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

作者：Tajiri Naoki; De La Pena Ike; Acosta Sandra A; Kaneko Yuji; Tamir Sharon; Landesman Yosef; Carlson Robert; Shacham Sharon; Borlongan Cesar V^*

来源：CNS Neuroscience & Therapeutics, 2016, 22(4): 306-315.

DOI：10.1111/cns.12501

• Cell death protein trafficking
• Neuroinflammation
• Nuclear export inhibitor
• Secondary cell death

BackgroundExportin 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 ResultsHere, we report that the SINE compounds (KPT-350 or KPT-335) sequestered TBI-induced neuroinflammation-related proteins (NF-B-k, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF- (20ng/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 invivo 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 2h post-TBI and once a day thereafter over the next 4days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100-200% improvements, as early as 4h 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).
ConclusionsBoth invitro and invivo experiments revealed that KPT-350 increased XPO1, AKT, and FOXP1 nuclear expression and relegated NF-B-k 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.

• 出版日期2016-4