# Evaluating the disease modifying properties of dimethyl fumarate (DMF) for the prevention and treatment of pharmacoresistant epilepsy

> **NIH NIH R61** · UNIVERSITY OF WASHINGTON · 2024 · $285,181

## Abstract

ABSTRACT
Progressive decline in seizure control and cognitive function, coupled with anxiety and depression are often
consequences of epilepsy that negatively impact a patient’s overall quality of life. None of the currently available
antiseizure medicines (ASMs) prevent or reverse pharmacoresistance or modify the risk for cognitive and
behavioral comorbidities associated with drug resistant epilepsy (DRE). Previous findings in our laboratory
suggest that oxidative stress contributes to epileptogenesis following a brain insult like TBI, stroke, or status
epilepticus (SE), and that treatment with dimethyl fumarate (DMF), the selective blood-brain barrier penetrant
activator of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), upregulates the intrinsic
antioxidant defenses of cells and reduces the severity of chronic epilepsy in animals following SE. We aim to
test the HYPOTHESIS that DMF is disease modifying when administered at the time of neurological insult and
at a time well after epilepsy diagnosis (e.g., post-symptomatic disease modification). Specifically, in the R61
Phase of this application, we will: 1) Determine the dose-dependent PK/PD relationship of DMF in naïve male
and female Sprague-Dawley (SD) rats (R61 Aim 1A); 2) Demonstrate that sub-chronic (7-day) drug-in-food
delivery of an optimized dose of DMF using our innovative automated medication-in-food delivery system will
result in predictable and stable blood and brain levels and Nrf2 target engagement roughly equivalent to levels
observed in Aim 1A (R61 Aim 1B); 3) Determine whether adjunctive oral DMF treatment with the ASMs,
levetiracetam (LEV) or lamotrigine (LTG) will affect steady state blood levels when administered sub-chronically
using our innovative drug-in-food delivery system (R61 Aim 1C). In Aim 1 of the R33 Phase of this application,
we will define the potential of short-term systemic administration of DMF to prevent or mitigate the anxiety,
cognitive decline, long-term seizure burden and ASM pharmacoresistance associated with kainic acid-induced
SE in male and female SD rats. In R33 Aim 2, we will determine whether late intervention with orally administered
DMF in rats with established DRE will improve pharmacosensitivity to the ASMs, LEV and LTG. At the
completion of these studies, we will have defined the early and late treatment disease modifying potential of the
novel first-in-class Nrf2 activator, DMF, using a clinically relevant approach in an etiologically relevant model of
acquired DRE. The development of a safe and novel first-in-class disease-modifying treatment for patients at-
risk for epilepsy would reduce the burden of disease and lead to significant improvements in their quality of life,
cognitive function and reduce the incidence of pharmacoresistant epilepsy.

## Key facts

- **NIH application ID:** 10785216
- **Project number:** 1R61NS130134-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Tawfeeq  Shekh-Ahmad
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $285,181
- **Award type:** 1
- **Project period:** 2024-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10785216

## Citation

> US National Institutes of Health, RePORTER application 10785216, Evaluating the disease modifying properties of dimethyl fumarate (DMF) for the prevention and treatment of pharmacoresistant epilepsy (1R61NS130134-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10785216. Licensed CC0.

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