Role In Traumatic Brain Injury Research Articles

Tannic Acid Provides Neuroprotective Effects Against Traumatic Brain Injury Through the PGC-1α/Nrf2/HO-1 Pathway.

The present research was conducted to elucidate a possible molecular mechanism related to neuromodulatory effects of tannic acid (TA) supplementation against traumatic brain injury (TBI) in a rodent model. Oxidative damage and neuroinflammation play a critical role in TBI and lead to behavioral alterations and neuronal dysfunction and death. These changes suggest a potential avenue in neurotherapeutic intervention. The aim of the present study was to investigate the neuroprotective effects of TA and potential mechanism of these effects in a controlled cortical impact injury model of TBI in Wistar rats that were treated with TA (50mg/kg body weight. i.p.) before 30min and 6 and 18h after TBI. TBI-induced rats were examined after 24h for behavioral dysfunction, Nissl stain, lipid peroxidation rate, glutathione level, activities of antioxidant enzymes (catalase, glutathione S-transferase, glutathione peroxidase, and superoxide dismutase), the expression level of 4-hydroxynonenal, pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-1 beta, as well as brain edema and immunoreactivity of glial fibrillary acidic protein. Results indicated that TA supplementation significantly modulated above mentioned alterations. Moreover, TA treatment effectively upregulated the protein expression of peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) and nuclear factor-E2-related factor-2 (Nrf2) as well as mitochondrial transcription factor A and heme oxygenase-1 (HO-1) following TBI. Overall, our results suggest that TA effectively ameliorates the behavioral alterations, oxidative damage, mitochondrial impairment, and inflammation against TBI that may be attributed to activation of PGC-1α/Nrf-2/HO-1 signaling pathway.

Combat-related posttraumatic stress disorder: the historical evolution of concept from «irritable heart syndrome» to «psycho-organic disorder». Biological aspect

To study a role of traumatic brain injury (TBI) in the development of posttraumatic stress disorder (PTSD) in ex combatants. Eighty-seven ex combatants were studied. The duration of follow-up was 15-18 years. The diagnosis was established in accordance with ICD-10 criteria. Patients were stratified by diagnosis into main group (PTSD) and comparison group (organic brain injury with reduced symptoms of PTSD). A psychopathological method and a battery of questionnaires and scales, including those adapted for assessment of consequences of combat trauma, were administered. Clinical presentations of both groups in posttraumatic period show the similarity and homogeneity of posttraumatic disorders in these groups. In the future, the pathogenetic role of TBI severity appears more clearly, which, depending on the severity, leads to the formation of an organic lesion of the brain or performs only a pathoplastic role, giving some features to the clinical picture of PTSD. It was found that the more severe the injury, the greater the likelihood of PTSD transition to organic brain damage. It is emphasized that PTSD treatment is a continuous, long-term, complex and graded process that includes pharmacotherapy, psychopharmacotherapy, psychotherapy, psychosocial interventions.

Combat stress and organic brain injury: type of the dynamics of posttraumatic stress disorder

To study a role of traumatic brain injury (TBI) in the development of posttraumatic stress disorder (PTSD) in ex combatants. Eighty-seven ex combatants were studied. The duration of follow-up was 15-18 years. The diagnosis was established in accordance with ICD-10 criteria. Patients were stratified by diagnosis into main group (PTSD) and comparison group (organic brain injury with reduced symptoms of PTSD ). A psychopathological method and a battery of questionnaires and scales, including those adapted for assessment of consequences of combat trauma, were administered. Clinical presentations of both groups in posttraumatic period show the similarity and homogeneity of posttraumatic disorders in these groups. In the future, the pathogenetic role of TBI severity appears more clearly, which, depending on the severity, leads to the formation of an organic lesion of the brain or performs only a pathoplastic role, giving some features to the clinical picture of PTSD. It was found that the more severe the injury, the greater the likelihood of PTSD transition to organic brain damage. It is emphasized that PTSD treatment is a continuous, long-term, complex and graded process that includes pharmacotherapy, psychotherapy, psychosocial interventions.

MicroRNA-23a-3p improves traumatic brain injury through modulating the neurological apoptosis and inflammation response in mice

ABSTRACT Secondary brain damage plays an important role in Traumatic brain injury (TBI) and inhibition of this damage has benefit for TBI treatment. However, the pathogenesis of secondary brain damage remains largely unknown. Here, we tried to explore the influence of microRNAs (miRNAs) on neuron apoptosis and inflammatory response after TBI. Firstly, the miRNA expression profiles were analyzed in the cerebral cortex tissues from the TBI mice model (controlled cortical impact) using miRNA microarray. miR-23a-3p (miR-23a) attracted our attention as its suppressive effects on apoptosis and inflammation. The further results showed that miR-23a upregulation improved long-term neurological function, the neuron apoptosis, and inhibited neuroinflammation, whereas knockdown of miR-23a had an opposite result. Using etoposide-induced primary cortical neurons injury model, we found that miR-23a was decreased in this cell model and miR-23a overexpression-suppressed etoposide induced the activity of caspase 3 and the releases of inflammatory mediators in primary cortical neurons. Phosphatase and tensin homolog (PTEN), a well‑known regulator of the AKT/mTOR pathway, was found to be a direct target of miR‑23a in the primary cortical neurons. Most importantly, it was found that miR-23a overexpression reactivated the AKT/mTOR pathway in TBI mice model, as demonstrated by the upregulation of phosphorylated (p‑)AKT and p‑mTOR. Taken together, these data indicate that miR-23a may serve as a therapeutic target for the treatment of TBI.

