Early Stage Of Traumatic Brain Injury Research Articles

Edaravone Alleviates Traumatic Brain Injury by Inhibition of Ferroptosis via FSP1 Pathway.

Traumatic brain injury (TBI) is a highly severe form of trauma with complex series of reactions in brain tissue which ultimately results in neuronal damage. Previous studies proved that neuronal ferroptosis, which was induced by intracranial haemorrhage and other reasons, was one of the most primary causes of neuronal damage following TBI. However, the association between neuronal mechanical injury and ferroptosis in TBI and relevant treatments remain unclear. In the present study, we first demonstrated the occurrence of neuronal ferroptosis in the early stage of TBI and preliminarily elucidated that edaravone (EDA), a cerebroprotective agent that eliminates oxygen radicals, was able to inhibit ferroptosis induced by TBI. A cell scratching model was established in PC12 cells, and it was confirmed that mechanical injury induced ferroptosis in neurons at the early stage of TBI. Ferroptosis suppressor protein 1 (FSP1) plays a significant role in inhibiting ferroptosis, and we found that iFSP, a ferroptosis agonist which is capable to inhibit FSP1 pathway, attenuated the anti-ferroptosis effect of EDA. In conclusion, our results suggested that EDA inhibited neuronal ferroptosis induced by mechanical injury in the early phase of TBI by activating FSP1 pathway, which could provide evidence for future research on prevention and treatment of TBI.

Effect of Bevacizumab on traumatic penumbra brain edema in rats at different time points

ABSTRACT Traumatic penumbra (TP) is a secondary injury area located around the core area of traumatic brain injury after brain trauma, and is an important factor affecting the outcome of traumatic brain injury (TBI). The main pathological change caused by TP is brain edema, including (cellular brain edema and vascular brain edema). The formation and development of brain edema in the TP area are closely related to the blood-brain barrier (BBB) and vascular endothelial growth factor (VEGF). VEGF is a vascular permeability factor that can promote angiogenesis and increase BBB permeability, and there is a debate on the pros and cons of its role in early TBI. Therefore, in the early stage of TBI, when using the VEGF inhibitor bevacizumab to treat TP area brain edema, the timing of bevacizumab administration is particularly important, and there are currently no relevant literature reports. This article explores the treatment time window and optimal treatment time point of bevacizumab in the treatment of cerebral edema in the TP area by administering the same dose of bevacizumab at different time points after brain injury in rats. The results showed that there was traumatic brain edema in TP area, BBB structure and function were damaged, VEGF expression and angiogenesis were increased. Compared with TBI + NS Group, after Bevacizumab treatment, brain edema in TP area was alleviated, BBB structure and function were improved, VEGF expression and angiogenesis were decreased in each treatment group, and the effect of TBI + Bevacizumab 1 h group was the most significant. Bevacizumab can be used as a targeted therapy for traumatic brain edema. The therapeutic time window of bevacizumab for traumatic brain edema is within 12 hours after TBI, and 1 h is the optimal therapeutic time point.

Systemic Immune-Inflammation Index Predicts the Prognosis of Traumatic Brain Injury

ObjectiveSystemic inflammation following traumatic brain injury (TBI) has been extensively studied over the past decades, as it contributes significantly to the pathophysiological injury mechanisms and subsequent poor outcomes. Systemic immune-inflammation (SII) index is a novel biomarker of systemic inflammatory response. However, its predictive value regarding TBI prognosis in clinical practice remains insufficiently investigated. MethodsA total of 102 TBI patients admitted to Nanjing Drum Tower Hospital from July 2019 to February 2022 were enrolled. We employed various statistical analyses to evaluate the correlation between inflammatory indicators upon admission and patient prognosis, compared the predictive accuracy of these indicators, and generated ROC analysis to test their prognostic performance. ResultsThe SII index, platelet count (PLT), absolute lymphocyte count (ALC), and neutrophil/lymphocyte ratio (NLR) were capable of distinguishing TBI prognosis according to univariate logistic regression models (P<0.05). Multivariate logistic regression models revealed that increased SII index, PLT, and NLR upon admission were independent predictors of poor TBI prognosis (P<0.05). ROC analysis further demonstrated that the SII index (AUC=0.845, 95% CI 0.769-0.921, P=0.000) exhibited higher predictive ability than the NLR (AUC=0.694, 95% CI 0.591-0.796, P=0.001). ConclusionsOur findings suggested that increased SII index during the early stages of TBI was an independent risk factor for poor prognosis with satisfactory predictive value. The SII index provides a reliable, convenient, and cost-effective prognostic model to evaluate systemic inflammation after TBI and identify patients at risk of poor outcomes, thereby offering valuable guidance for clinical practice.

