A computational study of the mouse brain under multidirectional rotational loading.

Traumatic brain injury (TBI) and intracerebral hemorrhage (ICH) are leading causes of neurological mortality and disability in the U.S. However, therapeutic options are limited and clinical management remains largely supportive. HMG-CoA reductase inhibitors (statins) have pleiotropic mechanisms of action in the setting of acute brain injury, and have been demonstrated to improve outcomes in preclinical models of ICH and TBI. To facilitate translation to clinical practice, we now characterize the optimal statin and dosing paradigm in murine models of ICH and TBI. In a preclinical model of TBI, mice received vehicle, simvastatin, and rosuvastatin at doses of 1 mg/kg and 5 mg/kg for 5 days after the impact. Immunohistochemistry, differential gene expression, and functional outcomes (rotarod and Morris water maze testing) were assessed to gauge treatment response. Following TBI, administration of rosuvastatin 1 mg/kg was associated with the greatest improvement in functional outcomes. Rosuvastatin treatment was associated with histological evidence of reduced neuronal degeneration at 24 h post-TBI, reduced microgliosis at day 7 post-TBI, and preserved neuronal density in the CA3 region at 35 days post-injury. Administration of rosuvastatin following TBI was also associated with downregulation of inflammatory gene expression in the brain. Following ICH, treatment with simvastatin 1 mg/kg was associated with the greatest improvement in functional outcomes, an effect that was independent of hemorrhage volume. Clinically relevant models of acute brain injury may be used to define variables such as optimal statin and dosing paradigms to facilitate the rational design of pilot clinical trials.

Neuropsychiatric symptoms and cognitive deficits are common among victims of a traumatic brain injury (TBI), and currently, there are no effective treatments to improve outcome. We first developed a clinically-relevant blast TBI model based on lung scaling parameters to elucidate mechanisms of neuronal cell death. In order to discover effective treatments to improve outcome, we had to validate our novel preclinical model of TBI. TBI is an external force that can cause damage to the neurovascular unit (NVU), which can lead to secondary effects, cell death and behavioral dysfunction. In our first study we observed that our model damaged the NVU, increased neuronal cell death, and produced cognitive deficits in young adult Sprague-Dawley rats. The link between damage to the NVU and neurobehavioral dysfunction following TBI is poorly understood. Recently secondary injury cascades, such as endoplasmic reticulum (ER) stress and neuroinflammation, have been hypothesized to be early indicators for the development of neurobehavioral dysfunction. Therefore, we examined the regional and temporal profile of these secondary injury cascades using our validated rodent TBI model. We also measured neurobehavioral dysfunction using a variety of functional assays at various time points post-TBI. Tissues from brain regions associated with the behavioral sequelae of TBI were evaluated for biochemical changes. Furthermore, we investigated the neurophysiological response in brain slice recordings at various time points after TBI. We discovered that TBI produced spatial memory deficits in the rats and altered synaptic firing rates in the hippocampus. In our next study, we revealed a robust increase in markers of ER stress and neuroinflammation within the frontal cortex after TBI. Interestingly, we observed impulsive-like behavior in rats after TBI, which is indicative of damage to the frontal cortex. After characterization of the injury response, we investigated the role of ER stress modulation in mediating secondary injury cascades and neurobehavioral dysfunction following TBI. Salubrinal, an ER stress modulator, attenuated markers of neuroinflammation and neuronal cell death. Most importantly, ER stress modulation ameliorated impulsive-like behavior in rats after TBI. The final portion of this study was to elucidate a link between ER stress and the development of Chronic Traumatic Encephalopathy (CTE). We revealed a potential link between repetitive blast injury and neuropsychiatric symptoms associated with CTE. Tau phosphorylation and aggregation are considered hallmarks of CTE development. We observed an increase in marker of tau phosphorylation and conformational change in rats exposed to repetitive blast. We also observed spatial memory deficits

