Cellular and Molecular Pathophysiology of Traumatic Brain Injury: What Have We Learned So Far?

Abstract

Traumatic brain injury (TBI) is one of the leading causes of long-lasting morbidity and mortality worldwide, being a devastating condition related to the impairment of the nervous system after an external traumatic event resulting in transitory or permanent functional disability, with a significant burden to the healthcare system. Harmful events underlying TBI can be classified into two sequential stages, primary and secondary, which are both associated with breakdown of the tissue homeostasis due to impairment of the blood-brain barrier, osmotic imbalance, inflammatory processes, oxidative stress, excitotoxicity, and apoptotic cell death, ultimately resulting in a loss of tissue functionality. The present study provides an updated review concerning the roles of brain edema, inflammation, excitotoxicity, and oxidative stress on brain changes resulting from a TBI. The proper characterization of the phenomena resulting from TBI can contribute to the improvement of care, rehabilitation and quality of life of the affected people.

Keywords: brain edema; excitotoxicity; inflammation; oxidative stress; traumatic brain injury.

Figure 1

Summary of the general events associated with inflammatory response following a TBI. Traumatic lesion results in blood–brain barrier (BBB) breakdown, causing influx of neutrophils into the nervous tissue. In a few minutes, both astrocytic reactivity and microglial activation induce the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukins (IL-1β, IL-6, IL-12), reactive oxygen species (ROS) and nitric oxide (NO), which further induce the release of these substances by the cells, establishing an inflammatory feedback loop, ultimately leading to tissue impairment and both necrotic and apoptotic death. Figure created in BioRender.com (accessed on 7 June 2023).

Figure 2

Summary of the general events associated with excitotoxicity following a TBI. Traumatic injury induces massive glutamate excitotoxicity that activates NMDA and AMPA receptors, inducing an excessive influx of Ca²⁺ that accumulates in the mitochondria, which responds by producing ROS. In addition, Ca²⁺ induces an impairment of ATP synthesis and release of cyto c into cytoplasm, activating the APAF1/caspase 9 complex, inducing caspase 3, which induce apoptosis by DNA fragmentation. Ca²⁺ also activates the nitric oxide synthase (NOS) enzyme, leading to NO synthesis, inducing the production of oxygen-derivate species that attack the cell membrane. Excessive Ca²⁺ overload activates calpains, and the intracellular increase in ROS production causes damage to DNA, lipids, and proteins, ultimately impairing cell function. Figure created in BioRender.com (accessed on 7 June 2023).

Figure 3

Summary of the general mechanism associated with oxidative stress following a TBI. Traumatic injury induces massive glutamate excitotoxicity that causes an excessive influx of Ca²⁺ that accumulates in the mitochondria, which responds by producing ROS. In parallel, a TBI causes an increased expression of NOX, which also produce ROS. The intracellular increase in ROS production causes damage to DNA, lipids, and proteins, ultimately impairing cell function. Figure created in BioRender.com (accessed on 7 June 2023).

Figure 4

Summary of signaling pathways following a TBI. Nuclear factor-kappa B (NF-κB) signaling pathway, mitogen-activated protein kinase (MAPK) pathway, PI3K/Akt/mTOR signaling pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Figure created in BioRender.com (accessed on 27 July 2023).