# Inflammatory control of blood-brain barrier integrity and epileptogenesis after seizures

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $422,180

## Abstract

Project Summary
Accumulating evidence in animal models highlights that inflammation ensuing in the brain during status epilepticus
(SE) may play a determinant role in ongoing seizures and their long-term detrimental consequences, independent
of an infection or auto-immune cause. Studies in a multitude of animal models demonstrate that SE causes a rapid
and intense inflammatory cascade in the forebrain involving interactions among neurons, reactive astrocytes,
activated microglia, vascular endothelial cells and, eventually, infiltrating neutrophils and monocytes from the
blood. The pathophysiological interactions among the various inflammatory molecules, and the sequence of events
leading to their induction, have not yet been dissected. The broad cytokine burst and gliosis following SE is blunted
in mice that have genetic ablations of COX-2 restricted to those principal forebrain neurons in which COX-2 is
normally induced by SE, pointing to a role for COX-2 pathways in SE-induced inflammation including breakdown of
the blood-brain barrier (BBB), which is sufficient to produce epilepsy. Previous work showed that the EP2 receptor
mediates much of the COX-2 effect. We hypothesize that SE-related morbidity is largely due to activation of
microglial EP2 receptors, which modulates production of cytokines that degrade the BBB. Our specific aims are: 1.
To test the hypothesis that activated microglia rather than inflammatory monocytes are responsible for EP2-
regulated BBB breakdown after seizures; 2. To test the hypothesis that IL- -secreted
mediator and Epac the major EP2 signaling pathway that degrades the integrity of the blood-brain barrier after SE;
3. To determine whether EP2 activation plays a dominant role in the development of epilepsy or its comorbidities
after SE. To address these aims we employ in vitro culture models of the BBB and in vivo SE models with cell-
specific conditional knockouts of EP2. Immunohistochemical, western blot, FACS, qRT-PCR, EEG and behavioral
assays are performed.

## Key facts

- **NIH application ID:** 9914359
- **Project number:** 5R01NS097776-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** RAYMOND J DINGLEDINE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,180
- **Award type:** 5
- **Project period:** 2016-05-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914359

## Citation

> US National Institutes of Health, RePORTER application 9914359, Inflammatory control of blood-brain barrier integrity and epileptogenesis after seizures (5R01NS097776-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9914359. Licensed CC0.

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