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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
- 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.
- Subjects :
- 0301 basic medicine
Dynamins
Cancer Research
Traumatic brain injury
Immunology
Cell death in the nervous system
Hippocampus
Apoptosis
Diffuse Axonal Injury
Neuropathology
Neuroprotection
Trauma
Article
Sodium-Calcium Exchanger
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Medicine
Animals
Humans
lcsh:QH573-671
Cell damage
Brain Concussion
Dynamin
business.industry
lcsh:Cytology
Assay systems
Diffuse axonal injury
Cell Biology
medicine.disease
3. Good health
Disease Models, Animal
030104 developmental biology
Drug screening
Mitochondrial fission
business
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 10
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....40fe96316ae6945c96e3472a9725b46c