Human neural stem cells (hNSCs) possess significant therapeutic potential for the treatment of traumatic brain injury (TBI), a leading cause of global death and disability. Recent pre-clinical studies have shown that hNSCs reduce tissue damage and promote functional recovery through neuroprotective and regenerative signaling and cell replacement. Yet the overall efficacy of hNSCs for TBI indications remains unclear. Therefore, this systematic review aims to evaluate hNSC interventions compared with controls in pre-clinical TBI models. Through this process, variations in hNSC administration protocols were consolidated, and key knowledge gaps were identified. Meta-analysis was applied to primary outcomes of lesion volume, Morris Water Maze (MWM) performance, modified Neurological Severity Scores (mNSS), and the rotarod task. Narrative review of secondary outcomes included hNSC survival and differentiation, endogenous neuron survival, axonal injury, and inflammation. Overall, hNSC intervention reduced lesion volume, enhanced MWM performance, and led to trending decreases in acute and chronic neurological deficits at acute and chronic time points. These results suggest hNSCs demonstrate clear efficacy in pre-clinical TBI models. However, further studies are needed to address key questions regarding optimal hNSC administration (e.g., dosing, treatment window) and underlying mechanisms of action prior to progressing to human clinical trials.

BackgroundThe occurrence of traumatic brain injury (TBI) has been progressively increasing over the years, mainly due to factors such as driving accidents and falls. Globally, TBI is now considered a significant cause of death and disability, particularly among young adults. TBI leads to inflammation and oxidative stress, significantly contributing to increased mortality and long-term complications. The importance of early therapeutic interventions in patients with TBI has been highlighted in several studies. The impact of trehalose as an anti-inflammatory and antioxidant on TBI has been well documented in animal models; however, this effect remains inconclusive in humans. This study aims to assess the effects of trehalose on inflammatory markers, oxidative stress, clinical outcomes, and mortality in TBI patients.MethodIn this double-blind randomized controlled trial, we will recruit 80 patients aged 18 to 65 years with TBI from Al-Zahra Hospital, Isfahan, Iran, and randomly allocate them at the individual level into two groups of 40. One group will receive 10 g of trehalose daily (intervention group), while the other will receive 10 g of maltodextrin (placebo group) for 7 days. Primary outcomes include inflammatory markers (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin 6 (IL-6)), oxidative stress markers (total antioxidant capacity (TAC), superoxide dismutase (SOD), malondialdehyde (MDA)), clinical scores (sequential organ failure assessment (SOFA), Acute Physiology and Chronic Health Evaluation II (APACHE II), Nutrition Risk In Critically Ill (NUTRIC)), mortality (days 28, 60, 90), and hospital stay (day).DiscussionGiven the anti-inflammatory and antioxidant effects of trehalose observed in preclinical TBI models, its supplementation in patients with TBI may potentially improve the outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13063-025-09220-y.

