As the third most prevalent brain disorder, epilepsy affects virtually three million Americans and results in an estimated annual health care cost of $17.6 billion. There are about 150,000 new cases of epilepsy annually diagnosed in the U.S., mostly in children and the elderly. Current antiepileptic drugs (AEDs) dampen seizures mainly via enhancing GABA function or blocking sodium channels. However, the conventional AEDs cause well-documented side effects and lack efficacy in about a third of epilepsy patients. In addition, no current drug has been shown to prevent epileptogenesis, i.e., the development of epilepsy after acute brain insults. Identifying new drug targets and developing novel therapies are urgently needed to achieve the ultimate goal of ?no seizures, no side effects? in the management of epilepsy. We previously demonstrated that prostaglandin E2 (PGE2) via its EP2 receptor subtype plays essential roles in prolonged seizure-induced neuroinflammation and neurodegeneration. We also found that EP2 receptor regulates the expression of a variety of pro-inflammatory genes in microglia likely via cAMP/Epac signaling. A better understanding of inflammatory prostaglandin signaling pathways that contribute to the pathophysiology of seizures and epilepsy might help identify novel drug targets with more specificity. In this proposal, we will test the hypothesis that prostaglandin PGE2 receptor EP2 in microglia mediates seizure-provoked brain inflammation and injury through cAMP/Epac signaling. We will utilize a combination of novel molecular genetics, pharmacology and behavior strategies that we developed in our laboratory to test this hypothesis in rodent models of epilepsy. Successful completion of these studies will provide new insights into the regulation of inflammation and injury in epileptic brain that should be also relevant to many other acute or chronic neurological conditions involving neuroinflammation with elevated COX-2 and PGE2 activities, including stroke, multiple sclerosis, Alzheimer's disease, Parkinson's disease, etc. More importantly, this research is expected to provide critical information that will guide drug discovery efforts aimed at developing novel therapeutic agents to treat these brain conditions.
Acute brain attacks such as seizures induce severe brain inflammation and injury; however, the underlying mechanisms are poorly understood. The goal of the proposed research is to understand, at the molecular and cellular levels, how prostaglandins promote microglia- mediated inflammatory storm in the brain and thus contribute to the pathophysiology of seizures and epilepsy.
|Jiang, Jianxiong; Van, Tri Minh; Ganesh, Thota et al. (2018) Discovery of 2-Piperidinyl Phenyl Benzamides and Trisubstituted Pyrimidines as Positive Allosteric Modulators of the Prostaglandin Receptor EP2. ACS Chem Neurosci 9:699-707|
|Jiang, Jianxiong; Qiu, Jiange; Li, Qianqian et al. (2017) Prostaglandin E2 Signaling: Alternative Target for Glioblastoma? Trends Cancer 3:75-78|
|Qiu, Jiange; Shi, Zhi; Jiang, Jianxiong (2017) Cyclooxygenase-2 in glioblastoma multiforme. Drug Discov Today 22:148-156|
|Kang, Xu; Qiu, Jiange; Li, Qianqian et al. (2017) Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype. Sci Rep 7:9459|
|Hartings, Jed A; York, Jonathan; Carroll, Christopher P et al. (2017) Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction. Brain 140:2673-2690|
|Dey, Avijit; Kang, Xu; Qiu, Jiange et al. (2016) Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside. Trends Pharmacol Sci 37:463-484|
|Du, Yifeng; Kemper, Timothy; Qiu, Jiange et al. (2016) Defining the therapeutic time window for suppressing the inflammatory prostaglandin E2 signaling after status epilepticus. Expert Rev Neurother 16:123-30|
|Fu, Yujiao; Yang, Myung-Soon; Jiang, Jianxiong et al. (2015) EP2 Receptor Signaling Regulates Microglia Death. Mol Pharmacol 88:161-70|
|Jiang, Jianxiong; Yang, Myung-Soon; Quan, Yi et al. (2015) Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus. Neurobiol Dis 76:126-136|
|Ganesh, Thota; Jiang, Jianxiong; Dingledine, Ray (2014) Development of second generation EP2 antagonists with high selectivity. Eur J Med Chem 82:521-35|