# Exploiting EP2 receptor biology to target seizure-related neuroinflammation selectively

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $520,230

## Abstract

Project Summary
Accumulating evidence in humans and in animal models indicates that inflammation of the brain that
develops after status epilepticus (SE) may play a determinant role in long-term detrimental consequences,
independent of an infection or auto-immune cause. The pathophysiological interactions among the various
inflammatory molecules, and the sequence of events leading to their induction, have not yet been dissected.
Previous work pointed to a role for cyclooxygenase-2 (COX-2) pathways in SE-induced inflammation, and
showed that the EP2 receptor mediates much of the COX-2 effect. Our recent work suggests that PGE2
released from neurons after SE activates EP2 receptors on nearby neurons and myeloid cells, and that EP2
activation on neurons and myeloid cells might cause opposing effects. We hypothesize that EP2 activation
on neurons after SE is neuroprotective, whereas EP2 activation on microglia or invading monocytes results
in cytokine synthesis and subsequent development of epilepsy. Here we use a novel HaloTag technology to
target neurons and myeloid cells separately with EP2 antagonists and agonists to test this hypothesis. Our
specific aims are: 1. To test the hypothesis that pharmacologic block of EP2 receptors on neurons and
myeloid cells has opposing effects after SE. 2. To test the hypothesis that blocking EP2 receptors on myeloid
cells interferes with the process of epileptogenesis. 3. To test the hypothesis that EP2-mediated
neuroprotection involves neuronal EP2 receptors, utilizes a cAMP rather than β-arrestin pathway, and
requires CX3CL1 (fractalkine). To address these aims we employ in vitro culture models and in vivo SE
models with novel EP2 antagonists and agonists targeted by HaloTag to neurons or microglia.
Immunohistochemical, western blot, qRT-PCR, cell viability, EEG and behavioral assays are performed.

## Key facts

- **NIH application ID:** 10171930
- **Project number:** 5R01NS112308-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** RAYMOND J DINGLEDINE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $520,230
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171930

## Citation

> US National Institutes of Health, RePORTER application 10171930, Exploiting EP2 receptor biology to target seizure-related neuroinflammation selectively (5R01NS112308-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10171930. Licensed CC0.

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