Dobson, Geoffrey P., Morris, Jodie L., and Letson, Hayley L. (2024) Traumatic brain injury: Symptoms to systems in the 21st century. Brain Research, 1845. 149271.

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Abstract

Severe traumatic brain injury (TBI) is a devastating injury with a mortality of ∼ 25–30 %. Despite decades of high-quality research, no drug therapy has reduced mortality. Why is this so? We argue two contributing factors for the lack of effective drug therapies include the use of specific-pathogen free (SPF) animals for translational research and the flawed practice of single-nodal targeting for drug design. A revolution is required to better understand how the whole body responds to TBI, identify new markers of its progression, and discover new system-acting drugs to treat it. In this review, we present a brief history of TBI, discuss its system’s pathophysiology and propose a new research strategy for the 21st century. TBI progression develops from injury signals radiating from the primary impact, which can cause local ischemia, hemorrhage, excitotoxicity, cellular depolarization, immune dysfunction, sympathetic hyperactivity, blood-brain barrier breach, coagulopathy and whole-body dysfunction. Metabolic reprograming of immune cells drives neuroinflammation and secondary injury processes. We propose if sympathetic hyperactivity and immune cell activation can be corrected early, cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored, and secondary injury minimized with improved patient outcomes. The therapeutic goal is to switch the injury phenotype to a healing phenotype by restoring homeostasis and maintaining sufficient tissue O2 delivery. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat TBI and have shown that it blunts the CNS-stress response, supports cardiovascular function and reduces secondary injury. Future research will investigate its suitability for human translation.

Item ID:	84868
Item Type:	Article (Research - C1)
ISSN:	1872-6240
Copyright Information:	© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Date Deposited:	12 Mar 2025 04:20
FoR Codes:	32 BIOMEDICAL AND CLINICAL SCIENCES > 3209 Neurosciences > 320903 Central nervous system @ 100%
SEO Codes:	28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 100%
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