Epilepsy is a common neurological disorder that afflicts about 1% of the population. Although seizures can be partially controlled by current medications, there is no US FDA-approved drug that can provide disease prevention or modification despite remarkable advances in epilepsy treatment over the past decades. A major obstacle to finding such an antiepileptogenic drug is that the molecular mechanisms by which a normal brain is transformed to generate epileptic seizures remain unsolved. Accumulating evidence from recent clinical and preclinical studies suggests that the abnormal activation of the brain-derived neurotrophic factor (BDNF) receptor TrkB (tropomyosin-related kinase receptor B) and its downstream effector phospholipase C?1 (PLC?1) is sufficient to produce epilepsy following status epilepticus (SE). As TrkB and PLC?1 are emerging as attractive molecular targets to prevent acquired epilepsy, a key unsolved puzzle is the signaling events that are triggered by SE and cause the irregular BDNF/TrkA activity in the hippocampus, thereby leading to epileptogenesis. In preliminary studies we have demonstrated that the seizure-induced hippocampal BDNF/TrkB abnormality is largely suppressed by blocking prostaglandin E2 (PGE2) synthesis or signaling. Our main hypothesis is that PGE2 via a G?s-dependent signaling pathway upregulates hippocampal BDNF/TrkB activity and contributes to epileptogenesis following prolonged seizures. Our general approach is to use biochemical, pharmacological, genetic tools, and multiple in vitro and in vivo model systems to test a hypothesis that PGE2 is involved in the hippocampal BDNF induction and TrkB activation after SE, to determine whether seizure-mediated BDNF/TrkB activity involves cAMP/PKA signaling and which G?s-coupled PGE2 receptor is engaged, and to determine whether PGE2 signaling via its G?s-coupled receptors plays a dominant role in the development of epilepsy and/or the associated behavioral comorbidities after SE. Successful completion of this project might lead to the discovery of novel molecular targets for the prevention strategies of acquired epilepsy.
Epilepsy is one of the most common neurological disorders, yet there is lack of prevention treatment. As another very unfortunate fact, more than 30% of patients with epilepsy have insufficient response to the current antiepileptic drugs. The work proposed here will identify signaling pathways that are upregulated in patients with epilepsy as well as in experimental animals that experienced status epilepticus, and may underlie the molecular basis for the development of acquired epilepsy. By dissecting these signaling pathways in model systems, we will identify the key epileptogenic mediators as potential molecular targets for epilepsy prevention strategies.
| 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 |