Overexpression of GPX4 attenuates cognitive dysfunction through inhibiting hippocampus ferroptosis and neuroinflammation after traumatic brain injury.

Ferroptosis is a newly discovered form of regulated cell death that is triggered primarily by lipid peroxidation. A growing body of evidence has implicated ferroptosis in the pathophysiology of traumatic brain injury (TBI). However, none of these studies focused its role on TBI-induced hippocampal injury. Here, we demonstrated that the distinct ferroptotic signature was detected in the injured hippocampus at the early stage of TBI. Besides, a prominent pro-ferroptosis environment was detected in the ipsilateral hippocampus after TBI, including elevated levels of arachidonic acid (AA), ACLS4, and ALXO15, and deficiency of GPX4. Subsequently, we used AAV-mediated Gpx4 overexpression to counteract ferroptosis in the hippocampus, and found that TBI-induced cognitive deficits were significantly alleviated after Gpx4 overexpression. Biochemical results also confirmed that TBI-induced hippocampal ferroptosis and synaptic damage were partially reversed by Gpx4 overexpression. In addition, Gpx4 overexpression inhibited TBI-induced neuroinflammation and peripheral macrophage infiltration. Interestingly, the results of transwell migration assay showed that ferroptotic neurons increased CCL2 expression and promoted iBMDM cell migration. However, this effect was inhibited by CCL2 antagonist, RS102895. These data suggested that inhibition of ferroptosis may be as a potential strategy to ameliorate TBI-induced cognitive deficits through blockade of hippocampal ferroptosis and neuroinflammation.

Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis.

Posttraumatic epilepsy (PTE) is one of the most critical complications of traumatic brain injury (TBI), significantly increasing TBI patients' neuropsychiatric symptoms and mortality. The abnormal accumulation of glutamate caused by TBI and its secondary excitotoxicity are essential reasons for neural network reorganization and functional neural plasticity changes, contributing to the occurrence and development of PTE. Restoring glutamate balance in the early stage of TBI is expected to play a neuroprotective role and reduce the risk of PTE. To provide a neuropharmacological insight for drug development to prevent PTE based on regulating glutamate homeostasis. We discussed how TBI affects glutamate homeostasis and its relationship with PTE. Furthermore, we also summarized the research progress of molecular pathways for regulating glutamate homeostasis after TBI and pharmacological studies aim to prevent PTE by restoring glutamate balance. TBI can lead to the accumulation of glutamate in the brain, which increases the risk of PTE. Targeting the molecular pathways affecting glutamate homeostasis helps restore normal glutamate levels and is neuroprotective. Taking glutamate homeostasis regulation as a means for new drug development can avoid the side effects caused by direct inhibition of glutamate receptors, expecting to alleviate the diseases related to abnormal glutamate levels in the brain, such as PTE, Parkinson's disease, depression, and cognitive impairment. It is a promising strategy to regulate glutamate homeostasis through pharmacological methods after TBI, thereby decreasing nerve injury and preventing PTE.

Effects of apolipoprotein E polymorphism on cerebral oxygen saturation, cerebral perfusion, and early prognosis after traumatic brain injury.

To investigate the effects of the apolipoprotein E (APOE) gene on oxygen saturation and cerebral perfusion in the early stages of traumatic brain injury (TBI). This study included 136 consecutive TBI patients and 51 healthy individuals. The APOE genotypes of all subjects were determined using quantitative fluorescence polymerase chain reaction (QF-PCR). Regional cerebral oxygen saturation (rScO2) of patients with TBI and normal subjects was monitored using near-infrared spectroscopy (NIRS). Computed tomography (CT) perfusion was used to obtain cerebral perfusion in patientswith TBI and normal subjects. In the TBI group, the rScO2 of APOEε4 carriers (53.06 ± 6.87%) was significantly lower than that of non-carriers (58.19 ± 5.83%, p < 0.05). Meanwhile, the MTT of APOEε4 carriers (6.75 ± 1.30 s) was significantly longer than that of non-carriers (5.87 ± 1.00 s, p < 0.05). Furthermore, correlation analysis showed a negative correlation between rSCO2 and MTT in patients with TBI. Both the univariate and multifactorial logistic regression analyses revealed that APOE ε4, hypoxia, MTT >5.75 s, Marshall CT Class, and GCS were independent risk factors for early poor prognosis in patients with TBI. Both cerebral perfusion and cerebral oxygen were significantly impaired after TBI, and low cerebral perfusion and hypoxia were related to poor prognosis of patients with TBI. Compared with APOE ε4 non-carriers, APOE ε4 carriers not only had poorer cerebral perfusion and cerebral oxygen metabolism but also worse prognosis in the early stages of TBI. Furthermore, a negative correlation was observed between the rSCO2 and MTT levels. In addition, both CT perfusion scanning (CTP) and NIRS are reliable for monitoring the condition of patients with TBI in the neurological intensive care unit (NICU).

