**1. Introduction**

Traumatic brain injuries (TBI) are one of the leading causes of death and chronic disability especially among the working population, and represent an important public health problem worldwide. Globally, about 10 million people are affected by TBI every year with projections that TBI will be one of the major causes of death and disability by the year 2020 [1]. Since TBI is a complex injury that encompasses a broad spectrum of symptoms and disabilities, the manifestations of head injury may be clinically very variable ranging from mild, to moderate or severe, depending on the extent and duration of damage to the brain. Many cognitive, physical and psychological skills can be affected, exerting a devastating impact on the patients and their family [2]. Over the years more than 30 phase III clinical trials failed emphasizing the urgent need for efficient treatment modalities and new directions in the future research to improve posttraumatic morbidity and mortality. Considering the complexity of TBI it is reasonable to assume that only combination of different treatment protocols could provide better prognosis for recovery to all forms of TBI [3]. In this view, hyperbaric oxygenation (HBO) or hyperbaric oxygen therapy (HBOT) appeared as an adjunctive therapy that may have the synergistic effect with other treatment protocols, suggesting that combining therapies with HBOT could provide better results than either alone [4]. According to definition given by the Undersea and Hyperbaric Medical Society (UHMS), hyperbaric medicine is a therapeutic approach in which a patient breathes 100% oxygen intermittently, while the pressure of the treatment chamber is higher than ambient (1 atmosphere absolute, 1 ATA = 101.3 kPa) [5–7]. In comparison to the normobaric conditions increased oxygen supply under hyperbaric conditions enables easier diffusion of oxygen into the injured tissue [8]. Accordingly, the HBOT can be used to obtain 100% saturation of hemoglobin and to significantly elevate the volume of physically dissolved oxygen fraction in blood plasma. This increased blood oxygen level then can penetrate to ischemic areas and perilesioned tissue more deeply than under normobaric conditions [9–11]. Thus, the HBOT has found its place, as the primary or adjuvant therapy in the treatment protocols for different clinical conditions [12, 13].

**2. Potential cellular and molecular mechanisms underlying HBOT**

plasticity; (10) promoting of synaptogenesis, neurogenesis and angiogenesis.

**2.1. HBOT suppresses development of secondary brain damage**

Increasing number of animal studies on HBOT in experimental TBI revealed a myriad of diverse mechanisms that may underlie neuroprotective effects of HBOT. Researchers suggested that many of these cellular and molecular mechanisms and signaling pathways work in parallel, or together, contributing to repair of the injured brain [6, 7, 23, 25, 28]. These mechanisms involve: (1) alleviation of secondary injury; (2) increasing of tissue oxygenation; (3) reducing of neurodegeneration; (4) decreasing of apoptosis; (5) regulation of oxidant/antioxidant status; (6) reduction of oxidative stress; (7) attenuation of reactive gliosis (microgliosis and astrogliosis) and glial scarring; (8) reducing of inflammation; (9) enhancement of neuronal

Hyperbaric Oxygen Therapy in Traumatic Brain Injury: Cellular and Molecular Mechanisms

http://dx.doi.org/10.5772/intechopen.75025

27

TBI involves primary and secondary injury. Primary injury occurs at the time of the impact and is the result of immediate mechanical damage of neural pathways followed by a permanent neuronal lost. The site of mechanical impact is called the "core". Surrounding regions consist of neuronal tissue that have not been directly affected by trauma and are often addressed to as "penumbra area". Neurons inside this zone are at risk due to a cascade of events, known as secondary injury that involves: impaired blood flow (limited or not at all), inflammation, development of edema, acidosis and hemorrhage, and the loss of most of their connections with the other neurons [11, 21, 22]. Secondary degeneration can also progress into the surrounding intact regions of the brain. Compromised blood flow and insufficient oxygen supply leads to tissue hypoxia and the resulting energy failure, which initiates a cascade of cellular events that culminate with neuronal cell apoptosis [23]. Thus, the consequence of secondary injury is degeneration of neurons that previously have not been exposed to trauma [29–31]. Most of the neurotherapeutic strategies are directed toward the containment of the secondary processes and the preservation and reactivation of the penumbra area and perilesioned region [30]. Cumulative evidence have proved that HBOT may reduce development of secondary brain damage and prevent neuronal apoptosis in animal models of TBI [32, 25], ischemic stroke [33–37], and hypoxia-ischemia [38–40], which was manifested by diminishing of brain infarction area and improvement of neurological deficits. Recently, Baratz-Goldstein et al. [41] demonstrated that both immediate (initiated 3 h post-injury) and delayed treatments with HBO (initiated 7 days post-injury) have a potential to prevent a neuronal loss in mouse model of moderate TBI.

**2.2. HBOT reduces neuronal degeneration and prevents apoptosis after brain injury** 

One of the main processes in this pathological cascade is oxidative stress that develops in the cells which have been exposed to trauma and in the cells at "penumbra area". Reactive oxygen species (ROS) are one of the products of oxidative stress [2] that are responsible for cellular damaging and apoptosis. The first line of the defense against ROS are enzymes located in mitochondria, such as manganese superoxide dismutase (SOD2) [42]. In our previous study, we have shown that repetitive HBOT influenced the pattern of SOD2 expression both on gene and protein level in

**by regulation of oxidant/antioxidant status and reduction of oxidative stress**

On the other hand, opinions about usage of HBOT as adjunctive therapy for the treatment of patients with brain injuries are still controversial [14–16]. In this way HBO is a very motivating therapeutic modality, which is known to produce oxidative stress by itself [17], but reduces oxidative stress when used in pathological conditions [18, 19]. The main concern in HBOT is oxidative stress and/or oxygen toxicity that can affect multiple organs. However, these side-effects are dependent on treatment parameters – pressure and duration of the treatment [20–23].

Substantial amount of evidences has been published indicating that HBOT can interfere with the processes that are following brain injury and moderate its consequences [14, 24–27]. Recent results of experimental and clinical studies and potential mechanisms of HBOT in TBI are reviewed by Wang et al. [28] and Hu et al. [7]. However, knowledge about the exact mechanisms by which HBOT exerts its beneficial effects is still deficient. Therefore, data presented in this chapter are meant to put more light on cellular and molecular mechanisms underlying neuroprotective effects of hyperbaric oxygenation after the brain injury.
