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Hippocampal dysfunction contributes to multiple traumatic brain injury sequala. Female rodents' outcome is superior to male which has been ascribed the neuroprotective sex hormones 17β-estradiol and progesterone. Cytochrome P450 1B1 (CYP1B1) is an oxidative enzyme influencing the neuroinflammatory response by creating inflammatory mediators and metabolizing neuroprotective 17β-estradiol and progesterone. In this study, we aimed to describe hippocampal CYP1B1 mRNA expression, protein presence of CYP1B1 and its key redox partner Cytochrome P450 reductase (CPR) in both sexes, as well as the effect of penetrating traumatic brain injury (pTBI). A total 64 adult Sprague Dawley rats divided by sex received pTBI or sham-surgery and were assigned survival times of 1-, 3-, 5- or 7 days. CYP1B1 mRNA was quantified using in-situ hybridization and immunohistochemistry performed to verify protein colocalization. CYP1B1 mRNA expression was present in all subregions but greatest in CA2 irrespective of sex, survival time or intervention. At 3-, 5- and 7 days post-injury, expression in CA2 was reduced in male rats subjected to pTBI compared to sham-surgery. Females subjected to pTBI instead exhibited increased expression in all CA subregions 3 days post-injury, the only time point expression in CA2 was greater in females than in males. Immunohistochemical analysis confirmed neuronal CYP1B1 protein in all hippocampal subregions, while CPR was limited to CA1 and CA2. CYP1B1 mRNA is constitutively expressed in both sexes. In response to pTBI, females displayed a more urgent but brief regulatory response than males. This indicates there may be sex-dependent differences in CYP1B1 activity, possibly influencing inflammation and neuroprotection in pTBI.

Because traumatic brain injury (TBI)-most often caused by exposure to high-level blast (HLB)-is a leading cause of medical evacuations of deployed U.S. service members in recent conflicts, researchers seek to identify risk factors for TBI. Previous research using self-reported data has identified low-level blast (LLB) as one such risk factor and suggests an association with susceptibility to and symptoms associated with TBI. This article presents a population-based study of all branches of military service that examines the association between occupational risk for LLB and both clinically diagnosed TBIs-from concussions to severe and penetrating TBIs-and conditions commonly comorbid with concussion. Using archival medical and career records from >2 million service members between 2005-2015, this work demonstrates that occupational risk of LLB is associated with any TBI, mild TBI, moderate TBI, cognitive problems, communication problems, hearing problems, headaches, any behavioral health condition, anxiety, drug abuse/dependence, alcohol abuse/dependence, delirium/dementia, posttraumatic stress disorder, post-concussive syndrome, tinnitus, fatigue, and migraines. Understanding the full scope of the effects of LLB on service members will help ensure the health and readiness of service members and may influence both military policy and clinical practice guidelines for blast-induced injuries.

Androgens have been shown to have a beneficial effect on brain injury and lower reactive astrocyte expression after TBI. Androgen receptors (ARs) are known to mediate the neuroprotective effects of androgens. However, whether ARs play a crucial role in TBI remains unknown. In this study, we investigated the role of ARs in TBI pathophysiology, using AR knockout (ARKO) mice. We used the controlled cortical impact model to produce primary and mechanical brain injuries and assessed motor function and brain-lesion volume. In addition, the AR knockout effects on necrosis and autophagy were evaluated after TBI. AR knockout significantly increased TBI-induced expression of the necrosis marker alpha-II-spectrin breakdown product 150 and astrogliosis marker glial fibrillary acidic protein. In addition, the TBI-induced astrogliosis increase in ARKO mice lasted for three weeks after a TBI. The autophagy marker Beclin-1 was also enhanced in ARKO mice compared with wild-type mice after TBI. Our results also indicated that ARKO mice showed a more unsatisfactory performance than wild-type mice in a motor function test following TBI. Further, they were observed to have more severe lesions than wild-type mice after injury. These findings strongly suggest that ARs play a role in TBI.

This study aimed to assess the neuro-regenerative properties of co-ultramicronized PEALut (Glialia ® ), composed of palmitoylethanolamide (PEA) and the flavonoid luteolin (Lut), in an in vivo model of traumatic brain injury (TBI) and patients affected by moderate TBI. An increase in neurogenesis was seen in the mice at 72 h and 7 d after TBI. The co-ultra PEALut treatment helped the neuronal reconstitution process to restore the basal level of both novel and mature neurons; moreover, it induced a significant upregulation of the neurotrophic factors, which ultimately led to progress in terms of memory recall during behavioral testing. Moreover, our preliminary findings in a clinical trial suggested that Glialia ® treatment facilitated neural recovery on working memory. Thus, co-ultra PEALut (Glialia ® ) could represent a valuable therapeutic agent for intensifying the endogenous repair response in order to better treat TBI.

