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

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.

Keywords: Biologics; Blood–brain barrier; Caveolin; Membrane/lipid rafts; Neuroinflammation; Traumatic brain injury.

Fig. 1

Proposed mechanisms of SynCav1-mediated neuronal growth and plasticity. a Schematic depicting axonal shaft, F-actin arc and growth cone containing membrane/lipid rafts (MLR), caveolin-1 (Cav-1) and MLR-localized functional TrkB and GPCR-AC8, and Cav-1 modulation of RhoA-ROCK signaling in MLR at the leading edge. Traumatic brain injury (TBI) causes a decrease in Cav-1 and MLR, loss of MLR-localized receptor expression and functional signaling, uncontrolled RhoA/ROCK activity leading to actin destabilization. b Closer view of MLR from a. Neuron-targeted Cav-1 over-expression (SynCav1) increases MLR formation and MLR-localization of functional (1) TrkB and (2) AC8, and (3) modulation of RhoA activity. Genetic interventions that promoter MLR formation may enhance the capacity for neurons to respond to pharmacologic agents that stimulate TrkB, activate AC8, or inhibit RhoA, resulting in structural and functional neuroplasticity and improvements in motor performance and cognitive behavior after TBI