title: A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus.
abstract: BACKGROUND
  Exportin 1 (XPO1/CRM1) 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 XPO1, 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.
  
  
  RESULTS
  Here, we report that the SINE compounds (KPT-350 or KPT-335) sequestered TBI-induced neuroinflammation-related proteins (NF-(k)B, AKT, FOXP1) 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 XPO1, AKT, and FOXP1 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.
authors: Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
authors: Naoki
authors: N
authors: Tajiri
authors: Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
authors: Ike
authors: I
authors: De La Peña
authors: Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
authors: Sandra A
authors: SA
authors: Acosta
authors: Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
authors: Yuji
authors: Y
authors: Kaneko
authors: Karyopharm Therapeutics Inc, Newton, MA, USA.
authors: Sharon
authors: S
authors: Tamir
authors: Karyopharm Therapeutics Inc, Newton, MA, USA.
authors: Yosef
authors: Y
authors: Landesman
authors: Karyopharm Therapeutics Inc, Newton, MA, USA.
authors: Robert
authors: R
authors: Carlson
authors: Karyopharm Therapeutics Inc, Newton, MA, USA.
authors: Sharon
authors: S
authors: Shacham
authors: Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
authors: Cesar V
authors: CV
authors: Borlongan
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014230:Triazoles
chemical_list: D000178:Acrylamides; D051858:Forkhead Transcription Factors; D006834:Hydrazines; D016328:NF-kappa B; D018696:Neuroprotective Agents; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; C561586:FoxP1 protein, rat; C000593855:verdinexor; D014230:Triazoles
keywords: Cell death protein trafficking; Neuroinflammation; Nuclear export inhibitor; Secondary cell death