Search Results (101)

Traumatic brain injury (TBI) is a major cause of death and disability, mainly in persons under 45 years of age and it remains clinically challenging due to its heterogeneous pathophysiology and unpredictable course. Except from the initial mechanical damage, secondary injury —largely driven by neuroinflammation—plays a critical role in outcome and extent of recovery. Cytokines are central mediators of this immune response and have therefore been extensively studied as potential biomarkers for TBI diagnosis, need of imaging and prognosis. Among pro-inflammatory cytokines, IL-1β is rapidly upregulated after TBI and contributes to blood–brain barrier disruption and secondary damage. Furthermore, experimental studies suggest that IL-1 inhibition could be neuroprotective. IL-6 is up to date the most extensively studied cytokine and shows strong associations with injury severity, neuroimaging abnormalities, mortality and long-term functional outcomes across multiple adult and pediatric studies. Nevertheless, results vary depending on the biological compartment and timing. Anti-inflammatory IL-10 levels correlate with injury severity and has shown promise in distinguishing CT-positive from CT-negative mild TBI patients, potentially reducing unnecessary imaging, though findings are inconsistent. Other cytokines, including IL-17, TNF-α, IL-8, IL-9, and IL-15, have been correlated to post-traumatic neuroinflammation and may have diagnostic or prognostic value. Overall, IL-6 and IL-10 currently appear to be the most promising cytokine as biomarkers, however future research should focus on standardized cytokines assessment methods and possible use of multimarker panels. Full article

The presence of traumatic brain injury (TBI) is a critical determinant of post-traumatic mortality and morbidity. Not only is TBI one of the leading causes of death among severely injured patients, but it also substantially impacts long-term outcomes following severe trauma. Neurocritical care has a profound effect on outcomes following brain injury; nevertheless, its application in preclinical studies remains infrequent. This review therefore discusses strategies to improve the translational relevance of experimental TBI research, including the integration of neurocritical care principles in animal models. The review further addresses the impact of observation periods after injury and the selection of appropriate animal models (large vs. small animal models). In addition, commonly used injury induction methods—including controlled cortical impact (CCI), fluid percussion injury (FPI), weight-drop models, and blast injury paradigms—are discussed in terms of their reproducibility and clinical relevance. Finally, the review explores whether age, comorbidities, and sex influence TBI outcomes—and, if so, how these variables should be incorporated into experimental designs to improve translational fidelity. Full article

Background: Traumatic brain injury (TBI) frequently leads to long-term neurological deficits. Recent research also implicates cellular senescence—a state of permanent cell cycle arrest driven by DNA damage—as a key contributor to neuroinflammation and cognitive decline. This study investigates the cell-type specificity of senescence within glial and vascular cells of the neurovascular unit (NVU) following experimental TBI in a rat model. Methods: Rats underwent various TBI scenarios, including single severe TBI (sTBI), single mild TBI (mTBI), repetitive mild TBI (rmTBI) and repetitive sham-operated control (rSham). Twenty-four hours or four weeks later, brains were harvested and brain sections were co-stained for γH2AX and cell type-specific markers. Immunofluorescence microscopy was used to comprehensively assess senescence in both glial and vascular cells of the NVU, specifically astrocytes, microglia, endothelial cells, and pericytes. Results: We observed acute increased astrocyte senescence in sTBI samples and microglial senescence in mTBI and sTBI samples in the neocortex, while endothelial cell senescence was significantly elevated in the neocortex of the sTBI group after four weeks. Pericytes did not exhibit significant signs of senescence at either time point. Conclusion: These findings demonstrate differential γH2AX labelling of NVU components following TBI, suggesting that vulnerability to TBI-induced senescence can be specific both to the cell type and the time after the injury. This has implications on therapies targeting senescent cells for mitigating the long-term consequences of TBI. Full article

