| Autor: |
Omelchenko A; Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854-8082, USA.; Neuroscience Graduate Program, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854-8082, USA., Shrirao AB; Department of Biomedical Engineering, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854-8082, USA., Bhattiprolu AK; Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854-8082, USA., Zahn JD; Department of Biomedical Engineering, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854-8082, USA., Schloss RS; Department of Biomedical Engineering, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854-8082, USA., Dickson S; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104-6391, USA., Meaney DF; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104-6391, USA., Boustany NN; Department of Biomedical Engineering, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854-8082, USA., Yarmush ML; Department of Biomedical Engineering, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854-8082, USA., Firestein BL; Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854-8082, USA. firestein@biology.rutgers.edu. |
| Abstrakt: |
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 H 2 O 2 -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. |
