# Antiepileptic action of JNK2 inhibition

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2022 · $427,625

## Abstract

Project summary / abstract
 c-Jun N-terminal kinases (JNKs) are a family of protein kinases that are members of the
larger category of “stress activated protein kinases.” JNKs are known to be hyperactivated in
neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and are more
recently implicated in medically refractory epilepsy. In these diseases, hyperactivation of JNK is
a pathological event, and appears to contribute to the progressive apoptotic death of neurons. We
recently found, somewhat unexpectedly, that JNK is hyperactivated in an animal model of
temporal lobe epilepsy, and that partial pharmacological inhibition of JNK produced a
significant, dose-dependent reduction of spontaneous seizure frequency in chronically epileptic
animals. In addition, of the three JNK isoforms (JNK1, 2, and 3), only JNK2 was hyperactivated
in our animal model. Thus, we hypothesized that selective inhibition of JNK2 could produce a
significant antiepileptic action and avoid potential CNS adverse effects of broad spectrum JNK
inhibition.
 In this two-year, focused proposal we plan to further study JNK as a novel target of
antiepileptic therapy. In the first Aim, we will seek more complete knockdown of JNK2
expression in an animal model of epilepsy using a novel AAV-delivered CRISPR/Cas9
approach. Published data shows that this approach is capable of knocking down gene expression
to a degree comparable to that of constitutive gene deletion. We will measure the effect of near-
complete JNK2 knockdown on spontaneous seizure frequency in an animal model of temporal
lobe epilepsy.
 In the second Aim, we will seek evidence that JNKs are hyperactivated in human epilepsy as
they are in our animal model by looking for total and phosphorylated (activated) JNK expression
for all three isoforms in brain tissue from human epilepsy patients undergoing brain resection for
medically refractory epilepsy. We will also measure JNK expression and activation in
cerebrospinal fluid from refractory epilepsy patients compared to individuals without a
neurological disorder.
 These experiments will provide further validation of JNK as a novel target of antiepileptic
therapy. Such targets are desperately needed in order to advance therapy for patients with
medically refractory epilepsy.

## Key facts

- **NIH application ID:** 10515751
- **Project number:** 1R21NS128846-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** NICHOLAS P POOLOS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $427,625
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10515751

## Citation

> US National Institutes of Health, RePORTER application 10515751, Antiepileptic action of JNK2 inhibition (1R21NS128846-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10515751. Licensed CC0.

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