While sudden loss of perfusion is responsible for ischemia, failure to supply the required amount of oxygen to the tissues is defined as hypoxia. Among several pathological conditions that can impair brain perfusion and oxygenation, cardiocirculatory arrest is characterized by a complete loss of perfusion to the brain, determining a whole brain ischemic-anoxic injury. Differently from other threatening situations of reduced cerebral perfusion, i.e., caused by increased intracranial pressure or circulatory shock, resuscitated patients after a cardiac arrest experience a sudden restoration of cerebral blood flow and are exposed to a massive reperfusion injury, which could significantly alter cellular metabolism. Current evidence suggests that cell populations in the central nervous system might use alternative metabolic pathways to glucose and that neurons may rely on a lactate-centered metabolism. Indeed, lactate does not require adenosine triphosphate (ATP) to be oxidated and it could therefore serve as an alternative substrate in condition of depleted energy reserves, i.e., reperfusion injury, even in presence of adequate tissue oxygen delivery. Lactate enriched solutions were studied in recent years in healthy subjects, acute heart failure, and severe traumatic brain injured patients, showing possible benefits that extend beyond the role as alternative energetic substrates. In this manuscript, we addressed some key aspects of the cellular metabolic derangements occurring after cerebral ischemia-reperfusion injury and examined the possible rationale for the administration of lactate enriched solutions in resuscitated patients after cardiac arrest., Competing Interests: All authors declare not to have any conflict of interest regarding the manuscript.

Cytokines are important neuroinflammatory modulators in neurodegenerative brain disorders including traumatic brain injury (TBI) and stroke. However, their temporal effects on the physiological properties of microglia and neurons during the recovery period have been unclear. Here, using an ATP-induced cortical injury model, we characterized selective effects of ATP injection compared to needle-control. In the damaged region, the fluorescent intensity of CX 3 CR1-GFP (+) cells, as well as the cell density, was increased and the maturation of newborn BrdU (+) cells continued until 28 day-post-injection (dpi) of ATP. The excitability and synaptic E/I balance of neurons and the inward and outward membrane currents of microglia were increased at 3 dpi, when expressions of tumor necrosis factor (TNF)-α/interleukin (IL)-1β and IL-10/IL-4 were also enhanced. These changes of both cells at 3 dpi were mostly decayed at 7 dpi and were suppressed by any of IL-10, IL-4, suramin (P2 receptor inhibitor) and 4-AP (K + channel blocker). Acute ATP application alone induced only small effects from both naïve neurons and microglial cells in brain slice. However, TNF-α alone effectively increased the excitability of naïve neurons, which was blocked by suramin or 4-AP. TNF-α and IL-1β increased and decreased membrane currents of naïve microglia, respectively. Our results suggest that ATP and TNF-α dominantly induce the physiological activities of 3 dpi neurons and microglia, and IL-10 effectively suppresses such changes of both activated cells in K + channel- and P2 receptor-dependent manner, while IL-4 suppresses neurons preferentially.

The secondary injury process after traumatic brain injury (TBI) results in motor dysfunction, cognitive and emotional impairment, and poor outcomes. These injury cascades include excitotoxic injury, mitochondrial dysfunction, oxidative stress, ion imbalance, inflammation, and increased vascular permeability. Electron microscopy is an irreplaceable tool to understand the complex pathogenesis of TBI as the secondary injury is usually accompanied by a series of pathologic changes at the ultra-micro level of the brain cells. These changes include the ultrastructural changes in different parts of the neurons (cell body, axon, and synapses), glial cells, and blood-brain barrier, etc. In view of the current difficulties in the treatment of TBI, identifying the changes in subcellular structures can help us better understand the complex pathologic cascade reactions after TBI and improve clinical diagnosis and treatment. The purpose of this review is to summarize and discuss the ultrastructural changes related to neurons (e.g., condensed mitochondrial membrane in ferroptosis), glial cells, and blood-brain barrier in the existing reports of TBI, to deepen the in-depth study of TBI pathomechanism, hoping to provide a future research direction of pathogenesis and treatment, with the ultimate aim of improving the prognosis of patients with TBI.