Traumatic brain injury (TBI) is one of the main causes of disability in children and young adults, as well as a significant concern for elderly individuals. Depending on the severity, TBI can have a long-term impact on the quality of life for survivors of all ages. The primary brain injury can result in severe disability or fatality, and secondary brain damage can increase the complexities in cellular, inflammatory, neurochemical, and metabolic changes in the brain, which can last decades post-injury. Thus, survival from a TBI is often accompanied by lifelong disabilities. Despite the significant morbidity, mortality, and economic loss, there are still no effective treatment options demonstrating an improved outcome in a large multi-center Phase III trial, which can be partially attributed to poor target engagement of delivered therapeutics. Thus, there is a significant unmet need to develop more effective delivery strategies to overcome the biological barriers that would otherwise inhibit transport of materials into the brain to prevent the secondary long-term damage associated with TBI. The complex pathology of TBI involving the blood-brain barrier (BBB) has limited the development of effective therapeutics and diagnostics. Therefore, it is of great importance to develop novel strategies to target the BBB. The leaky BBB caused by a TBI may provide opportunities for therapeutic delivery via nanoparticles (NP). The focus of this review is to provide a survey of NP-based strategies employed in preclinical models of TBI and to provide insights for improved NP based diagnostic or treatment approaches. Both passive and active delivery of various NPs for TBI are discussed. Finally, potential therapeutic targets where improved NP-mediated delivery could increase target engagement are identified with the overall goal of providing insight into open opportunities for NP researchers to begin research in TBI.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, and is indiscriminate in who it affects, including children. Although there are currently no Food and Drug Administration-approved therapeutics, promising results from recent induced pluripotent stem cell-derived neural stem cell (iNSC) studies have demonstrated decreased tissue damage and functional deficits in pre-clinical TBI models. Moreover, while the rest has been traditionally identified as the standard of care following TBI, research now suggests that physical activity postinjury may significantly enhance neuroprotective and regenerative signaling in patients. Combining these two therapies may therefore synergistically improve recovery outcomes in TBI patients. In this study, we evaluated the combined therapeutic efficacy of iNSCs and structured treadmill walking on cellular, tissue, and functional recovery in a translational pediatric pig TBI model. One-month-old piglets received a controlled cortical impact-induced TBI and were randomly assigned to either a PBS (n = 4), PBS + treadmill (n = 4), iNSC (n = 4), or iNSC + treadmill (n = 4) treatment group. Piglets received intraparenchymal transplantations of either iNSCs or PBS 5 days post-TBI. At 1-week post-transplantation, piglets assigned to the treadmill treatment groups began a 12-week progressive walking regimen. Motor function and open field behavior assessments were performed pre-TBI and 12 weeks post-transplantation. Magnetic resonance imaging (MRI) and histological evaluation of collected brain tissue were performed 12 weeks post-transplantation. Immunohistochemistry revealed long-term survival, engraftment, and differentiation of transplanted iNSCs into neurons, astrocytes, and oligodendrocytes in treated piglets. Furthermore, iNSC + treadmill treatment showed increased endogenous neuron and oligodendrocyte survival, increased proliferation of neuroblasts, and decreased populations of reactive astrocytes and immune cells in TBI brain tissue. MRI analysis revealed a significant reduction in lesion volume, midline shift, and white matter degradation with preserved cerebral blood flow following both iNSC and iNSC + treadmill interventions. These cellular and tissue-level effects corresponded with significant motor function recovery as seen through increased step and stride length with decreased stance percentage and time. During open field behavioral assessments, iNSC and iNSC + treadmill-treated piglets demonstrated improved exploratory behaviors. These findings suggest that the combination of iNSCs with structured treadmill walking significantly enhanced TBI recovery beyond the therapeutic potential of iNSCs or exercise alone. Therefore, this novel combination therapy needs to be further explored as a potential transformative treatment option for pediatric TBI patients.

The extent of brain damage accompanying traumatic brain injury (TBI) depends on the type and severity of insult and is modulated by age, sex, and comorbidities. Nearly half of all US adults suffer from hypertension. Not surprisingly, hypertension is the most common premorbid condition in people aged 50 or above hospitalized with a TBI. Hypertension has been linked to cerebrovascular damage, neuroinflammation and cognitive decline. Neurogenic hypertension is elevated blood pressure initiated by the local renin angiotensin system within the brain; often times involved in resistant hypertension (high blood pressure poorly responsive to common antihypertensives). Despite an overlap in several aspects of brain pathology induced by hypertension and triggered by TBI, little is understood about the impact of premorbid hypertension on outcomes following TBI. We hypothesize that hypertension induces mild blood-brain barrier leakiness and neuroinflammation, priming the brain for greater cerebrovascular damage after TBI. To test this hypothesis, mice were rendered hypertensive via subcutaneous infusion of 1000 ng/kg/min angiotensin-II (Ang-II) two weeks prior to and one week following induction of a moderate severity controlled cortical impact or sham injury. Vascular damage and astrocyte and microglia activation were examined using histology and immunohistochemistry. Quantification was performed using HALO image analysis software. Compared to injured normotensive mice, injured hypertensive mice exhibited significantly more IgG extravasation in the cortex denoting a potentiation of blood-brain barrier damage. Despite robust injury-induced astrogliosis and microgliosis, neither GFAP nor Iba1 immunostaining was further increased by hypertension. Microbleeds were observed more in the cortex and corpus callosum but much less in the hippocampi or thalami after injury and were equivalent in hypertensive and normotensive injured mice. This study contributes to laying the groundwork of identifying and characterizing hypertension as a significant premorbid risk factor for poor outcome after TBI and provides a logical basis for incorporation of pre-existing hypertension in preclinical models of TBI, increasing their clinical relevance and predictive validity.