Antioxidant and neuroprotective effects of dexpanthenol in rats induced with traumatic brain injury

Trauma-induced primary damage is followed by secondary damage, exacerbating traumatic brain injury (TBI). Dexpanthenol has been shown to protect tissues against oxidative damage in various inflammation models. This study aimed to investigate possible antioxidant and neuroprotective effects of dexpanthenol in TBI.Wistar albino male rats were randomly assigned to control (n = 16), trauma (n = 16) and dexpanthenol (500 mg/kg; n = 14) groups. TBI was induced under anesthesia by dropping a 300 g weight from 70-cm height onto the skulls of the rats. Twenty-four hours after the trauma, the rats were decapitated and myeloperoxidase (MPO) levels, luminol- and lucigenin-enhanced chemiluminescence (CL), malondialdehyde (MDA) levels, superoxide dismutase (SOD) levels, and catalase (CAT) and caspase-3 activities were measured in brain tissues. Following transcardiac paraformaldehyde perfusion, histopathological damage was graded on hematoxylin-eosin-stained brain tissues.In the trauma group, MPO level, caspase-3 activity and luminol-lucigenin CL levels were elevated (p < 0.05–0.001) when compared to controls; meanwhile in the dexpanthenol group these increases were not seen (p < 0.05–0.001) and MDA levels were decreased (p < 0.05). Decreased SOD and CAT activities (p < 0.01) in the vehicle-treated TBI group were increased above control levels in the dexpanthenol group (p < 0.05–0.001). in the dexpanthenol group there was relatively less neuronal damage observed microscopically in the cortices after TBI.Dexpanthenol reduced oxidative damage, suppressed apoptosis by stimulating antioxidant systems and alleviated brain damage caused by TBI. Further experimental and clinical investigations are needed to confirm that dexpanthenol can be administered in the early stages of TBI.

The effects of early exercise in traumatic brain-injured rats with changes in motor ability, brain tissue, and biomarkers

Traumatic brain injury (TBI) is brain damage which is caused by the impact of external mechanical forces. TBI can lead to the temporary or permanent impairment of physical and cognitive abilities, resulting in abnormal behavior. We recently observed that a single session of early exercise in animals with TBI improved their behavioral performance in the absence of other cognitive abnormalities. In the present study, we investigated the therapeutic effects of continuous exercise during the early stages of TBI in rats. We found that continuous low-intensity exercise in early-stage improves the locomotion recovery in the TBI of animal models; however, it does not significantly enhance short-term memory capabilities. Moreover, continuous early exercise not only reduces the protein expression of cerebral damage-related markers, such as Glial Fibrillary Acid Protein (GFAP), Neuron-Specific Enolase (NSE), S100β, Protein Gene Products 9.5 (PGP9.5), and Heat Shock Protein 70 (HSP70), but it also decreases the expression of apoptosis-related protein BAX and cleaved caspase 3. Furthermore, exercise training in animals with TBI decreases the microglia activation and the expression of inflammatory cytokines in the serum, such as CCL20, IL-13, IL-1α, and IL-1β. These findings thus demonstrate that early exercise therapy for TBI may be an effective strategy in improving physiological function, and that serum protein levels are useful biomarkers for the predicition of the effectiveness of early exercise therapy.[BMB Reports 2022; 55(10): 506-511].

