Using the Selective Inhibitor of Nuclear Export (SINE) Compound KPT-350 to Reduce Cortical Circuit Hyperexcitability and Interneuron Cell Loss in the Controlled Cortical Impact (CCI) Model of Traumatic Brain Injury (TBI) (P5.243)

Objective: This study evaluated the effects of the SINE compound KPT-350 on cortical network dysfunction in a murine model of TBI. Background: CCI injury has been shown to cause increased cortical excitability and loss of cortical interneurons. Previous studies have demonstrated that KPT-350 has neuroprotective capabilities, including preserving gross morphology and improving behavioral endpoints following CCI. Based on these findings, we hypothesized that treatment with KPT-350 would reduce CCI-induced hyperexcitability. Design/Methods: The neuroprotective and anti-epileptogenic effects of the SINE compound KPT-350 were investigated in a CCI model of TBI. A total of 24 CCI mice received either 10 mg/kg KPT-350 or vehicle 3 times daily for 3 weeks, starting 1 hour post-injury. Body weights were recorded before surgery and periodically over the course of treatment. Following the treatment period, the 12 vehicle- and 12 KPT-treated mice were sacrificed and brains were collected. Electrophysiological differences in network function were identified by measuring epileptiform activity, fEPSP area, coastline, input/output responses, and stimulus intensity in 6 KPT-treated and 6 vehicle-treated mice. Tissue samples from the 12 remaining animals were stained for markers of neuroinflammation and cell counts for inhibitory interneurons were performed. Results: Treatment with KPT-350 protected mice from the damaging electrophysiological changes associated with CCI injury. Field potentials from CCI-injured, vehicle-treated mice showed high epileptiform activity, while traces from KPT-350-treated brain slices were free of these signatures. Coastline values and input-output response relationships - measures known to correlate with network dysfunction - also normalized after treatment. KPT-350 increased the incidence of parvalbumin-positive interneurons, yet the levels of expression of somatostatin, a related interneuron marker, remained unchanged. Conclusions: Our findings demonstrate that treatment with KPT-350 has significant protective effects on cortical circuit function and survival of inhibitory interneurons, suggesting a potential anti-epileptogenic effect of KPT-350 treatment following TBI. Study Supported By: Karyopharm Therapeutics Disclosure: Dr. Cantu has nothing to disclose. Dr. Croker has nothing to disclose. Dr. Tamir has received personal compensation for activities with Karyopharm Therapeutics Inc. as an employee. Dr. Shacham has received personal compensation for activities with Karyopharm Therapeutics Inc. Dr. Dulla has nothing to disclose.