Treating Traumatic Brain Injury with Minocycline

Traumatic brain injury (TBI) is a public health burden affecting millions of people. Sustained neuroinflammation after TBI is often associated with poor outcome. As a result, increased attention has been placed on the role of immune cells in post-injury recovery. Microglia are highly dynamic after TBI and play a key role in the post-injury neuroinflammatory response. Therefore, microglia represent a malleable post-injury target that could substantially influence long-term outcome after TBI. This review highlights the cell specific role of microglia in TBI pathophysiology. Microglia have been manipulated via genetic deletion, drug inhibition, and pharmacological depletion in various pre-clinical TBI models. Notably, colony stimulating factor 1 (CSF1) and its receptor (CSF1R) have gained much traction in recent years as a pharmacological target on microglia. CSF1R is a transmembrane tyrosine kinase receptor that is essential for microglia proliferation, differentiation, and survival. Small molecule inhibitors targeting CSF1R result in a swift and effective depletion of microglia in rodents. Moreover, discontinuation of the inhibitors is sufficient for microglia repopulation. Attention is placed on summarizing studies that incorporate CSF1R inhibition of microglia. Indeed, microglia depletion affects multiple aspects of TBI pathophysiology, including neuroinflammation, oxidative stress, and functional recovery with measurable influence on astrocytes, peripheral immune cells, and neurons. Taken together, the data highlight an important role for microglia in sustaining neuroinflammation and increasing risk of oxidative stress, which lends to neuronal damage and behavioral deficits chronically after TBI. Ultimately, the insights gained from CSF1R depletion of microglia are critical for understanding the temporospatial role that microglia develop in mediating TBI pathophysiology and recovery.

Traumatic brain injury (TBI) represents physical damage to the brain tissue that induces transitory or permanent neurological disabilities. TBI contributes to 50% of all trauma deaths, with many enduring long-term consequences and significant medical and rehabilitation costs. There is currently no therapy to reverse the effects associated with TBI. An increasing amount of research has been undertaken regarding the use of different stem cells (SCs) to treat the consequences of brain damage. Neural stem cells (NSCs) (adult and embryonic) and mesenchymal stromal cells (MSCs) have shown efficacy in pre-clinical models of TBI and in their introduction to clinical research. The purpose of this review is to provide an overview of TBI and the state of clinical trials aimed at evaluating the use of stem cell-based therapies in TBI. The primary aim of these studies is to investigate the safety and efficacy of the use of SCs to treat this disease. Although an increasing number of studies are being carried out, few results are currently available. In addition, we present our research regarding the use of cell therapy in TBI. There is still a significant lack of understanding regarding the cell therapy mechanisms for the treatment of TBI. Thus, future studies are needed to evaluate the feasibility of the transplantation of SCs in TBI.

