose seizure-induced neurodegeneration, neuroinflammation and functional deficits in adults and children subject to chemical attack by nerve agents.
Specific aims 1 and 2 are designed to answer several key questions in order to better understand the basis of these neuropathologies: Which prostaglandin receptors are involved in neuronal injury and neuroinflammation after SE, and in delayed sensorimotor deficits? Which cell type(s) release PGE2 and PGD2? We will test the specific hypotheses that an allosteric EP2 receptor activator is neuroprotective after pilocarpine-induced SE, and a DP2 receptor blocker blunts the neuroinflammatory response.
In aims 3 and 4 we identify novel small molecule modulators of selected prostanoid receptors that are brain permeant and can be delivered after the period of acute convulsions to blunt SE-induced delayed neurodegeneration, neuroinflammation and cognitive deficits. Successful completion of these studies is an essential step to translate our research findings into a useful countermeasure to a prominent class of chemical threats, and will prepare the ground for subsequent validation in animals exposed to sarin-type nerve agents themselves, followed by GLP preclinical pharmacology studies, IND submission, and Phase I clinical safety trials.
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