Reactive Oxygen Species Scavenging Functional Hydrogel Delivers Procyanidins for the Treatment of Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) is accompanied by the overload of reactive oxygen species (ROS), which can result in secondary brain injury. Although procyanidins (PCs) have a powerful free radical scavenging capability and have been widely studied in the treatment of TBI, conventional systemic drug therapy cannot make the drug reach the targeted area in the early stage of TBI and will cause systemic side effects because of the presence of the blood-brain barrier (BBB). To address this tissue, we designed and fabricated a ROS-scavenging functional hydrogel loaded PC (GelMA-PPS/PC) to deliver the drug by responding to the traumatic microenvironment. In situ injection of the GelMA-PPS/PC hydrogel effectively avoided the BBB and was directly applied to the surface of brain tissue to target the traumatic area. Hydrophobic poly(propylene sulfide)60 (PPS60), an ROS quencher and H2O2-responsive substance, was covalently bound to GelMA and exposed in response to the trauma microenvironment. At the same time, the H2O2 response of PPS60 further caused the structure of the hydrogel to degrade and release the encapsulated PC. Then PC could regulate the oxidative stress response in the cells and synergistically deplete ROS to play a neurotrophic protective role. This work suggests a novel method for the treatment of secondary brain injury by inhibiting the oxidative stress response after TBI.

Ferroptosis in brain microvascular endothelial cells mediates blood-brain barrier disruption after traumatic brain injury

Ferroptosis is a newly recognized form of regulated cell death. Recently, growing evidence has shown that ferroptosis is involved in the pathogenesis of traumatic brain injury (TBI). However, less attention has been paid to its role in brain microvascular endothelial cells (BMVECs) and blood-brain barrier (BBB) damage, the central pathological process in secondary brain injury of TBI. Here, we established a mechanical stretch injury bEnd.3 model and a Controlled Cortical Impact (CCI) mouse model to explore the ferroptosis-related markers in brain endothelial cells after TBI in vitro and in vivo. From the results of RNA-seq analysis, RT-qPCR and immunostaining, glutathione peroxidase 4 (GPX4) downregulation, Cyclooxygenase-2 (COX-2) upregulation, and iron accumulation were observed in brain endothelial cells after TBI both in vitro and in vivo. Furthermore, we utilized Ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, to investigate the protective effects of ferroptosis inhibition on BBB disruption and neurological deficits. From the results of immunostaining, transmission electron microscopy (TEM), and western blotting, we demonstrated that Fer-1 significantly reduced BMVECs death, BBB permeability, and tight junction loss at 3 days after TBI. The neurological tests including grid walking, rotarod test, and wire-hanging test showed that Fer-1 administration exerted neuroprotective effects in the early stage of TBI. Our findings provided evidences for inhibition of BMVECs ferroptosis as a promising therapeutic target against TBI-induced BBB disruption.

Left Ventricular Function in the Initial Period After Severe Traumatic Brain Injury in Swine.

Cardiac dysfunction is common in the days after severe traumatic brain injury (TBI) and may contribute to hypotension episodes, leading to worse outcomes. Little is known about cardiac function in the minutes and hours immediately following TBI. By using fluid percussion TBI in a swine model, we aimed to characterize the immediate post injury cardiac function. Intubated, anesthetized immature (25.8 ± 1.5kg) female swine were subjected to severe fluid percussion TBI (4.2 ± 0.2atm). Beginning at 45min, simulating hospital arrival, all animals were resuscitated with normal saline (NS), mannitol, and phenylephrine as needed to maintain a cerebral perfusion pressure more than 60mm Hg and intracranial pressure (ICP) less than 20mm Hg. Primary outcomes of cardiac function were cardiac output measured by thermodilution and transesophageal echo measurements of cardiac function recorded at prespecified time points and tested for trends over time using linear regression with spline at the time of resuscitation onset. Secondary outcomes included hemodynamic measurements, ICP, and cerebral perfusion pressure. Eighteen animals were included. Post-TBI hemodynamic changes demonstrated an early decrease in mean arterial pressure and cerebral perfusion pressure with a corresponding increase in heart rate and ICP. Immediately after injury, there was a significant decrease in both left atrial area and tissue Doppler imaging e' of the LV lateral wall. In addition, there was a simultaneous increase in LV end diastolic diameter and increase in E/e' ratio of the lateral mitral annulus. All other transesophageal echo measurements demonstrated no significant changes throughout the duration of the experiment. Traumatic brain injury is associated with cardiac dysfunction and increased mortality, however there is still a limited understanding of the hemodynamic and echocardiographic response associated with TBI. In this study we demonstrate the hemodynamic and echocardiographic changes in the early stages of TBI in swine. The authors hope that these results may help better understanding on the management of patients with severe head injury.

