Open AccessA Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus
Author(s) -
Tajiri Naoki,
De La Peña Ike,
Acosta Sandra A.,
Kaneko Yuji,
Tamir Sharon,
Landesman Yosef,
Carlson Robert,
Shacham Sharon,
Borlongan Cesar V.
Publication year - 2016
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12501
Subject(s) - traumatic brain injury , nucleus , neuroscience , medicine , psychology , psychiatry
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.