The use of explosive weapons and chemical agents has resulted in an increase in blast-induced traumatic brain injury (bTBI) among both military personnel and civilians. As advances in body armor have improved, there has been a decrease in lethal blast lung injury; however, there has been a corresponding rise in the prevalence of bTBI and resulting neurodeficits (Harper et al., 2020; Kuehn et al., 2011). In modern warfare, the prevalence of bTBI can be as high as 19.5–22.8%, with mild injuries accounting for the majority at 82.3% (Tweedie et al., 2016). In contrast to severe cases which are readily apparent and caused primarily by explosive fragments and impact, mild bTBI often lacks obvious clinical symptoms or detectable signals using traditional methods. This leads to missed opportunities for early diagnosis and treatment (DeKosky et al., 2010). However, individuals with untreated bTBI face a significant risk of developing post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), and other neurodegenerative disorders. These conditions can result in lifelong disabilities that place burdens on individuals, families, and society as a whole (Priemer et al., 2022; Ravula et al., 2022; Wolf et al., 2009).

Primary bTBI occurs as a result of the high-pressure shockwave generated during an explosion. From a biomechanical perspective, the frontal and parietal lobes of the brain are particularly vulnerable to the impacts of blast waves due to high-frequency pressure fluctuations and peak pressure in these regions (Panzer et al., 2012). Blast waves can reach the brain through various pathways, which can be categorized as either direct or indirect mechanisms (Rosenfeld et al., 2013). Direct mechanisms, known as direct-bTBI, involve the interaction of the blast wave directly with the head, resulting in skull deformation, cavitation, spallation due to acoustic impedance mismatch, and acceleration of the head. On the other hand, indirect mechanisms, referred to as indirect-bTBI, pertain to brain injuries caused by the blast wave's interaction with the body, leading to the transfer of kinetic energy to the brain. This may occur when blood surges from the torso, damaging the cerebral vasculature (Kuehn et al., 2011; Rubio et al., 2021).

In recent years, several studies have been conducted to examine the neuropathology of bTBI. The most widely recognized pathophysiological changes include early cerebral edema, hemorrhage, and long-term vasospasm (Bauman et al., 2009). Furthermore, bTBI has been found to induce various neuropathological alterations, including minor cerebral hemorrhages, subarachnoid hemorrhages (SAH), axonal and neuronal damage, cerebral swelling, and mitochondrial abnormalities (Garman et al., 2011; Kuehn et al., 2011; Song et al., 2019). However, most of these studies exposed animals to shockwaves without providing protection to the chest and abdomen, thereby failing to consider the separative effect of both direct and indirect mechanisms of bTBI. While the biological mechanisms of indirect-bTBI have been explored, our understanding of direct-bTBI remains incomplete (Tong et al., 2021). Notably, the neuropathology of bTBI is primarily associated with the direct mechanism rather than the indirect one (Rubio et al., 2021). Moreover, the biomarkers proposed based on these animal models may not exclusively relate to brain injury, as they can also be influenced by lung, gastrointestinal, or other injuries. Thus, uncovering the neuropathology and mechanism of direct-bTBI could significantly contribute to the development of clinical strategies for managing primary bTBI. Additionally, exposure to primary blast alone has been found to lead to hippocampus-dependent behavioral changes that align with electrophysiological alterations in area CA1 and are accompanied by reactive gliosis (Beamer et al., 2016). Therefore, investigating the neuropathology and mechanisms of direct-bTBI has the potential to advance the understanding and treatment of primary bTBI.

Limited research has focused on the neurobiological mechanisms underlying primary bTBI. It has been reported that mild bTBI can lead to axonal and synaptic damage, associated with signaling pathways involving substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis (Chen et al., 2018a, Chen et al., 2018b). Additionally, low-intensity blast shockwaves can trigger glutamatergic hyperexcitability, impacting synaptic plasticity and serine protease inhibitors, as well as mitochondrial dysfunction, leading to neurodeficits (Song et al., 2019; Tweedie et al., 2016). Furthermore, neuropathological changes, including axon/dendrite degeneration, have been linked to increased levels of phospho-tau proteins and subsequent neurodeficits, potentially contributing to the development of Alzheimer's disease (AD) (Chen et al., 2018a, Chen et al., 2018b). Hence, early control of neurological responses could be crucial in managing neuropathological changes and chronic neurodeficits in bTBI. Notably, detonation triggers pathological events at the cellular and molecular levels in brain tissue within milliseconds (Chen et al., 2018a, Chen et al., 2018b; Rodriguez et al., 2019; Song et al., 2019). However, there is still limited understanding of the pathological and biological mechanisms during the initial stage of bTBI.

Therefore, the objective of this study was to examine the early neuropathological characteristics and underlying neurobiological mechanisms of primary bTBI using rat models. The animal model involved exposing the rats' heads exclusively to blast shockwaves in a controlled laboratory setting. Through this approach, the study aimed to detect neuropathological changes and investigate sensitive pathways and key proteins associated with the observed neuropathology in bTBI. These findings have the potential to identify biomarkers and targets for the early diagnosis and treatment of bTBI.