Melatonin attenuates repeated mild traumatic brain injury-induced cognitive deficits by inhibiting astrocyte reactivation

Melatonin has been well documented for its neuroprotective role through inhibiting oxidative stress against traumatic brain injury (TBI). However, the specific role of melatonin and the exact effects on cell responses (neurons, astrocytes, and microglia) in different brain regions are unclear. Here, we subjected mice to closed head injury, to establish a repeated mild TBI model and detect neuronal activity and glial responses in cognition-related brain regions after melatonin administration. Melatonin only showed cognitive enhancement if administered during early pathological stages, but not in late (chronic) stages. Additionally, we observed a significant increase in neuronal activity and inhibition of astrocyte reactivation in medial prefrontal cortex and hippocampus, but not in other cognitive deficit related brain regions. Furthermore, by activating astrocytes in these brain regions, we found neuronal activity upregulation and cognitive improvement following melatonin treatment. Therefore, we concluded that melatonin administration during the early stages of TBI is necessary to inhibit astrocyte reactivation and to promote cognitive function. Our results provide evidence for use of melatonin for cognitive improvement after TBIs.

Effects of Apolipoprotein E Polymorphism on Cerebral Oxygen Saturation After Traumatic Brain Injury.

Objective: To investigate the effects of the apolipoprotein E gene (APOE) on the cerebral oxygen saturation of patients after traumatic brain injury (TBI).Methods: Clinical data of 114 patients with TBI and 54 normal people were collected. The APOE genotypes of all subjects were determined by quantitative fluorescent polymerase chain reaction (QF-PCR). The regional cerebral oxygen saturation (rScO2) of TBI patients and normal people were monitored by near-infrared spectroscopy (NIRS).Results: The mean rScO2 of patients was (55.06 ± 7.60)% in the early stage of TBI, which was significantly lower than that of normal people (67.21 ± 7.80)% (P < 0.05). Single-factor and multifactor logistic regression analyses showed APOEε4 was an independent risk factor that caused the early decline of rScO2 in TBI patients. Furthermore, in the TBI group, the rScO2 of APOEε4 carriers (52.23 ± 8.02)% was significantly lower than that of non-ε4 carriers (60.33 ± 7.12)% (P < 0.05). But in the normal group, no significant differences in rScO2 were found between APOEε4 carriers and non-carriers.Conclusion: The rScO2 may be significantly decreased after TBI, and APOEε4 may be a risk factor for decreased rScO2 in the early stage of TBI.

Effect of AQP4-RNAi in treating traumatic brain edema: Multi-modal MRI and histopathological changes of early stage edema in a rat model.

Traumatic brain injury (TBI) is one of the leading causes of mortality and permanent disabilities worldwide. Brain edema following TBI remains to be the predominant cause of mortality and disability in patients worldwide. Previous studies have reported that brain edema is closely associated with aquaporin-4 (AQP4) expression. AQP4 is a water channel protein and mediates water homeostasis in a variety of brain disorders. In the current study, a rat TBI model was established, and the features of brain edema following TBI were assessed using multimodal MRI. The results of the multimodal MRI were useful, reliable and were used to evaluate the extent and the type of brain edema following TBI. Brain edema was also successfully alleviated using an intracerebral injection of AQP4 small interfering (si)RNA. The expression of AQP4 and its role in brain edema were also examined in the present study. The AQP4 siRNA was demonstrated to downregulate AQP4 expression following TBI and reduced brain edema at the early stages of TBI (6 and 12 h). The current study revealed the MRI features of brain edema and the changes in AQP4 expression exhibited following TBI, and the results provide important information that can be used to improve the early diagnosis and treatment of brain edema.