Background and Objectives: Traumatic brain injury (TBI) triggers oxidative stress, mitochondrial dysfunction, and sterile inflammation. Amantadine (ATD), a weak NMDA receptor antagonist, has shown neuroprotective potential, but its mechanistic basis remains unclear. This study examined whether ATD treatment is associated with changes in molecular and histological markers related to the HIF-1α/BNIP3L/HMGB1-mediated hypoxia–mitophagy–inflammation response in a rat TBI model. Materials and Methods: Thirty-two Wistar rats were assigned to four groups: sham, trauma, trauma + ATD (1 day), and trauma + ATD (7 days). TBI was induced using the impact-acceleration model, and ATD (45 mg/kg, i.p.) was administered post-injury. Oxidative stress indices (TOS, TAS, OSI), histopathology, inflammatory/apoptotic markers (CRP, TNF-α, Caspase-3), and gene expression (HIF-1α, BNIP3L, HMGB1) were evaluated. Results: ATD improved oxidative balance and histopathological integrity while reducing TNF-α, CRP, and Caspase-3 immunoreactivity. qPCR analysis showed lower HIF-1α, BNIP3L, and HMGB1 expression in ATD-treated groups, which is consistent with attenuation of hypoxia-related, mitochondrial stress-associated, and damage-associated molecular pattern-associated signaling after injury. Conclusions: In this experimental model, amantadine ameliorated oxidative, inflammatory, and apoptotic markers and was associated with reduced expression of HIF-1α, BNIP3L, and HMGB1. These findings support a mechanistic correlation between ATD treatment and suppression of secondary injury signatures; however, causal pathway relationships and functional neurological outcomes were not assessed. Full article

Traumatic brain injury (TBI) is being increasingly recognized as a major risk factor for chronic neurodegenerative disease, including chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD). Biomechanical forces during head trauma, particularly rotational acceleration and angular deformation, produce diffuse axonal injury (DAI) and widespread white matter damage that trigger persistent neurobiological cascades. These include axonal transport failure, blood–brain barrier (BBB) disruption, neuroinflammation, neurovascular and mitochondrial dysfunction, and pathological protein aggregation, closely paralleling core AD features. Epidemiological data support a dose–response relationship between TBI severity or repetition and subsequent dementia risk, moderated by genetic factors such as apolipoprotein E4 (ApoE4). Converging experimental and early clinical studies have begun to target shared injury and neurodegenerative pathways through acute neuroprotection, stem cell-based strategies for BBB restoration and neural repair, transcriptional and hormonal modulation, mitochondrial stabilization, and immunomodulation of chronic inflammation. This review synthesizes evidence linking biomechanical injury to molecular and neurovascular pathways of neurodegeneration and summarizes emerging temporally targeted interventions. By integrating mechanistic and therapeutic perspectives, we aim to narrow the translational gap between TBI and AD, refine identification of at-risk populations, and inform priorities for prevention and development of disease-modifying therapies. Full article

Traumatic brain injury (TBI) is a highly heterogeneous disease and achieving an accurate diagnosis remains a significant challenge. Biomarkers play a crucial role in minimizing the reliance on invasive techniques like computed tomography, which also have significant economic costs. Human samples were obtained from prospective cohort studies. Mice were subjected to an experimental model of traumatic brain injury. Biomarker levels, gene expression, and blood–brain barrier integrity were analyzed using ELISA, qRT-PCR, and Evans Blue assay; data were statistically evaluated using parametric or non-parametric tests as appropriate. This study focuses on evaluating the role of matricellular protein thrombospondin-1 (TSP-1) and the tight junction proteins occludin and ZO-1 as potential biomarkers of TBI. We showed that lower serum TSP-1 levels correlated with poor patient outcomes at 6 months compared to those patients with a good outcome. Additionally, the disruption of the blood–brain barrier (BBB) and subsequent release of tight junction proteins allowed us to identify occludin as a potential biomarker for prognosis in a cohort of TBI patients and as a diagnosis biomarker in a subgroup of patients with mild TBI, but its discriminative power as a diagnosis biomarker appears modest, as reflected by an AUC of 0.693. On the other hand, ZO-1 exhibited increased levels but limited diagnostic utility. These findings highlight the critical role of TSP-1 in maintaining BBB integrity and regulating the inflammatory response after a TBI, supported by the worsened condition observed in TSP-1-deficient animals. These results demonstrate the potential of TSP-1 and occludin as valuable biomarkers for secondary injury and disease progression in patients with mild to moderate/severe TBI. Full article