Traumatic brain injury (TBI), also known as intracranial injury, occurs when an external force injures the brain. This study aimed to analyze the factors affecting the presence of TBI in the elderly occupants of motor vehicle crashes. We defined elderly occupants as those more than 55 years old. Damage to the vehicle was presented using the Collision Deformation Classification (CDC) code by evaluation of photos of the damaged vehicle, and a trauma score was used for evaluation of the severity of the patient's injury. A logistic regression model was used to identify factors affecting TBI in elderly occupants and a predictive model was constructed. We performed this study retrospectively and gathered all the data under the Korean In-Depth Accident Study (KIDAS) investigation system. Among 3697 patients who visited the emergency room in the regional emergency medical center due to motor vehicle crashes from 2011 to 2018, we analyzed the data of 822 elderly occupants, which were divided into two groups: the TBI patients (N = 357) and the non-TBI patients (N = 465). According to multiple logistic regression analysis, the probabilities of TBI in the elderly caused by rear-end (OR = 1.833) and multiple collisions (OR = 1.897) were higher than in frontal collision. Furthermore, the probability of TBI in the elderly was 1.677 times higher in those with unfastened seatbelts compared to those with fastened seatbelts (OR = 1.677). This study was meaningful in that it incorporated several indicators that affected the occurrence of the TBI in the elderly occupants. In addition, it was performed to determine the probability of TBI according to sex, vehicle type, seating position, seatbelt status, collision type, and crush extent using logistic regression analysis. In order to derive more precise predictive models, it would be needed to analyze more factors for vehicle damage, environment, and occupant injury in future studies.

Although traumatic brain injury (TBI) causes hospitalizations and mortality worldwide, there are no approved neuroprotective treatments, partly due to a poor understanding of the molecular mechanisms underlying TBI neuropathology and neuroprotection. We previously reported that the administration of low-dose methamphetamine (MA) induced significant functional/cognitive improvements following severe TBI in rats. We further demonstrated that MA mediates neuroprotection in part, via dopamine-dependent activation of the PI3K-AKT pathway. Here, we further investigated the proteomic changes within the rat cortex and hippocampus following mild TBI (TM), severe TBI (TS), or severe TBI plus MA treatment (TSm) compared to sham operated controls. We identified 402 and 801 altered proteins (APs) with high confidence in cortical and hippocampal tissues, respectively. The overall profile of APs observed in TSm rats more closely resembled those seen in TM rather than TS rats. Pathway analysis suggested beneficial roles for acute signaling through IL-6, TGFβ, and IL-1β. Moreover, changes in fibrinogen levels observed in TSm rats suggested a potential role for these proteins in reducing/preventing TBI-induced coagulopathies. These data facilitate further investigations to identify specific pathways and proteins that may serve as key targets for the development of neuroprotective therapies.

Traumatic brain injury (TBI) modelled by lateral fluid percussion-induction (LFPI) in rats is a widely used experimental rodent model to explore and understand the underlying cellular and molecular alterations in the brain caused by TBI in humans. Current improvements in imaging with positron emission tomography (PET) have made it possible to map certain features of TBI-induced cellular and molecular changes equally in humans and animals. The PET imaging technique is an apt supplement to nanotheranostic-based treatment alternatives that are emerging to tackle TBI. The present study aims to investigate whether the two radioligands, [ 11 C]PBR28 and [ 18 F]flumazenil, are able to accurately quantify in vivo molecular-cellular changes in a rodent TBI-model for two different biochemical targets of the processes. In addition, it serves to observe any palpable variations associated with primary and secondary injury sites, and in the affected versus the contralateral hemispheres. As [ 11 C]PBR28 is a radioligand of the 18 kD translocator protein, the up-regulation of which is coupled to the level of neuroinflammation in the brain, and [ 18 F]flumazenil is a radioligand for GABA A -benzodiazepine receptors, whose level mirrors interneuronal activity and eventually cell death, the use of the two radioligands may reveal two critical features of TBI. An up-regulation in the [ 11 C]PBR28 uptake triggered by the LFP in the injured (right) hemisphere was noted on day 14, while the uptake of [ 18 F]flumazenil was down-regulated on day 14. When comparing the left (contralateral) and right (LFPI) hemispheres, the differences between the two in neuroinflammation were obvious. Our results demonstrate a potential way to measure the molecular alterations in a rodent-based TBI model using PET imaging with [ 11 C]PBR28 and [ 18 F]flumazenil. These radioligands are promising options that can be eventually used in exploring the complex in vivo pharmacokinetics and delivery mechanisms of nanoparticles in TBI treatment.

