Back to Search Start Over

Dynamin and reverse-mode sodium calcium exchanger blockade confers neuroprotection from diffuse axonal injury

Dynamin and reverse-mode sodium calcium exchanger blockade confers neuroprotection from diffuse axonal injury

Authors :
Atul K. Bhattiprolu
Rene S. Schloss
Anil B. Shrirao
Samantha Dickson
Jeffrey D. Zahn
Nada N. Boustany
David F. Meaney
Bonnie L. Firestein
Martin L. Yarmush
Anton Omelchenko
Source :
Cell Death & Disease, Cell Death and Disease, Vol 10, Iss 10, Pp 1-18 (2019)
Publication Year :
2019
Publisher :
Nature Publishing Group UK, 2019.

Abstract

Mild traumatic brain injury (mTBI) is a frequently overlooked public health concern that is difficult to diagnose and treat. Diffuse axonal injury (DAI) is a common mTBI neuropathology in which axonal shearing and stretching induces breakdown of the cytoskeleton, impaired axonal trafficking, axonal degeneration, and cognitive dysfunction. DAI is becoming recognized as a principal neuropathology of mTBI with supporting evidence from animal model, human pathology, and neuroimaging studies. As mitochondrial dysfunction and calcium overload are critical steps in secondary brain and axonal injury, we investigated changes in protein expression of potential targets following mTBI using an in vivo controlled cortical impact model. We show upregulated expression of sodium calcium exchanger1 (NCX1) in the hippocampus and cortex at distinct time points post-mTBI. Expression of dynamin-related protein1 (Drp1), a GTPase responsible for regulation of mitochondrial fission, also changes differently post-injury in the hippocampus and cortex. Using an in vitro model of DAI previously reported by our group, we tested whether pharmacological inhibition of NCX1 by SN-6 and of dynamin1, dynamin2, and Drp1 by dynasore mitigates secondary damage. Dynasore and SN-6 attenuate stretch injury-induced swelling of axonal varicosities and mitochondrial fragmentation. In addition, we show that dynasore, but not SN-6, protects against H2O2-induced damage in an organotypic oxidative stress model. As there is currently no standard treatment to mitigate cell damage induced by mTBI and DAI, this work highlights two potential therapeutic targets for treatment of DAI in multiple models of mTBI and DAI.

Details

Language :
English
ISSN :
20414889
Volume :
10
Issue :
10
Database :
OpenAIRE
Journal :
Cell Death & Disease
Accession number :
edsair.doi.dedup.....40fe96316ae6945c96e3472a9725b46c