Objective: Traumatic brain injury (TBI) represents a significant clinical problem, with the biomechanical mechanisms of striking from different blunt instruments remaining unclear. This study aims to quantitatively evaluate TBI severity under blunt strikes and to assess the effects of strike velocity and blunt instrument size on biomechanical responses to provide a finite element approach for investigating injury mechanisms and informing clinical diagnosis. Methods: A head finite element model incorporating an outer cortical-cancellous-inner cortical bone structure was developed and verified against a previous cadaveric impact study. Strike velocities and blunt instrument parameters, obtained from experiments in which a long bat (LB) and a short bat (SB) were used to strike a dummy head, were applied as the loading conditions in the finite element simulation. Kinetic energy (KE), internal energy (IE), impact force, von Mises stress on skull, intracranial pressure (ICP), and Head_3ms acceleration were analyzed as indicators of injury severity. Results: Simulated force and ICP responses agreed with cadaveric experimental data within a 9.8% error. With increasing strike velocity (10–30 m/s), KE, IE, impact force, ICP, and Head_3ms all rose, while von Mises stress evolved from localized to dispersed distribution. Head_3ms reached an injury threshold of 80 g at a strike velocity of 10 m/s, and ICP peaks for LB and SB exceeded the brain injury threshold (235 kPa, ≈1760 mmHg) at 12 m/s and 14 m/s, respectively. At the same velocity, LB generated higher KE, IE, impact force, ICP and Head_3ms than SB. At 30 m/s, LB generated 390 J KE and 29.0 kN peak force, which were 50.0% and 11.1% higher than those of SB (260 J, 26.1 kN). Conclusion: This study reveals that increasing strike velocity and employing a larger blunt instrument elevate biomechanical responses, resulting in von Mises stress transitioning from localized concentration to multipolar dispersion. Specifically, when striking the head with the LB at velocities exceeding 12 m/s or with the SB exceeding 14 m/s, the impacts indicate a severely life-threatening level. These findings deepen our understanding of the mechanisms of blunt TBI. The constructed and validated finite element model can be repeatedly used for computer simulations of TBI under various blunt striking conditions, providing a scientific basis for clinical diagnosis and surgical planning. Full article

Background/Objectives: Traumatic brain injury (TBI) in the pediatric patient results in acute neurophysiological deficits and can have potential long-term sequelae, impacting neurodevelopment. Serum biomarkers are an active area of study for TBI prognosis and diagnosis. Cyclosporin A (CsA), an immunosuppressant drug with neuroprotective qualities, targets mitochondria to stabilize the neurometabolic energy crisis following TBI. The objective of this study was to determine the acute effect of CsA treatment following focal and diffuse TBI on piglet serum biomarkers associated with glial neurofilaments, axonal dysfunction, and neuronal injury. Methods: Biomarker concentrations of GFAP, Nf-L, and UCH-L1 were quantified retrospectively from porcine serum samples (n = 488) at multiple timepoints from three experimental groups: anesthetized sham (n = 10), controlled cortical impact (CCI, n = 49), or rapid, non-impact rotations (RNR, n = 151) of the head. Injured animals received 24 h post-injury intravenous administration of saline or one of four CsA treatment doses (10, 20, 40, or 60 mg/kg/day), and then, were sacrificed. Results: After RNR, GFAP levels significantly increased from baseline at 1 h and recovered by 1 day to healthy reference ranges, while Nf-L increased at 1 day. Multiple CsA treatment doses (10, 40 mg/kg/day) significantly reduced Nf-L levels at 1 day compared to the untreated group. After CCI, GFAP and Nf-L increased at 1 day; there were no significant treatment effects. Conclusions: Focal and diffuse brain injury mechanisms resulted in distinct biomarker timelines. CsA reduced Nf-L levels at 1 day after diffuse TBI, showing promise of acute therapeutic benefit and warranting further investigation in extended timelines. Full article

Loss of calcium homeostasis, a shared feature of Alzheimer’s Disease (AD) and Traumatic Brain Injury (TBI), activates enzyme-dependent cascades that promote protein misfolding, degrade synaptic architecture, impair axonal transport, and lead to neuronal death. Epidemiological studies identify TBI as a major risk factor for AD, yet the mechanistic basis for this association remains incompletely understood. Evidence from human and experimental studies implicate calcium dysregulation as a central link, triggering interconnected kinase, phosphatase, and protease networks that drive AD hallmark pathology, including amyloid-β (Aβ) accumulation and tau hyperphosphorylation. The calcium-dependent protease calpain is a key node in this network, regulating downstream enzyme activity, and cleaving essential scaffolding and signaling proteins. Selective vulnerability of the hippocampus and white matter to calcium-mediated damage may underlie cognitive deficits common to both conditions. In preclinical TBI and AD models, pharmacological inhibition of calcium-dependent enzymes confers neuroprotection. Recognizing disrupted calcium signaling as an upstream driver of post-traumatic neurodegeneration may enable early interventions to reduce AD risk among TBI survivors. Full article

