Combination of NRF2 Activation and NADPH Oxidase Inhibition Prevents Epileptogenesis and Modifies Chronic Epilepsy
Abstract number :
1.008
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2021
Submission ID :
1826367
Source :
www.aesnet.org
Presentation date :
12/9/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:53 AM
Authors :
Tawfeeq Shekh-Ahmad, PhD - Hebrew University of Jerusalem;
Rationale: Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neuronal death and the development of epilepsy. Here, we propose a combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through Nrf2 activation for preventing the development of seizures following SE and also for modifying the severity of epilepsy.
Methods: We studied the neuroprotective effect of the antioxidant therapies on cortical neuronal cultures in in vitro low Mg2+ model using live cell imaging. For the in vivo studies, we used the KA-induced SE model in rats and monitored the development of seizures using video-ECoG recordings for up to 18 weeks post SE.
Results: The combination of NADPH oxidase activation (by AEBSF) and Nrf2 activation (by RTA 408) had a greater effect (versus each treatment alone) on reducing ROS generation and neuronal cell death in vitro; and also, on increasing the TAC levels in plasma and hippocampus following KA-induced SE.
Further, the combination therapy prevented the development of spontaneous seizures in 40% of animals following 2 hr of KA-SE (70% of animals were seizure free after 8 weeks), and significantly decreased the seizure frequency when given to chronic epileptic animals.
Conclusions: Combined therapy inhibiting ROS generation via NOX and increasing antioxidant defenses via Nrf2 activation prevents seizure induced mitochondrial depolarization, ROS generation and neuronal cell death in vitro and was more effective than either intervention alone. Further, the combination therapy was more effective than either intervention alone for increasing antioxidant capacity following KA-induced SE in vivo, and for preventing the development of epilepsy and also modifying chronic epilepsy.
Funding: Please list any funding that was received in support of this abstract.: Israel Science Foundation (ISF).
Basic Mechanisms