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 show that combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through nuclear factor erythroid 2-related factor 2 (Nrf2) activation prevents excessive ROS accumulation, mitochondrial depolarisation and neuronal death during in vitro seizure-like activity. Moreover, this combination therapy prevented the development of spontaneous seizures in 40% of animals following status epilepticus (70% of animals were seizure free after 8 weeks) and modified the severity of epilepsy when given to chronic epileptic animals.
Bibliographical noteFunding Information:
European Union’s Seventh Framework Programme ( FP7/2007–2013 ) under grant agreement n°602102 (EPITARGET) Matthew C Walker; Epilepsy Research UK (Project Grant P1301 ) Matthew C Walker; Innovative Medizinische Forschung (IMF grant KO111715 grant to Stjepana Kovac) and Ursula von Euch Stiftung (fellowship to Stjepana Kovac).
© 2019 The Authors
- Keap1-Nrf2 pathway
- NADPH oxidase
- Oxidative stress
- Spontaneous seizures