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Updated: Mar 26, 2026
Controlled Cortical Impact Model for Traumatic Brain Injury
Published on: August 5, 2014
A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus
Naoki Tajiri1, Ike De La Peña1, Sandra A Acosta1
1Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
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-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.
Insights
Selective inhibitors of nuclear export (SINE) compounds like KPT-350 show promise for treating traumatic brain injury (TBI). These SINE compounds protect neurons from TBI-induced neuroinflammation and cell death, improving behavioral and histological outcomes in TBI models.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Exportin 1 (XPO1/CRM1) regulates nuclear protein export, and its inhibition via Selective Nuclear Export Inhibitors (SINE) shows anti-cancer effects.
- Traumatic brain injury (TBI) involves secondary cell death driven by neuroinflammation, potentially modulated by nuclear receptors.
Purpose of the Study:
- To investigate the efficacy of SINE compounds (KPT-350, KPT-335) in mitigating TBI-induced neuroinflammation and neurotoxicity.
- To evaluate the therapeutic potential of SINE compounds in both in vitro neuronal cultures and an in vivo TBI model.
Main Methods:
- In vitro: Cultured primary rat cortical neurons were treated with SINE compounds and exposed to TNF-α to assess neuroprotection.
- In vivo: A controlled cortical impact (CCI) model of TBI was used in Sprague-Dawley rats, with KPT-350 administered orally post-injury.
- Assessments included cell viability, enzymatic activity, behavioral tests (rotorod, motor asymmetry), and histological analysis of brain tissue.
Main Results:
- SINE compounds sequestered TBI-related proteins (NF-κB, AKT, FOXP1) in neuronal nuclei, significantly improving cell viability and enzymatic activity against TNF-α induced toxicity.
- In vivo, KPT-350 treatment reduced TBI-induced behavioral deficits (motor coordination, balance) by 100-200% and histological damage (cortical impact area, cell death).
- These improvements were observed as early as 4 hours post-injection and were sustained throughout the 18-day study period.
Conclusions:
- KPT-350 modulates nuclear expression of XPO1, AKT, FOXP1, and NF-κB in neurons, demonstrating a neuroprotective mechanism.
- SINE compounds effectively inhibit the nuclear trafficking of cell death proteins, presenting a promising therapeutic strategy for TBI.