Traumatic brain injury (TBI) is a relatively common occurrence following accidents or violence, and often results in long-term cognitive or motor disability. Despite the high health cost associated with this type of injury, presently there are no effective treatments for many neurological symptoms resulting from TBI. This is due in part to our limited understanding of the mechanisms underlying brain dysfunction after injury. In this study, we used the mouse controlled cortical impact (CCI) model to investigate the effects of TBI, and focused on Reelin, an extracellular protein that critically regulates brain development and modulates synaptic activity in the adult brain. We found that Reelin expression decreases in forebrain regions after TBI, and that the number of Reelin-expressing cells decrease specifically in the hippocampus, an area of the brain that plays an important role in learning and memory. We also conducted in vitro experiments using mouse neuronal cultures and discovered that Reelin protects hippocampal neuronal cells from glutamate-induced neurotoxicity, a well-known secondary effect of TBI. Together our findings suggest that the loss of Reelin expression may contribute to neuronal death in the hippocampus after TBI, and raise the possibility that increasing Reelin levels or signaling activity may promote functional recovery., Competing Interests: The authors declare no conflict of interest.

Mesenchymal stem cells (MSCs) are emerging as an attractive approach for restorative medicine in central nervous system (CNS) diseases and injuries, such as traumatic brain injury (TBI), due to their relatively easy derivation and therapeutic effect following transplantation. However, the long-term survival of the grafted cells and therapeutic efficacy need improvement. Here, we review the recent application of MSCs in TBI treatment in preclinical models. We discuss the genetic modification approaches designed to enhance the therapeutic potency of MSCs for TBI treatment by improving their survival after transplantation, enhancing their homing abilities and overexpressing neuroprotective and neuroregenerative factors. We highlight the latest preclinical studies that have used genetically modified MSCs for TBI treatment. The recent developments in MSCs' biology and potential TBI therapeutic targets may sufficiently improve the genetic modification strategies for MSCs, potentially bringing effective MSC-based therapies for TBI treatment in humans.

Traumatic brain injury (TBI) is among the most pressing global health issues and prevalent causes of cerebrovascular and neurological disorders all over the world. In addition to the brain injury, TBI may also alter the systemic immune response. Thus, TBI patients become vulnerable to infections, have worse neurological outcomes, and exhibit a higher rate of mortality and morbidity. It is well established that brain injury leads to impairments of the blood-brain barrier (BBB) integrity and function, contributing to the loss of neural tissue and affecting the response to neuroprotective drugs. Thus, stabilization/protection of the BBB after TBI could be a promising strategy to limit neuronal inflammation, secondary brain damage, and acute neurodegeneration. Herein, we present a review highlighting the significant post-traumatic effects of TBI on the cerebrovascular system. These include the loss of BBB integrity and selective permeability, impact on BBB transport mechanisms, post-traumatic cerebral edema formation, and significant pathophysiological factors that may further exacerbate post-traumatic BBB dysfunctions. Furthermore, we discuss the post-traumatic impacts of chronic smoking, which has been recently shown to act as a premorbid condition that impairs post-TBI recovery. Indeed, understanding the underlying molecular mechanisms associated with TBI damage is essential to better understand the pathogenesis and progression of post-traumatic secondary brain injury and the development of targeted treatments to improve outcomes and speed up the recovery process. Therapies aimed at restoring/protecting the BBB may reduce the post-traumatic burden of TBI by minimizing the impairment of brain homeostasis and help to restore an optimal microenvironment to support neuronal repair.

This study is aimed at investigating the influence of skull fractures on traumatic brain injury induced by blunt impact via numerous studies of head-ground impacts. First, finite element (FE) damage modeling was implemented in the skull of the Total HUman Model for Safety (THUMS), and the skull fracture prediction performance was validated against a head-ground impact experiment. Then, the original head model of the THUMS was assigned as the control model without skull element damage modeling. Eighteen (18) head-ground impact models were established using these two FE head models, with three head impact locations (frontal, parietal, and occipital regions) and three impact velocities (25, 35, and 45 km/h). The predicted maximum principal strain and cumulative strain damage measure of the brain tissue were employed to evaluate the effect of skull fracture on the cerebral contusion and diffuse brain injury risks, respectively. Simulation results showed that the skull fracture could reduce the risk of diffuse brain injury risk under medium and high velocities significantly, while it could increase the risk of brain contusion under high-impact velocity.