Research progress of reactive astrocytes transdifferentiation into neurons for repairing traumatic brain injury

Traumatic brain injury (TBI) is a central nervous system disease with increasing incidence, morbidity and mortality worldwide. TBI can affect the integrity of neuron, causing neuronal axons damage or death of neurons, which results in serious sequelae. After TBI, astrocytes (AST) in the cerebral cortex will be activated into reactive astrocytes (RAS). RAS in the early stage of TBI has a certain repair effect on the injury. However, RAS will proliferate to form glial scars, which has adverse effects on nerve function repair after injury. Therefore, controlling the status of RAS is the key to the treatment of TBI. In recent years, it has been proved that RAS can be transdifferentiated into neurons by transdifferentiation technology, which can not only remove glial scars, but also integrate with the micro-environment at the injury site to replace the injured neurons, which is of great significance for the repair of nerve function after TBI. This article reviews the types of transdifferentiation and the different pathways of RAS transdifferentiation into neurons, aiming to have a better understanding of the research progress of RAS transdifferentiation into neurons to repair TBI. Key words: Brain injuries; Astrocytes; Cell transdifferentiation; Nerve function

Early Intensified Rehabilitation Training with Hyperbaric Oxygen Therapy Improves Functional Disorders and Prognosis of Patients with Traumatic Brain Injury.

Objective: Traumatic brain injury (TBI) is a global public health problem. Hyperbaric oxygen (HBO) therapy may be beneficial for TBI because it improves cerebral blood flow into tissues exhibiting low blood flow. This was done to observe the clinical therapeutic effect of different intensities of rehabilitation training and HBO therapy in early stages of TBI.Approach: In this multicenter, randomized, stratified case-controlled prospective clinical trial, we selected 158 patients with moderate-severe TBI and assigned them into (1) a control group receiving routine once-daily (1/d) rehabilitation training without HBO, (2) study group A receiving routine 1/d rehabilitation training with HBO, (3) study group B receiving twice-daily (2/d) intensified rehabilitation training with HBO, and (4) study group C receiving 2/d intensified rehabilitation training without HBO, all for 3 months. The cognitive ability, activities of daily life (ADL), and movement ability were assessed before and after training with the Fugl-Meyer Assessment (FMA), Functional Independence Measure (FIM), Modified Barthel Index (MBI), and Mini-Mental State Examination (MMSE).Results: FIM, FMA, MBI, and MMSE scores were improved significantly after 1-, 2-, and 3-month rehabilitation training in all TBI patients (p < 0.01), and this improvement was especially remarkable in patients who received 2/d intensified rehabilitation training with HBO (p < 0.01).Innovation: With extensive and intensive research on TBI rehabilitation, it was proved that TBI rehabilitation intervention should be initiated as early as possible.Conclusion: Early intensified rehabilitation training in combination with HBO is more beneficial to the recovery of cognitive, ADL, and movement abilities of TBI patients.

Effects of long-term rapamycin treatment on glial scar formation after cryogenic traumatic brain injury in mice

Glial scar impedes axon regeneration and functional recovery following traumatic brain injury (TBI). Although it has been shown that rapamycin (a specific inhibitor of mammalian target of rapamycin) can reduce astrocyte reactivation in the early stage of TBI, its effect on glial scar formation has not been characterized in TBI and other acute brain injury models. To test this, ICR mice received daily administration of rapamycin (0.5 or 1.5 mg/kg, i.p.) beginning at 1 h after cryogenic TBI (cTBI). The results showed that at 3 d post-injury, 1.5 mg/kg rapamycin increased cTBI-induced motor functional deficits and infarct size, and attenuated astrocyte reactivation in the ipsilateral cortex, while 0.5 mg/kg rapamycin did not worsen brain damage and only slightly attenuated astrocyte reactivation. Furthermore, at 7 and 14 d after cTBI, 0.5 mg/kg rapamycin group showed a better motor functional performance than cTBI group. At 14 d post-injury, 0.5 mg/kg rapamycin significantly reduced the area and thickness of glial scar and chondroitin sulfate proteoglycan expression, accompanied by decreased expression of p-S6 and enhanced expression of growth associated protein 43 (an axon regeneration marker) in the region of glial scar. Our data suggest that long-term treatment with rapamycin can inhibit glial scar formation after cTBI, which may be involved in the mechanisms of increased axon regeneration and improved neurological functional recovery, and low-dose rapamycin may be more beneficial for such a therapy.

Medusa's Head: The Complement System in Traumatic Brain and Spinal Cord Injury.

Traumatic brain injury (TBI) and spinal cord injury (SCI) are critical medical conditions and a public health problem for which limited therapeutic options are available. The complement cascade is activated after TBI and SCI, and the resulting effects have been investigated in gene-knockout and pharmacological models. Multiple experimental studies support a net detrimental role of C3 and C5 activation in the early stages of TBI and SCI. Less firm experimental evidence suggests that, downstream of C3/C5, effector mechanisms, including the generation of membrane-activated complex and direct damage to membranes and neutrophils infiltration, may bring about the direct damage of central nervous system tissue and enhancement of neuroinflammation. The role of upstream classical, alternative, or extrinsic complement activation cascades remains unclear. Although several issues remain to be investigated, current evidence supports the investigation of a number of complement-targeting agents targeting C3 or C5, such as eculizumab, for repurposing in TBI and SCI treatment.

