# Anticonvulsant screening using chronic epilepsy models

> **NIH NIH R33** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $388,818

## Abstract

Abstract
The NINDS Anticonvulsant Screening Program (ASP) has identified most of the anticonvulsants in clinical use
today. However, one third of epileptic patients do not respond to these drugs. The ASP protocols are based
on seizures induced by subjecting normal animals to acute convulsant conditions. We have developed a
complimentary system of novel in vitro and in vivo assays of spontaneous seizures in chronically epileptic
preparations. This two-stage screening system provides a unique focus on recurrent spontaneous seizures in
chronic epilepsy models. The first stage is an in vitro assay comprised of the organotypic hippocampal slice
culture, which develops electrographic seizure activity and corresponding biochemical biomarkers over the first
week in vitro. The second stage is an in vivo assay comprised of the kainate model of epilepsy in which
spontaneous seizures are monitored using continuous telemetry and supervised, blinded, computerized
seizure detection. We used the rapid in vitro assay to screen over 400 compound-concentration combinations
from the NINDS Custom Compound Collection. We found a lead compound, celecoxib, and then verified this
lead by the second-stage testing in a randomized double blind in vivo crossover trial. Celecoxib had no effect
on seizures induced by acute application of convulsants to normal brain tissue, suggesting that its
anticonvulsant properties are unique to chronic epilepsy, and raising the possibility that its spectrum of action
will be distinct from anticonvulsants discovered by the ASP protocols.
The next step in development is medicinal chemistry to optimize celecoxib’s anticonvulsant efficacy. This is
most feasibly accomplished through the UH2 / UH3 Blueprint Neurotherapeutics Network. As our discussions
with BPN program officers clarified, to efficiently utilize the BPN medicinal chemistry program we must further
develop the in vitro and in vivo assays and acquire additional data on our lead compound. The UH2/3
mechanism was considered the most appropriate funding mechanism by the NINDS program officer. In the
R21 phase of this proposal, we will extend the in vitro assay’s concentration-response for celecoxib and 2,5
dimethyl celecoxib, a derivative that does not inhibit COX2 but has equal anticonvulsant efficacy in vitro. We
will then characterize the assay’s reproducibility and Z factor. We will also establish the dose-response of the
in vivo assays for celecoxib, and increase the number of in vitro and in vivo sites to two each in order to
improve robustness and throughput, as well as engage outstanding younger investigators in this effort. In the
R33 phase of the proposal, we will further characterize the lead compound by determining whether COX2
inhibition is necessary for anticonvulsant activity in the in vitro and in vivo assays.

## Key facts

- **NIH application ID:** 10206883
- **Project number:** 4R33NS096948-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** YEVGENY BERDICHEVSKY
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,818
- **Award type:** 4N
- **Project period:** 2017-06-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206883

## Citation

> US National Institutes of Health, RePORTER application 10206883, Anticonvulsant screening using chronic epilepsy models (4R33NS096948-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10206883. Licensed CC0.

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