Traumatic brain injury (TBI) is a leading cause of disability and death from trauma to central nervous system (CNS) tissues. For patients who survive the initial injury, TBI can lead to neurodegeneration as well as cognitive and motor deficits, and is even a risk factor for the future development of neurodegenerative disorders such as Alzheimer's disease. Preclinical studies of multiple neuropathological and neurodegenerative disorders have shown that lithium, which is primarily used to treat bipolar disorder, has considerable neuroprotective effects. Indeed, emerging evidence now suggests that lithium can also mitigate neurological deficits incurred from TBI. Lithium exerts neuroprotective effects and stimulates neurogenesis via multiple signaling pathways; it inhibits glycogen synthase kinase-3 (GSK-3), upregulates neurotrophins and growth factors (e.g., brain-derived neurotrophic factor (BDNF)), modulates inflammatory molecules, upregulates neuroprotective factors (e.g., B-cell lymphoma-2 (Bcl-2), heat shock protein 70 (HSP-70)), and concomitantly downregulates pro-apoptotic factors. In various experimental TBI paradigms, lithium has been shown to reduce neuronal death, microglial activation, cyclooxygenase-2 induction, amyloid-β (Aβ), and hyperphosphorylated tau levels, to preserve blood-brain barrier integrity, to mitigate neurological deficits and psychiatric disturbance, and to improve learning and memory outcome. Given that lithium exerts multiple therapeutic effects across an array of CNS disorders, including promising results in preclinical models of TBI, additional clinical research is clearly warranted to determine its therapeutic attributes for combating TBI. Here, we review lithium's exciting potential in ameliorating physiological as well as cognitive deficits induced by TBI.

Hypotension and hypoxemia worsen traumatic brain injury outcomes. Hyperoxic resuscitation is controversial. The authors proposed that hyperoxia would improve hemodynamics and neuronal survival by augmenting oxygen delivery despite increased oxidative stress and neuroinflammation in experimental combined controlled cortical impact plus hemorrhagic shock in mice. Adult C57BL6 mice received controlled cortical impact followed by 35 min of hemorrhagic shock (mean arterial pressure, 25-27 mmHg). The resuscitation phase consisted of lactated Ringer's boluses titrated to mean arterial pressure greater than 70 mmHg. Definitive care included returning shed blood. Either oxygen or room air was administered during the resuscitation phases. Brain tissue levels of oxidative stress and inflammatory markers were measured at 24 h and hippocampal neuronal survival was quantified at 7 days. Hyperoxia markedly increased brain tissue oxygen tension approximately four- to fivefold (n = 8) and reduced resuscitation fluid requirements approximately 15% (n = 53; both P < 0.05). Systemic and cerebral physiologic variables were not significantly affected by hyperoxia. Hippocampal neuron survival was approximately 40% greater with oxygen versus room air (n = 18, P = 0.03). However, ascorbate depletion doubled with oxygen versus room air (n = 11, P < 0.05). Brain tissue cytokines and chemokines were increased approximately 2- to 20-fold (n = 10) after combined controlled cortical impact injury plus hemorrhagic shock, whereas hyperoxia shifted cytokines toward a proinflammatory profile. Hyperoxic resuscitation of cortical impact plus hemorrhagic shock reduced fluid requirements and increased brain tissue oxygen tension and hippocampal neuronal survival but exacerbated ascorbate depletion and neuroinflammation. The benefits of enhanced oxygen delivery during resuscitation of traumatic brain injury may outweigh detrimental increases in oxidative stress and neuroinflammation.

Traumatic brain injury (TBI) is a primary global health concern, leading to long-term cognitive, neurological, and functional impairments. Secondary injury mechanisms, including excitotoxicity, oxidative stress, apoptosis, and neuroinflammation, contribute substantially to poor outcomes. Neuroprotective interventions that target these mechanisms are urgently needed. Xenon gas has emerged as a promising candidate due to its unique neuroprotective properties, including modulation of the N-methyl-D-aspartate (NMDA) receptor, anti-apoptotic effects, and anti-inflammatory actions. This narrative review critically evaluates Xenon gas as a neuroprotective intervention in TBI. A narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify studies evaluating Xenon gas as a neuroprotective agent in TBI. Search terms included “Xenon,” “neuroprotection,” and “traumatic brain injury,” including both in vivo and in vitro studies. Articles published in English without date restrictions were considered. Data were synthesized qualitatively, emphasizing experimental outcomes, mechanisms, and innovative delivery approaches. Preclinical studies consistently demonstrate that Xenon gas reduces neuronal injury, mitigates neuroinflammation, preserves cognitive and motor function, and improves survival in animal and in vitro models of TBI. Innovative delivery strategies, such as microbubbles and ultrasound-mediated delivery, allow for targeted cerebral administration and enhance therapeutic efficacy. Across studies, Xenon was generally well-tolerated, with minimal adverse effects reported. No clinical trials in human TBI patients were identified, highlighting a significant translational gap. Xenon gas exhibits multifaceted neuroprotective effects in preclinical TBI models, suggesting significant therapeutic potential. Its mechanisms of action, safety profile, and innovative delivery strategies support further investigation. However, rigorous clinical trials are needed to evaluate efficacy, optimize dosing and administration, and determine real-world applicability in human TBI patients. Addressing these gaps is crucial for translating Xenon therapy from the bench to the bedside.

