Kevin H Black

 Introduction: Traumatic  brain injury (TBI) is defined as the  “alteration in brain function, or other evidence of brain pathology, caused by an external force”.¹  Traumatic brain injury is the leading cause of death and disability in American’s under 45 years of age and currently there is no cure available for the loss of function associated with it.²  Two broad modes of TBI has been studied:  penetrating (open) injury and concussion/blast (closed) injury.  These two injury modalities result in different types of responses from the brain tissue.^3. In the mouse model, neurogenesis in the subventricular zone occurs in the normal brain with migration of neural progenitor cells (NPCs) in the olfactory bulbs, but after injury migration is altered towards the site of cortical injury.^4,5 Although there is a fast neurogenic response, instead differentiating into neurons, these NPCs become glial cells due to the “hostile environment” produced by the injury.⁶  This environment is strongly influenced by the ADAM17/TGFα/EGFR signaling cascade, and inhibition of this process can alter the differentiation of these NPCs into neurons instead of glial cells.⁶  Increased neurogenesis after TBI can lead to increased cognitive recovery after the injury.⁷  Methods:  Penetrating brain injury was performed on mice. In one group, a dominant negative version of the ADAM17 metalloprotease was engineered through site directed mutagenesis creating a truncated version of the protein containing only the pro-domain.⁶  This truncated version was introduced into the adult mice through a virus vector.  In another group, local infusion of a metalloprotease inhibitor was introduced into the injury area of adult mice.  Results:  Over-expression of this truncated metalloprotease increased the generation of new neurons in the injured brain of the mice.⁶  The inhibition of ADAM17 resulted in increased presence of neuroblasts and NPCs in the injured area due to the ability of these cells to migrate into the injury site from the SVZ.⁶  Conclusions:  The results indicate that there is a potential for inhibition of ADAM17 in post-traumatic brain injury recovery as a target to improve cognitive recovery.⁶  Inhibition of the signaling cascade reduces glial scarring which allows migration of NPCs to the injured area, as well as reduces differentiation of the NPCs into glial cells instead of neuronal cells.⁶  These effects can potentially enhance the ability of the brain to generate new neurons and integrate them into the injured area to improve recovery outcomes.⁶

1. Reis, C., Wang, Y., Akyol, O., Ho, W., II, R., Stier, G., Martin, R. and Zhang, J. (2015). What’s New in Traumatic Brain Injury: Update on Tracking, Monitoring and Treatment. International Journal of Molecular Sciences, 16(12), pp.11903-11965.
2. Sun, D., Daniels, T., Rolfe, A., Waters, M. and Hamm, R. (2015). Inhibition of Injury-Induced Cell Proliferation in the Dentate Gyrus of the Hippocampus Impairs Spontaneous Cognitive Recovery after Traumatic Brain Injury. Journal of Neurotrauma, 32(7), pp.495-505.
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4. Alvarez-Buylla A, Garcı́a-Verdugo J. Neurogenesis in Adult Subventricular Zone. The Journal of Neuroscience. 2002;22(3):629-634. doi:10.1523/jneurosci.22-03-00629.2002
5. Saha B, Jaber M, Gaillard A. Potentials of endogenous neural stem cells in cortical repair. Front Cell Neurosci. 2012;6. doi:10.3389/fncel.2012.00014
6. Geribaldi-Doldán N, Carrasco M, Murillo-Carretero M et al. Specific inhibition of ADAM17/TACE promotes neurogenesis in the injured motor cortex. Cell Death Dis. 2018;9(9). doi:10.1038/s41419-018-0913-2
7. Villasana L, Kim K, Westbrook G, Schnell E. Functional Integration of Adult-Born Hippocampal Neurons after Traumatic Brain Injury. eNeuro. 2015;2(5). doi:10.1523/eneuro.0056-15.201