Diffuse Axonal Injury and Oxidative Stress: A Comprehensive Review

Abstract

Traumatic brain injury (TBI) is one of the world's leading causes of morbidity and mortality among young individuals. TBI applies powerful rotational and translational forces to the brain parenchyma, which results in a traumatic diffuse axonal injury (DAI) responsible for brain swelling and neuronal death. Following TBI, axonal degeneration has been identified as a progressive process that starts with disrupted axonal transport causing axonal swelling, followed by secondary axonal disconnection and Wallerian degeneration. These modifications in the axonal cytoskeleton interrupt the axoplasmic transport mechanisms, causing the gradual gathering of transport products so as to generate axonal swellings and modifications in neuronal homeostasis. Oxidative stress with consequent impairment of endogenous antioxidant defense mechanisms plays a significant role in the secondary events leading to neuronal death. Studies support the role of an altered axonal calcium homeostasis as a mechanism in the secondary damage of axon, and suggest that calcium channel blocker can alleviate the secondary damage, as well as other mechanisms implied in the secondary injury, and could be targeted as a candidate for therapeutic approaches. Reactive oxygen species (ROS)-mediated axonal degeneration is mainly caused by extracellular Ca²⁺. Increases in the defense mechanisms through the use of exogenous antioxidants may be neuroprotective, particularly if they are given within the neuroprotective time window. A promising potential therapeutic target for DAI is to directly address mitochondria-related injury or to modulate energetic axonal energy failure.

Keywords: biomarkers; immunohistochemistry; oxidative stress; reactive oxygen species; traumatic brain injury.

Figure 1

Hypothetical inter-relationship between (traumatic brain injury) TBI-induced oxidative damage and neurodegeneration. Secondary injury cascade in TBI induces oxidative stress related to increase of free radicals reactive oxygen species/reactive nitrogen species (ROS/RNS) and increase calcium entry both from intracellular stores and injury-induced increases in glutamate (excitotoxicity). Oxidative stress induces cell membrane lipoperoxidation and calcium release, which activates calpain. ROS and RNS induced oxidative damage in neuronal mitochondria and compromise Ca²⁺ homeostasis. Activated calpain mediates further Ca²⁺ entry, forming a positive feedback loop and induces mitochondrial membrane permeability and releases the apoptosis inducing factor (AIF) from mitochondria. Caspase-3 is also activated by Calpain-1. The released AIF and activated caspase-3 together induce neurodegeneration. Activated calpain proteolyzes large groups of cellular proteins varying from structural proteins and soluble proteins (e.g., apoptotic proteins). Changing either or both the structure or activity of the protein substrates can have important effects such as axonal deterioration and neuronal death.

Figure 2

(A) Scattered axonal retraction balls stained with Congo Red (arrows), scale bar: ×250; (B) diffuse β-APP positivity expression in the corpus callosum is an indicator of axonal injury (grade II), scale bar: ×80; (C) β-APP (brown reactions) reaction exhibited a strong positive reaction typically occurring in the dorsolateral quadrant or quadrants adjacent to a superior cerebellar peduncle (grade III), scale bar: ×100; (D) morphological features of neuronal apoptosis (green) associated with marked condensation of chromatin and its fragmentation into discrete bodies (arrows), scale bar: ×250.

Figure 3

CT at 6 h after the trauma: (A) Absence of the basal cisterns (arrow); and (B) massive brain edema and intraventricular hemorrhage (arrow); MRI scan of the same patient 5 days after the trauma: (C) DWI sequence disclosing the axonal injury of the corpus callosum (arrow); and (D) injury of the dorsal aspect of the pons (arrow) (FLAIR).