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Summary   Background  Exportin 1 ( XPO 1/ CRM 1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export ( SINE ) are small orally bioavailable molecules that serve as drug‐like inhibitors of  XPO 1, with potent anti‐cancer properties. Traumatic brain injury ( TBI ) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors.    Aims and Results  Here, we report that the  SINE  compounds ( KPT ‐350 or  KPT ‐335) sequestered  TBI ‐induced neuroinflammation‐related proteins ( NF ‐  k B ,  AKT ,  FOXP 1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against  TNF ‐ α  (20 ng/mL)‐induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non‐treated neuronal cells ( P 's < 0.05). In parallel, using an  in vivo  controlled cortical impact ( CCI ) model of  TBI , we demonstrate that adult Sprague‐Dawley rats treated post‐injury with  SINE  compounds exhibited significant reductions in  TBI ‐induced behavioral and histological deficits. Animals that received  KPT ‐350 orally starting at 2 h post‐ TBI  and once a day thereafter over the next 4 days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100–200% improvements, as early as 4 h after initial  SINE  compound injection that was sustained during subsequent  KPT ‐350 dosing, and throughout the 18‐day post‐ TBI  study period compared to vehicle treatment ( P 's < 0.05). Moreover,  KPT ‐350 reduced cortical core impact area and peri‐impact cell death compared to vehicle treatment ( P 's < 0.05).    Conclusions  Both  in vitro  and  in vivo  experiments revealed that  KPT ‐350 increased  XPO 1,  AKT , and  FOXP 1 nuclear expression and relegated  NF ‐  k B  expression within the neuronal nuclei. Altogether, these findings advance the utility of  SINE  compounds to stop trafficking of cell death proteins within the nucleus as an efficacious treatment for TBI.

A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus