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

• Published in: CNS neuroscience & therapeutics 2016-04, Vol.22 (4), p.306-315
• Main Authors: Tajiri, Naoki, De La Peña, Ike, Acosta, Sandra A., Kaneko, Yuji, Tamir, Sharon, Landesman, Yosef, Carlson, Robert, Shacham, Sharon, Borlongan, Cesar V.
• Format: Article
• Language: English
• Subjects: Acrylamides - pharmacology; Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - physiology; Animals; Brain - drug effects; Brain - pathology; Brain - physiopathology; Brain Injuries, Traumatic - drug therapy; Brain Injuries, Traumatic - pathology; Brain Injuries, Traumatic - physiopathology; Cell Death - drug effects; Cell Death - physiology; Cell death protein trafficking; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Nucleus - pathology; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Disease Models, Animal; Forkhead Transcription Factors - metabolism; Hydrazines - pharmacology; Male; Motor Activity - drug effects; Motor Activity - physiology; Neuroimmunomodulation - drug effects; Neuroimmunomodulation - physiology; Neuroinflammation; Neuroprotective Agents - pharmacology; NF-kappa B - metabolism; Nuclear export inhibitor; Original; Proto-Oncogene Proteins c-akt - metabolism; Rats, Sprague-Dawley; Recovery of Function - drug effects; Recovery of Function - physiology; Repressor Proteins - metabolism; Secondary cell death; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12501

Summary 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‐kB, 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