The brain is undoubtedly the most complex and intriguing structure in the human organism. Its organization is characterized by a myriad of cells with distinct morphophysiological characteristics that establish an intricate network of connections that originate and modulate all the individual’s behaviors. Though, despite the ever-increasing range of information about this organ, much remains to be determined, especially concerning tissue and cell responses as a result of disturbances of any nature, either mechanical (traumatic), chemical or physiological.
One of the most common and detrimental events that can generate permanent impacts on brain functioning is traumatic brain injury (TBI), which is a complex and heterogeneous disorder in the brain structure as a result of an external force in the form of mechanical, electrical, thermal or chemical energy, or a set of these, applied on it
[1], emerging as a serious public health concern globally
[2][3]. TBI corresponds to the third most prevalent cause of death and neurological impairment worldwide, also resulting in serious dysfunctions that severely interfere with the quality of life of affected individuals
[4]. In the long term, a TBI can, through secondary damage, lead to neurodegenerative pathologies such as Alzheimer’s disease, Parkinson’s disease and dementia
[5].
Projections from the Global Burden of Disease (GBD) point out that the incidence of TBI tends to increase in the coming years due to the growth in population density and the increasing use of automobiles, motorcycles and bicycles as a way of transport
[6]. One of the most devastating consequences of a TBI is the cognitive and/or functional impairment observed in surviving patients, which is directly associated to the degree of the injury
[3], generating not only repercussions on the quality of life of affected individuals but also directly affecting the lives of their relatives and caregivers
[7], with an important economic burden involved
[8].
TBI is triggered by a sudden event that elicits morphophysiological disturbances in the brain parenchyma, with variable impact depending on the location and extent of the injury. The deleterious events underlying TBI can be classified into two sequential stages: primary and secondary
[9][10]. The primary injury is a disturbing event that occurs at the time of the initial trauma, causing an irreversible loss of tissue in the core of the lesion. The nature of the insult is highly relevant for a proper characterization of the levels of damage, early diagnosis, and therapeutic interventions.
Depending on whether or not the skull is ruptured, the primary injury can be classified as a penetrating (open-head) or nonpenetrating (closed-head or blunt) lesion
[9][10]. Penetrating injury is mainly defined by an open wound in the head caused by a foreign body, resulting in a focal disturbance that occurs along the path taken by the object through the tissue. It is associated with perforation or fracture of the skull, laceration of the meninges, and structural damage to nervous tissue
[10]. Conversely, nonpenetrating injury is characterized by tissue damage caused by indirect impact without penetration of a foreign body into the brain. The skull may or may not be injured, but the meninges are not structurally disrupted
[10].
Concerning the nature of trauma, nonpenetrating lesions can be classified into acceleration and non-acceleration injuries. While the first is associated with whiplash-type injury, resulting in the impact of the brain with the skull due to abrupt incidental acceleration or deceleration of the head, causing a contusion at the site of impact, as seen in blast injury
[11], the latter is elicited by repeated blows to the head
[12], resulting in deformation of the skull and causing focal localized damage to both meninges and brain tissue
[10]. Mechanical tissue deformation, disturbance in the blood flow, osmotic/electrolyte imbalance, necrotic cell death, and the influx of inflammatory cells (neutrophils and monocytes) from bloodstream are hallmarks of the primary lesion in both animal models and humans, which is irreversible and amenable only to preventive measures to reduce the extent of damage
[13].
The harmful effects following primary injury are not restricted to the site of the lesion. A primary lesion elicits a cascade of pathophysiological events that affects remote brain regions initially not affected, resulting in the so-called secondary injury, referred to as the additional damage that occurs after the primary insult following TBI. While the primary injury is the initial physical impact or event, the secondary injury involves a cascade of complex pathophysiological processes that can exacerbate the initial damage and lead to further neurological dysfunction and tissue loss
[13][14].
Secondary brain injury can result from various mechanisms, including ischemia, excitotoxicity, oxidative stress, inflammation, and mitochondrial dysfunction in both animal models and humans
[13][14]. These processes can cause a myriad of harmful events, such as brain edema, blood–brain barrier (BBB) disruption, increased intracranial pressure, metabolic disfunction, excitotoxicity, oxidative and cellular apoptosis or necrosis, ultimately leading to neurological disfunctions
[13][15][16][17].
The secondary injury cascade typically unfolds over time, evolving from minutes to days after the initial insult. It can be influenced by factors such as systemic hypotension, hypoxemia, increased intracranial pressure, and metabolic imbalances
[18]. The severity of the secondary injury and its impact on the patient’s outcome depend on various factors, including the nature and extent of the primary injury as well as the effectiveness of medical interventions to mitigate its progression
[14].