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Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics

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Abstract

Traumatic brain injury (TBI) is one of the leading causes of death of young people in the developed world. In the United States alone, 1.7 million traumatic events occur annually accounting for 50,000 deaths. The etiology of TBI includes traffic accidents, falls, gunshot wounds, sports, and combat-related events. TBI severity ranges from mild to severe. TBI can induce subtle changes in molecular signaling, alterations in cellular structure and function, and/or primary tissue injury, such as contusion, hemorrhage, and diffuse axonal injury. TBI results in blood–brain barrier (BBB) damage and leakage, which allows for increased extravasation of immune cells (i.e., increased neuroinflammation). BBB dysfunction and impaired homeostasis contribute to secondary injury that occurs from hours to days to months after the initial trauma. This delayed nature of the secondary injury suggests a potential therapeutic window. The focus of this article is on the (1) pathophysiology of TBI and (2) potential therapies that include biologics (stem cells, gene therapy, peptides), pharmacological (anti-inflammatory, antiepileptic, progrowth), and noninvasive (exercise, transcranial magnetic stimulation). In final, the review briefly discusses membrane/lipid rafts (MLR) and the MLR-associated protein caveolin (Cav). Interventions that increase Cav-1, MLR formation, and MLR recruitment of growth-promoting signaling components may augment the efficacy of pharmacologic agents or already existing endogenous neurotransmitters and neurotrophins that converge upon progrowth signaling cascades resulting in improved neuronal function after injury.

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Abbreviations

AAV:

Adeno-associated virus

AC:

Adenylyl cyclase

AD:

Alzheimer’s disease

BBB:

Blood–brain barrier

BDNF:

Brain-derived neurotrophic factor

cAMP:

Cyclic adenosine monophosphate

CBF:

Cerebral blood flow

CCI:

Controlled cortical impact

CDK:

Cyclic-dependent kinase

CHI:

Closed head injury

CNS:

Central nervous system

CREB:

cAMP response element-binding protein

DAI:

Diffuse axonal injury

DMN:

Default mode network

EPO:

Erythropoietin

ERK:

Extracellular response kinase

FGF:

Fibroblast growth factor

FPI:

Fluid percussion injury

HSP:

Heat shock protein

ICP:

Increased intracranial pressure

MLR:

Membrane/lipid rafts

MMP:

Matrix metalloproteinases

NMDA:

N-Methyl-d-aspartate

PCC:

Posterior cingulate cortex

PD:

Parkinson’s disease

PDE:

Phosphodiesterase

PKA:

Protein kinase A

PPAR:

Peroxisome proliferator-activated receptor

ROCK:

Rho kinase

ROS:

Reactive oxygen species

SDRI:

Serotonin-dopamine reuptake inhibitor

SCI:

Spinal cord injury

SN:

Salience network

SOD:

Superoxide dismutase

SSRI:

Selective serotonin reuptake inhibitor

TMS:

Transcranial magnetic stimulation

TrkB:

Tyrosine receptor kinase B

VEGF:

Vascular endothelial growth factor

VMPFC:

Ventromedial prefrontal cortex

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    Authors and Affiliations

    1. Department of Anesthesiology, Veterans Affairs San Diego Healthcare System, VA Medical Center 125, University of California, 3350 La Jolla Village Drive, San Diego, CA, 92161-5085, USA

      Matthew L. Pearn, Junji Egawa, Atsushi Sawada & Brian P. Head

    2. Department of Anesthesiology, School of Medicine, University of California, La Jolla, San Diego, CA, 92093, USA

      Matthew L. Pearn, Junji Egawa, Atsushi Sawada & Brian P. Head

    3. Department of Cellular and Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA

      Ingrid R. Niesman & Angels Almenar-Queralt

    4. Sanford Consortium for Regenerative Medicine, La Jolla, San Diego, CA, 92037, USA

      Ingrid R. Niesman & Angels Almenar-Queralt

    5. UCSD Departments of Orthopaedic Surgery and Bioengineering, University of California, La Jolla, San Diego, CA, 92093, USA

      Sameer B. Shah

    6. Department of Neurology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA

      Josh L. Duckworth

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    M. L. Pearn and B. P. Head contributed to the drafting of the text. All authors contributed to the editing of the text.

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    Pearn, M.L., Niesman, I.R., Egawa, J. et al. Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics. Cell Mol Neurobiol 37, 571–585 (2017). https://doi.org/10.1007/s10571-016-0400-1

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