S100 Calcium-Binding Protein A9 Knockout Contributes to Neuroprotection and Functional Improvement after Traumatic Brain Injury.

S100 calcium-binding protein A9 (S100a9), a proinflammatory protein, has been shown to be involved in the development of neuroinflammatory disorders and neurodegenerative diseases. Upregulation of S100a9 in the brain during acute brain injury has been proposed to be associated with acute neuroinflammation. However, it remains unclear whether eliminating S100a9 expression will show beneficial outcomes after traumatic brain injury (TBI). Using S100a9 knockout mice, this study has demonstrated that S100a9 deletion ameliorates post-TBI anxiety, improves TBI-impaired motor and cognitive function, reduces lesion size, prevents perilesional neuron loss and neurodegeneration, diminishes neuroinflammation and TBI-induced neurogenesis, and enhances perilesional expression of neuroplasticity protein. These findings suggest that S100a9 plays a detrimental role in TBI. Genetic deletion of S100a9 enhances neuroprotection and improves functional outcome after TBI. This study sheds light on the pathological involvement of S100a9 in TBI, which would provide a new therapeutic target to minimize TBI-induced brain damage.

Sugar as a therapeutic target for the cognitive restoration following traumatic brain injury.

This review aims to discuss examples of changes in glucose (sugar) metabolism after traumatic brain injury (TBI). It will attempt to provide an understanding of what changes in glucose metabolism mean for the injured brain. It will further identify potential therapeutic target(s) emanating from our growing understanding of glucose pathways and their roles in TBI. Although a significant fraction of glucose is utilized for the energy production in the brain, a small fraction is utilized in other, often ignored pathways. Recent studies have unraveled unexpected biological effects of glucose through these pathways, including redox regulation, genetic and epigenetic regulation, glycation of proteins, nucleotide synthesis and amino acid synthesis. A number of regulatory players in minor glucose metabolic pathways, such as folate and chondroitin sulfate proteoglycans, have recently been identified as potential targets to restore cognitive functions. Targeting of these players should be combined with the supplementation of alternative energy substrates to achieve the maximal cognitive restoration after TBI. This multimodal therapeutic strategy deserves testing in various models of TBI. Supplemental digital video content 1: Video that demonstrates an effective therapeutic strategy for the cognitive restoration after TBI. http://links.lww.com/CONR/A46.

Therapeutic Hypothermia: Its Potential and Questionable Role in Traumatic Brain Injury

From the acute management of cardiac arrest and stroke to traumatic brain injury, the implementation of hypothermia therapy since the past two decades has progressed from various guidelines committees’ consideration of minimal benefit to mixed favorable outcomes being obtained from numerous randomized controlled trials [1]. As far as cases of traumatic brain injury are concerned, there were evidences of positive benefit in terms of mortality rates and neurological outcomes. According to a systematic analysis by Peterson et al. (2008), the relative risks (RR) of mortality (95% confidence interval) in comparison with control treatment groups were lower in subgroups of hypothermic procedures which utilized a cooling duration of over 48 hours (RR = 0.51), delivered at a temperature range of 33 degrees Celsius and above that was defined as milder than below 33 degrees Celsius (RR = 0.77), and when the patient was rewarmed passively (RR = 0.49).

18F-FAC PET Visualizes Brain-Infiltrating Leukocytes in a Mouse Model of Multiple Sclerosis.