Measures of absolute and relative growth modulation were used to determine the effects of static and dynamic asymmetric loading of vertebrae in the rat tail. To quantify the differences between static and dynamic asymmetric loading in vertebral bone growth modulation. The creation and correction of vertebral wedge deformities have been previously described in a rat-tail model using static loading. The effects of dynamic loading on growth modulation in the spine have not been characterized. A total of 36 immature Sprague-Dawley rats were divided among four different groups: static loading (n = 12, 0.0 Hz), dynamic loading (n = 12, 1.0 Hz), sham operated (n = 6), and growth controls (n = 6). An external fixator was placed across the sixth and eighth caudal vertebrae as the unviolated seventh caudal vertebra was evaluated for growth modulation. Static or dynamic asymmetric loads were applied at a loading magnitude of 55% body weight. After 3 weeks of loading, growth modulation was assessed using radiographic measurements of vertebral wedge angles and vertebral body heights. The dynamically loaded rats had a final average wedge deformity of 15.2+/- 6.4 degrees, which was significantly greater than the statically loaded rats whose final deformity averaged 10.3 degrees +/- 3.7 degrees (P < 0.03). The deformity in both groups was statistically greater than the sham-operated (1.1+/- 2.0 degrees) and growth control rats (0.0+/- 1.0 degrees) (P < 0.001). The longitudinal growth was significantly lower on the concavity compared with the convexity in both the dynamically (0.34 +/- 0.23 mm vs. 0.86 +/- 0.23 mm) and statically (0.46 +/- 0.19 mm vs. 0.83 +/- 0.32 mm) loaded rats (P < 0.001). These growth rates were significantly less than the sham operated and growth control rats (P < 0.001). A variety of fusionless scoliosis implant strategies have been proposed that use both rigid and flexible implants to modulate vertebral bone growth. The results from this study demonstrate that dynamic loading of the vertebrae provides the greatest growth modulation potential.

Mesenchymal stromal cells (MSCs) are widely used in preclinical models of traumatic brain injury (TBI). Results are promising in terms of neurological improvement but are hampered by wide variability in treatment responses. We made a systematic review and meta-analysis: (1) to assess the quality of evidence for MSC treatment in TBI rodent models; (2) to determine the effect size of MSCs on sensorimotor function, cognitive function, and anatomical damage; (3) to identify MSC-related and protocol-related variables associated with greater efficacy; (4) to understand whether MSC manipulations boost therapeutic efficacy. The meta-analysis included 80 studies. After TBI, MSCs improved sensorimotor and cognitive deficits and reduced anatomical damage. Stratified meta-analysis on sensorimotor outcome showed similar efficacy for different MSC sources and for syngeneic or xenogenic transplants. Efficacy was greater when MSCs were delivered in the first-week post-injury, and when implanted directly into the lesion cavity. The greatest effect size was for cells embedded in matrices or for MSC-derivatives. MSC therapy is effective in preclinical TBI models, improving sensorimotor, cognitive, and anatomical outcomes, with large effect sizes. These findings support clinical studies in TBI.