Traumatic brain injury (TBI) remains a significant public health concern, particularly among military personnel and contact sport athletes who are frequently exposed to repeated blast overpressure waves and mild concussive impacts, respectively. While moderate and severe TBIs have been extensively studied, the long-term neuroendocrine consequences of mild, repetitive brain trauma are poorly understood. In this study, we investigated the temporal dynamics of hypothalamic–pituitary–adrenal (HPA) axis dysregulation following repeated mild concussive head impacts and blast exposures using two clinically relevant rodent models. Male Sprague-Dawley rats were subjected to repeated mild concussive impacts using a modified weight drop model or repeated blast exposures using an advanced blast simulator. Plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone were measured on days 1 and 30 post-injuries. Our findings revealed that repeated blast exposures induced elevation of plasma ACTH and corticosterone on days 1 and 30 post-blasts. After the repeated mild concussive impacts, increased plasma levels of corticosterone were observed on days 1 and 30, but ACTH levels were increased only on day 30. This study is among the first to directly compare neuroendocrine outcomes of repeated mild concussive impacts and blast exposures within a unified experimental framework. Our findings demonstrate distinct temporal trajectories of HPA axis dysregulation depending on injury type and highlight plasma levels of ACTH and corticosterone as potential biomarkers of subclinical brain trauma. These insights may inform early diagnostic approaches and therapeutic strategies aimed at mitigating long-term stress-related complications following mild traumatic brain injuries. Full article

Traumatic brain injury (TBI) is a major neurological condition affecting millions of individuals each year. Mild TBI (mTBI) manifests differently, with some individuals experiencing persistent, debilitating symptoms while others recover more rapidly. Despite its classification as “mild,” mTBI leads to both short- and long-term neurological effects, many of which occur due to functional changes in the brain. TBI-induced environmental changes within the brain play a critical role in shaping these functional outcomes. The importance of astrocytes in maintaining central nervous system (CNS) homeostasis has been increasingly recognized for their pivotal role in the brain’s response to TBI. Previous studies showed significant TBI-associated metabolic dysregulations. Therefore, we sought to analyze how astrocytes might adapt to persistent metabolic stressors in the post-injury microenvironment and identify injury-induced shifts occurring in vivo that may contribute to chronic metabolic dysfunction. We used an astrocyte-specific genome-scale metabolic model that allowed for the input of biologically relevant uptake rates corresponding to healthy astrocytes to analyze how the activity of metabolic pathways differed in hypoxic and acidic conditions. Additionally, these fluxes were integrated with mass spectrometry-based proteomics from male Sprague-Dawley rats subjected to mTBI to identify chronic adaptive neural responses post-injury. Comparison of modeled metabolic fluxes and experimental proteomic data demonstrated remarkable alignment, with both predicting significant changes in key metabolic processes including glycolysis, oxidative phosphorylation, the TCA cycle, and the Pentose Phosphate Pathway. These overlapping signatures may represent core survival strategies, offering insight into metabolic priorities and potentially serving as biomarkers of injury adaptation or recovery capacity. Full article

Background: Traumatic brain injury (TBI) and hypoxic–ischemic encephalopathy (HIE) are major causes of long-term neurological disability in children, with limited options for effective neuronal recovery. Recent research has highlighted the therapeutic potential of nerve growth factor (NGF) in promoting neural repair through mechanisms such as neuroprotection, neurogenesis, and the modulation of neuroinflammation. This review evaluates the current evidence on NGF as a treatment strategy for pediatric brain injury, emphasizing its mechanisms of action and translational clinical applications. Methods: A comprehensive review was conducted using the PubMed, Scopus, and Cochrane CENTRAL databases to identify studies published between 1 January 1978 and 1 March 2025, investigating NGF in the context of brain injury. The inclusion criteria comprised studies assessing neurological outcomes through clinical scales, biochemical markers, neuroimaging, or electrophysiological examinations. Results: Seventeen studies met the inclusion criteria, encompassing both preclinical and clinical research. Preclinical models consistently demonstrated that NGF administration reduces neuroinflammation, enhances neurogenesis, and supports neuronal survival following TBI and HIE. Clinical studies, including case reports of pediatric patients treated with intranasal NGF, reported improvements in motor and cognitive function, neuroimaging findings, and electrophysiological parameters, with no significant adverse effects observed. Conclusions: NGF demonstrates significant promise as a neuroprotective and neuroregenerative agent in pediatric brain injury, with both experimental and early clinical evidence supporting its safety and efficacy. Large-scale controlled clinical trials are warranted to validate these preliminary findings and to determine the optimal dosage regimens and administration schedules for NGF in the treatment of TBI and HIE. Full article

