Monday, April 21, 2025
4/21/2025
Inflammatory regulation of epileptogenesis after status epilepticus - PROJECT SUMMARY As the second most common neurological emergency, status epilepticus (SE) is a group of life-threatening conditions that are characterized by hypersynchronous epileptic activity that lasts for five minutes or longer without full return of consciousness, and the overall SE-associated mortality rate in adults is about 20-30%. The generalized convulsive SE constitutes about 45-74% of all cases and has long been known to trigger neuronal damage, and patients who survive SE can develop long-term neurological sequelae. As such, SE triggers changes in the brain that can lead to lifelong epilepsy and overall increases the risk of epilepsy by more than three times compared to non-SE seizures. Despite an increasing list of US FDA-approved antiseizure drugs (ASDs), about 23-43% of SE patients will progress to refractory SE and do not satisfactorily respond to current medications, and the mortality rates in these patients can approach up to 39%. Current ASDs are also well known for their broad neurotoxic adverse effects that are often unbearable and can further complicate the management of seizures. It is another unfortunate fact that these medications only provide symptomatic relief and have not been shown to prevent the development of epilepsy after de novo SE or modify the progression of seizures. Development of the prevention and/or modification strategies for post-SE epilepsy must hinge on a good understanding of signaling pathways that are provoked by SE and in turn trigger epileptogenic processes, such as brain cytokine surge, reactive gliosis, neuronal damage, blood-brain barrier disruption, and brain infiltration of leukocytes and blood proteins, which eventually accumulate in the occurrence of unprovoked seizures, i.e., chronic epilepsy. Previous studies by us and others show that the prostaglandin E2 (PGE2) receptor EP2 plays essential roles in brain inflammation, neuronal damage, and behavioral deficits after SE in rodents. Our results from the previous grant cycle also reveal that Gαs-coupled EP2 regulates microglial activation to release cytokines via its downstream effector – exchange protein activated by cAMP (EPAC), and the SE-upregulated EPAC in turn contributes to neuroinflammation. Objective of this proposed study is to reveal the molecular and cellular mechanisms whereby PGE2/EP2/EPAC axis triggers these neuroinflammatory processes after SE and thus contributes to acquired epilepsy and behavioral comorbidities. To achieve this goal, we will use multiple in vitro (aim 1) and in vivo (aims 2 and 3) models engaging a unique set of genetic and pharmacological approaches that we developed during the previous funding cycle. Completion of this study will provide novel insights into the regulation of neuroinflammatory processes in the epileptogenesis after de novo SE, which should be also relevant to epilepsies triggered by other brain insults, such as strokes, TBIs, brain infections and tumors, owing to the shared commonalities in epileptogenic processes. If successful, this work will have identified new targets for disease modification and/or prevention of epilepsy and could guide the drug development for novel antiepileptogenic pharmacotherapies.
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