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

摘要

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 ‐ kB , 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 Conclusions Both in vitro and in vivo experiments revealed that KPT ‐350 increased XPO 1, AKT , and FOXP 1 nuclear expression and relegated NF ‐ kB 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.