Caffeine is a weak, nonselective adenosine receptor antagonist. At low-to-moderate doses, caffeine has a stimulating effect; however, at higher doses, it can act as a depressant. It can function both as a neuroprotectant and a neurotoxin. In experimental Traumatic Brain Injury (TBI), administration of this psychoactive drug has been associated with beneficial or detrimental effects, depending on the dose, model, and timing. In a healthy brain, caffeine can enhance alertness and promote wakefulness. However, its consumption during late adolescence and early adulthood disrupts normal pruning processes in the context of repetitive moderate TBI (mTBI), leading to changes in dendritic spine morphology, resulting in neurological and behavioral impairments. Caffeine can potentially reduce TBI-associated intracranial pressure, oxidative stress, lipid peroxidation, cytotoxic edema, inflammation, and apoptosis. It can enhance alertness and reduce mental fatigue, which is critical for the cognitive rehabilitation of TBI patients. Additionally, caffeine positively affects immune cells and aids recovery post-TBI. Antagonizing adenosine receptors involved in controlling synaptic transmission, synaptic plasticity, and synapse toxicity can improve cognitive function. Conversely, studies have also shown that caffeine consumers report significantly higher somatic discomfort compared to non-consumers. This review aims to explore various studies and thoroughly examine the positive and negative roles of caffeine in TBI. Full article

Traumatic brain injuries (TBIs) are a serious problem affecting individuals of all ages. Mitochondrial dysfunctions represent a significant form of secondary injury and may serve as a promising target for therapeutic intervention. Our research demonstrated that craniotomy, which precedes the experimental induction of trauma in mice, can cause considerable damage to mitochondrial DNA (mtDNA), disrupt the regulatory expression of angiogenesis, and increase inflammation. However, the reduction in the mtDNA copy number and glial activation occur only after a direct impact to the brain. We explored two potential therapeutic agents: the dietary supplement L-carnitine—a potential reserve source of ATP for the brain—and the cardiac drug mildronate, which inhibits L-carnitine but activates alternative compensatory pathways for the brain to adapt to metabolic disturbances. We found that L-carnitine injections could protect against mtDNA depletion by promoting mitochondrial biogenesis. However, they also appeared to aggravate inflammatory responses, likely due to changes in the composition of the gut microbiome. On the other hand, mildronate enhanced the expression of genes related to angiogenesis while also reducing local and systemic inflammation. Therefore, both compounds, despite their opposing metabolic effects, have the potential to be used in the treatment of secondary injuries caused by TBI. Full article

Background/Objectives: A traumatic brain injury (TBI) is a brain lesion caused by external or internal factors, resulting in cognitive, behavioral, physical, relational, and sensory sequelae, depending on the affected brain area and the severity of the injury. Within neuropsychological rehabilitation (NR), multiple methods have been developed that are aimed at restoring, compensating, and substituting deteriorated cognitive functions resulting from a TBI. This systematic review aimed to identify the state of the scientific literature regarding the efficacy of NR methods in individuals with a TBI. Methods: Articles were analyzed in the SCOPUS and PUBMED databases. Initially, 5347 studies were found. After applying inclusion and exclusion criteria, 17 articles remained and were included in the data extraction process. Results: Of the seventeen included articles, eleven employed randomized or semi-randomized controlled trials, five were clinical studies, and one was a comparative study, in which the percentage of computerized NR methods was 58.82% in the experimental and clinical groups. In contrast, traditional methods constituted 35.3%, and the remaining 5.88% conducted holistic NR. Ninety percent of the methods employed in these investigations showed efficacy. Conclusions: While most of the evaluated NR methods demonstrated efficacy, the analysis of these findings should not be isolated from variables such as the etiology and phase of the TBI, the intervention duration, and the symptoms treated. Furthermore, the NR implementation must be adapted to the specific context of each patient. Full article