Topical application of the hematostatic agent Surgiflo® could attenuate brain injury in experimental TBI mice

Object: The pathologies resulting from traumatic brain injury (TBI) have been thoroughly studied, but rarely have the effects of bleeding and coagulation in the early stage of TBI been considered. In this study, we investigated the effects of topical Surgiflo® application on brain injury in experimental TBI mice using S100β, MAP-2 and mNSS scores.Methods: TBI was induced by modified weight drop injury in male C57BL/6 mice. The mice were then randomly divided into (i) the sham group, (ii) TBI mice applied with saline (vehicle), and (iii) TBI mice applied with Surgiflo® in the same volume. Modified neurological severity scores (mNSS) were measured on days 0 (before surgery), 1, 3, 7, and 28 to evaluate neurologic functional deficits. At day 28, the mice were sacrificed, and the forebrains were sliced. The effects of Surgiflo® on microtubule-associated protein 2 and serum S100β protein were examined by immunohistochemistry and electro-chemiluminescence immunoassay.Results: Serum S100β protein levels were significantly elevated at different time points (24 h, 3 days, 7 days) in the TBI groups (p < 0.01) compared to normal control groups. Surgiflo® induced a lower concentration of serum S100β protein levels at day 3 (p < 0.05) and day 7 (p < 0.05) compared to the TBI group applied with saline. H&E staining showed that Surgiflo® treatment led to a 45% decrease in cortical brain lesion volume and in subcortical white matter 28 days after TBI. Compared with the saline-treated group, the number of MAP2-positive cells was significantly increased in the perilesional area of the Surgiflo®-treated group. The Surgiflo®-treated group exhibited lower mNSS scores on days 7 and 28 than did the saline-treated group.Discussion: Surgiflo® treatment produced a significant decrease in serum S100β protein levels in TBI mouse models, which may lead to an improvement in the recovery of TBI models.

Cortisol-induced immune suppression by a blockade of lymphocyte egress in traumatic brain injury.

BackgroundAcute traumatic brain injury (TBI) represents one of major causes of mortality and disability in the USA. Neuroinflammation has been regarded both beneficial and detrimental, probably in a time-dependent fashion.MethodsTo address a role for neuroinflammation in brain injury, C57BL/6 mice were subjected to a closed head mild TBI (mTBI) by a standard controlled cortical impact, along with or without treatment of sphingosine 1-phosphate (S1P) or rolipram, after which the brain tissue of the impact site was evaluated for cell morphology via histology, inflammation by qRT-PCR and T cell staining, and cell death with Caspase-3 and TUNEL staining. Circulating lymphocytes were quantified by flow cytometry, and plasma hydrocortisone was analyzed by LC-MS/MS. To investigate the mechanism whereby cortisol lowered the number of peripheral T cells, T cell egress was tracked in lymph nodes by intravital confocal microscopy after hydrocortisone administration.ResultsWe detected a decreased number of circulating lymphocytes, in particular, T cells soon after mTBI, which was inversely correlated with a transient and robust increase of plasma cortisol. The transient lymphocytopenia might be caused by cortisol in part via a blockade of lymphocyte egress as demonstrated by the ability of cortisol to inhibit T cell egress from the secondary lymphoid tissues. Moreover, exogenous hydrocortisone severely suppressed periphery lymphocytes in uninjured mice, whereas administering an egress-promoting agent S1P normalized circulating T cells in mTBI mice and increased T cells in the injured brain. Likewise, rolipram, a cAMP phosphodiesterase inhibitor, was also able to elevate cAMP levels in T cells in the presence of hydrocortisone in vitro and abrogate the action of cortisol in mTBI mice. The investigation demonstrated that the number of circulating T cells in the early phase of TBI was positively correlated with T cell infiltration and inflammatory responses as well as cell death at the cerebral cortex and hippocampus beneath the impact site.ConclusionsDecreases in intracellular cAMP might be part of the mechanism behind cortisol-mediated blockade of T cell egress. The study argues strongly for a protective role of cortisol-induced immune suppression in the early stage of TBI.