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