The large heterogeneity of epileptic syndromes and their underlying pathophysiology represent a particular challenge to the development of pathway-specific therapies for epilepsy prevention. In many people, epilepsy is produced by specific brain ?insults?, such as trauma, infarcts, or episodes of prolonged status epilepticus (SE), while in others, epilepsy is a result of a primary genetic abnormality producing either structural or functional alterations in the developing brain. In all cases, patients are at high risk for developing epilepsy. Studies in the last decade have contributed to the view that there is an important link between oxidative stress, inflammation and epilepsy, such that seizures can induce oxidative stress and inflammation, but also that oxidative stress and enhanced pro-inflammatory signals in the brain contribute to epilepsy progression. Recent animal and human studies have identified a potential novel target that may be a central component of a cascade of such processes - the nuclear factor erythroid 2-related factor 2 (Nrf2). This transcription factor promotes the expression of multiple protective antioxidant and anti-inflammatory proteins. The major objective of this project is to determine whether dimethyl fumarate (DMF), a Nrf2 inducer that uniquely reduces oxidative stress and inflammation and is approved for other clinical indications, can prevent epilepsy in two distinct mouse models of epileptogenesis. To increase the translational potential of our study, we will also determine whether select systemic biomarkers of oxidative stress and inflammation are able to predict the development of epilepsy and epilepsy-associated co-morbidities (prognostic biomarkers) and monitor the acute response to treatment (pharmacodynamic biomarkers).
Aim 1 will use long-term video EEG recordings of seizures and behavioral testing to determine whether DMF, when administered following induction of SE, will reduce the incidence and severity of epilepsy and reduce the associated behavioral comorbidities. Using immunohistochemical and biochemical methods, Aim 2 will assess changes in proteins associated with redox modulation, inflammation and cytokine signaling in the brain and plasma following DMF treatment in the same model, with the hypothesis that mediators that most strongly associate with disease progression will be more affected by treatment than the ones that are not. Finally, to examine whether there is more generalizable applicability of this drug to other epilepsies, in Aim 3 we will determine whether DMF can prevent or delay the development of epilepsy in a tuberous sclerosis model of epilepsy and cognitive dysfunction.
The proposed research will provide novel insight into regulation of endogenous anti-oxidant systems and pro- inflammatory pathways in epilepsy and proposes innovative treatments directed to prevent or restrain the development of chronic epilepsy using two established mouse models of epileptogenesis. The project will also test the utility of systemic oxidative stress and inflammation biomarkers to monitor the epileptogenesis process and to demonstrate target engagement, which along with epileptic electrophysiological features detected by non-invasive EEG and behavioral testing, could provide useful biomarkers for following the therapeutic effects in humans.
