RGD Reference Report - A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus. - Rat Genome Database

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

Authors: Tajiri, N  De La Pena, I  Acosta, SA  Kaneko, Y  Tamir, S  Landesman, Y  Carlson, R  Shacham, S  Borlongan, CV 
Citation: Tajiri N, etal., CNS Neurosci Ther. 2016 Apr;22(4):306-15. doi: 10.1111/cns.12501. Epub 2016 Feb 4.
RGD ID: 11561903
Pubmed: PMID:26842647   (View Abstract at PubMed)
PMCID: PMC5067638   (View Article at PubMed Central)
DOI: DOI:10.1111/cns.12501   (Journal Full-text)

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. 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, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF-alpha (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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Brain Injuries treatmentISOFoxp1 (Rattus norvegicus)11561903; 11561903 RGD 
Brain Injuries treatmentIDA 11561903 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to tumor necrosis factor  IEP 11561903 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Foxp1  (forkhead box P1)

Genes (Mus musculus)
Foxp1  (forkhead box P1)

Genes (Homo sapiens)
FOXP1  (forkhead box P1)


Additional Information