Abstracts

Rationale: After traumatic brain injury (TBI) or other head trauma, the risk of developing epilepsy is significantly increased. Epilepsy risk is increased: 10-fold with a skull fracture; 5-fold with a severe TBI; 3-fold with a mild TBI; and 38-fold within the first year of TBI. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to have significant antioxidant and neuroprotective effects in both epilepsy and traumatic brain injury. Artificially raising the level of Nrf2 in the brain has proven effective at reducing secondary injury from TBI as well as reducing seizure incidence in animal disease models. Karyopharm Therapeutics has developed KPT-350, a member of the novel class of Selective Inhibitors of Nuclear Export (SINE) compounds, which are slowly reversible small molecule inhibitors of exportin 1 (XPO1). One of the >200 known cargoes of XPO1 is Nrf2, and inhibiting the nuclear export of Nrf2 has been shown to increase the Nrf2-mediated oxidative stress response in vitro, suggesting a potential therapeutic approach for TBI and epilepsy. Methods: To assess whether inhibiting the nuclear export of Nrf2 with KPT-350 could be a potential therapeutic mechanism for treating post-traumatic epilepsy, KPT-350 was administered to a mouse model of TBI and a mouse model of epilepsy. Male C57B mice received a moderate-severe controlled cortical impact (CCI) injury and were dosed PO with 10 mg/kg KPT-350 or vehicle, 3x/week for 3 weeks. KPT-350 was also tested in the mouse pilocarpine model of epilepsy with spontaneous recurrent seizures (SRS). After 2-week baseline SRS monitoring, the epileptic mice were dosed with vehicle or 0.3, 3 or 7.5 mg/kg KPT-350 PO QoD for 2 weeks. Results: After the dosing period in the CCI model, traces from KPT-350-treated brain slices showed a decrease in field excitatory postsynaptic potential (fEPSP) duration and high frequency activity compared to vehicle treatment. Additionally, KPT-350 reduced measures of the percent epileptiform activity per slice, fEPSP area and coastline values. These results suggest reduced epileptic activity following a TBI. In the pilocarpine model, dosing with 3 or 7.5 mg/kg KPT-350 significantly reduced SRS incidence during the treatment period (p < 0.001). A significant proportion of mice treated with 3 or 7.5 mg/kg KPT-350 responded with a 50% decrease in SRS count when compared to the vehicle-treated group (p < 0.001), and 6 out of 24 mice treated with 7.5 mg/kg became seizure free. Furthermore, mice treated with 3 mg/kg showed a sustained reduction in SRS during the 2-week drug washout period; effects at 7.5 mg/kg were not assessed in the washout phase. This suggests that KPT-350 has significant anti-seizure activity. Conclusions: In addition to KPT-350’s anti-epileptic activity, the compound has been shown in various animal models to significantly reduce the secondary injury following a TBI. Together these data suggest that KPT-350 has significant potential as a single agent TBI and epilepsy therapeutic to reduce seizure frequency and number by upregulating the Nrf2 and other anti-inflammatory pathways in both generalized and post-traumatic settings. Funding: No external sources of funding.