Secondary Mechanisms of Neurotrauma: A Closer Look at the Evidence

Abstract

Traumatic central nervous system injury is a leading cause of neurological injury worldwide. While initial neuroresuscitative efforts are focused on ameliorating the effects of primary injury through patient stabilization, secondary injury in neurotrauma is a potential cause of cell death, oxidative stress, and neuroinflammation. These secondary injuries lack defined therapy. The major causes of secondary injury in neurotrauma include endoplasmic reticular stress, mitochondrial dysfunction, and the buildup of reactive oxygen or nitrogenous species. Stress to the endoplasmic reticulum in neurotrauma results in the overactivation of the unfolded protein response with subsequent cell apoptosis. Mitochondrial dysfunction can lead to the release of caspases and the buildup of reactive oxygen species; several characteristics make the central nervous system particularly susceptible to oxidative damage. Together, endoplasmic reticulum, mitochondrial, and oxidative stress can have detrimental consequences, beginning moments and lasting days to months after the primary injury. Understanding these causative pathways has led to the proposal of various potential treatment options.

Neurotrauma—From Injury to Repair: Clinical Perspectives, Cellular Mechanisms and Promoting Regeneration of the Injured Brain and Spinal Cord

“…Triggered by a variety of stimuli in the post-injury tissue environment, the loss of CNS cells can persist in the chronic phase after injury due to apoptosis. Apoptosis, as a controlled process of programmed cell death, contrasts with the disordered events of necrosis, which are typical of immediate traumatic cell death in the acute phase [ 102 ]. Apoptosis may occur either as an intracellular (intrinsic) stress response, mediated by Bcl-2/Bax, or due to extracellular factors (extrinsic) in response to a variety of local cell signalling molecules [ 56 , 102 , 103 , 104 ].…”

“…Apoptosis, as a controlled process of programmed cell death, contrasts with the disordered events of necrosis, which are typical of immediate traumatic cell death in the acute phase [ 102 ]. Apoptosis may occur either as an intracellular (intrinsic) stress response, mediated by Bcl-2/Bax, or due to extracellular factors (extrinsic) in response to a variety of local cell signalling molecules [ 56 , 102 , 103 , 104 ]. Intrinsic pathways to apoptosis may be triggered via a variety of the mechanisms discussed, including mitochondrial dysfunction, oxidative stress, lipid peroxidation and excitotoxicity [ 91 ].…”

Nervous System Response to Neurotrauma: A Narrative Review of Cerebrovascular and Cellular Changes After Neurotrauma

“…Despite the extensive research and substantial improvement in the management of neurotrauma, secondary injuries in the form of chemical and molecular responses to primary injuries are considered inevitable (Aghili-Mehrizi et al 2022 ). Secondary injuries, persisting for days to months, can have more serious and life-long implications than the primary events (Centers for Disease Control and Prevention (CDC) 2013 ; Osier et al 2015 ).…”

“…This includes neuron, axon, glia, and blood vessel damage that initiates a dynamic series of complex alterations at the cellular, inflammatory, mitochondrial, neurochemical, and metabolic levels leading to secondary injuries (McKee and Daneshvar 2015 ). Secondary injuries cause endoplasmic reticulum (ER) stress, mitochondrial malfunction, and toxic oxidant and nitrogenous species accumulation, which may persist for days or months (Aghili-Mehrizi et al 2022 ).…”

The Multiple Functions of Melatonin: Applications in the Military Setting

“…In reference to military personnel in battlefield situations, organs that are especially vulnerable include skin, eyes, and lungs. Damage to these organs results from toxin exposure and environmental pollutants, including mustard gas, particulate matter in smoke and soot, airborne heavy metals, exposure to viruses and bacteria [111][112][113][114], and a result of physical harm, for example, contusion [115,116]. The oxidatively-mediated molecular damage resulting from these destructive agents is known to be mitigated by melatonin [117][118][119].…”