Authors :
Presenting Author: Tawfeeq Shekh-Ahmad, PhD – The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem; Jerusalem, Israel
Sereen Sandouka, MSc – The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem; Jerusalem, Israel.; Aseel Saadi, MSc – The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem; Jerusalem, Israel.; Rhoda Olowe Taiwo, MSc – The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem; Jerusalem, Israel.; Prince Kumar Singh, MSc – The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem; Jerusalem, Israel.; Yara Sheeni, Ms – The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem; Jerusalem, Israel.; Taige Zhang, Mr – The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem; Jerusalem, Israel.; Larin Deeb, Ms – The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem; Jerusalem, Israel.; Michelle Guignet, PhD – University of Washington, Department of Pharmacy, Seattle, WA, USA; Steve H White, PhD – University of Washington, Department of Pharmacy, Seattle, WA, USA
Rationale:
Epilepsy is a prevalent neurological condition with significant physical, psychological, social, and economic burdens. Despite the use of anti-seizure medications, a substantial number of patients remain resistant to treatment, leading to recurrent unprovoked seizures. Accumulating evidence suggests that oxidative stress plays a role in the development of epilepsy following brain insults. Activation of the Nrf2 pathway, known for its role in cellular defense against oxidative stress, presents a potential approach to treating epilepsy and reducing oxidative damage. Dimethyl fumarate (DMF), a compound with antioxidant and anti-inflammatory properties, has shown promise in preclinical studies and is currently used in multiple sclerosis treatment.
Methods:
We used a rat model of temporal lobe epilepsy to investigate the potential antiepileptogenic and disease-modifying effects of DMF. The rats were administered DMF for seven days following status epilepticus (SE). Various assessments were conducted to evaluate the effects of DMF, including measurements of Nrf2 activity, neuronal cell death, seizure frequency, the total number of seizures, and behavioral deficits in the open field and elevated plus maze. We also examined the long-term effects of DMF treatment initiated after epilepsy diagnosis.
Results:
The results of the study showed that DMF administration following SE led to increased Nrf2 activity, reduced SE-induced neuronal cell death, decreased seizure frequency (per week), and the total number of seizures compared to the control group treated with a vehicle. Furthermore, DMF treatment reversed SE-induced behavioral deficits observed in the open field and elevated plus maze tests. Notably, the study also revealed that DMF treatment, even when initiated after epilepsy diagnosis, could effectively reduce symptomatic seizures long after the drug had been eliminated from the body.
Conclusions:
Our results showed that activating the Nrf2 pathway through DMF represents a potential therapeutic target for modifying the course of epilepsy in preclinical models. The study demonstrated the antiepileptogenic and disease-modifying effects of DMF, including its ability to reduce seizure frequency, neuronal cell death, and behavioral deficits associated with epilepsy. The results suggest that DMF treatment could have beneficial effects even when administered after epilepsy diagnosis, highlighting its potential as a disease-modifying intervention in epilepsy management.
Funding:
This research was supported by: The Israel Science Foundation (grant no. 1976/20 to TSA) and The Ministry of Science and Technology, Israel (grant no. 5100 to TSA).