Brain-infiltrating leukocytes contribute to multiple sclerosis (MS) and autoimmune encephalomyelitis and likely play a role in traumatic brain injury, seizure, and stroke. Brain-infiltrating leukocytes are also primary targets for MS disease-modifying therapies. However, no method exists for noninvasively visualizing these cells in a living organism. 1-(2'-deoxy-2'-18F-fluoroarabinofuranosyl) cytosine (18F-FAC) is a PET radiotracer that measures deoxyribonucleoside salvage and accumulates preferentially in immune cells. We hypothesized that 18F-FAC PET could noninvasively image brain-infiltrating leukocytes. Methods: Healthy mice were imaged with 18F-FAC PET to quantify if this radiotracer crosses the blood-brain barrier (BBB). Experimental autoimmune encephalomyelitis (EAE) is a mouse disease model with brain-infiltrating leukocytes. To determine whether 18F-FAC accumulates in brain-infiltrating leukocytes, EAE mice were analyzed with 18F-FAC PET, digital autoradiography, and immunohistochemistry, and deoxyribonucleoside salvage activity in brain-infiltrating leukocytes was analyzed ex vivo. Fingolimod-treated EAE mice were imaged with 18F-FAC PET to assess if this approach can monitor the effect of an immunomodulatory drug on brain-infiltrating leukocytes. PET scans of individuals injected with 2-chloro-2'-deoxy-2'-18F-fluoro-9-β-d-arabinofuranosyl-adenine (18F-CFA), a PET radiotracer that measures deoxyribonucleoside salvage in humans, were analyzed to evaluate whether 18F-CFA crosses the human BBB. Results:18F-FAC accumulates in the healthy mouse brain at levels similar to 18F-FAC in the blood (2.54 ± 0.2 and 3.04 ± 0.3 percentage injected dose per gram, respectively) indicating that 18F-FAC crosses the BBB. EAE mice accumulate 18F-FAC in the brain at 180% of the levels of control mice. Brain 18F-FAC accumulation localizes to periventricular regions with significant leukocyte infiltration, and deoxyribonucleoside salvage activity is present at similar levels in brain-infiltrating T and innate immune cells. These data suggest that 18F-FAC accumulates in brain-infiltrating leukocytes in this model. Fingolimod-treated EAE mice accumulate 18F-FAC in the brain at 37% lower levels than control-treated EAE mice, demonstrating that 18F-FAC PET can monitor therapeutic interventions in this mouse model. 18F-CFA accumulates in the human brain at 15% of blood levels (0.08 ± 0.01 and 0.54 ± 0.07 SUV, respectively), indicating that 18F-CFA does not cross the BBB in humans. Conclusion:18F-FAC PET can visualize brain-infiltrating leukocytes in a mouse MS model and can monitor the response of these cells to an immunomodulatory drug. Translating this strategy into humans will require exploring additional radiotracers.

Traumatic brain injury (TBI) in collision sports: Possible mechanisms of transformation into chronic traumatic encephalopathy (CTE)

Traumatic brain injury (TBI) is a leading cause of death and disability, contributing to ~30% of all injury-related deaths in the US. TBI occurs when a force transmitted to the head causes neuropathologic damage and impairment of brain function. TBI doubles risk of suicide and is the major determinant of acquired seizure disorders. TBI arising from closed head trauma (CHT) significantly increases the risk of developing Alzheimer's disease (AD), Parkinson's disease (PD) and chronic traumatic encephalopathy (CTE). Evidence for a possible role of TBI as a risk factor for sporadic amyotrophic lateral sclerosis (sALS) has been provided by studies of professional players of European football. Depending on age, genetic make-up (in particular, being a carrier of one or two ApoE4 alleles), the number of TBIs sustained, their severity, the time periods involved, and many other factors that affect vulnerability, decades may pass after occurrence of one or more TBIs before sequelae such as AD, PD, sALS or CTE become clinically evident. Among college and professional football players who experience repeated concussions and sub-concussive blows to the head, the risk of developing CTE increases with the number of years actively devoted to the sport, and the degree of exposure to physical impacts inherent in the position played. Following a moderate or severe concussion, or a series of mild blows to the head, the brain may undergo subtle pathophysiological changes that are unlikely to be detected with confidence using available diagnostic methods. Biomarkers are being sought that can help the attending physician infer the likely presence of an ongoing occult neurodegenerative process. One example of the adverse effect of collision on the brain is “heading” the soccer ball—a feat that, repeated over years of competition, has been found to produce severe brain damage in veteran players. CTE has attracted increasing national attention because of its devastating effects in a high proportion of retired professional players of American football. In a study of brains from deceased former football players, contributed mostly by family members, CTE was neuropathologically diagnosed in 110 of 111 of National Football League (NFL) veterans. In the CTE-positive subjects, the authors observed extensive brain atrophy, astrogliosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. CTE's neuropathology has been formally defined as a tauopathy characterized by a distinct perivascular accumulation of hyperphosphorylated tau in neurons and astrocytes within cerebral sulci. Although the mechanism that underlies the unforeseen emergence of CTE long after the occurrence of one or more closed head traumas is unknown, an explanation proposed by Albayram and associates is persuasive. They discovered TBI-induced neuronal production of the toxic compound cis P-tau, an abnormal and destructive isomer of the normal and benign trans P-tau, in mouse models of CTE. Cis P-tau produced a CTE-like syndrome via a process they termed cistauosis. Cistauosis can be blocked in laboratory animals by cis P-tau monoclonal antibody, which prevents later development of tau tangles, brain atrophy and virtual CTE. In a subsequent study, the same group found in human samples obtained post-TBI from a variety of causes, that cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Thus, cis P-tau appears to contribute to short-term and long-term sequelae after TBI, but may be subject to neutralization by cis-antibody treatment.

Shear shock evolution in incompressible soft solids

Nonlinear evolution of shear waves into shocks in incompressible elastic materials is investigated using the framework of large deformation elastodynamics, for a family of loadings and commonly used hyperelastic material models. Closed form expressions for the shock formation distance are derived and used to construct non-dimensional phase maps that determine regimes in which a shock can be realized. These maps reveal the sensitivity of shock evolution to the amplitude, shape, and ramp time of the loading, and to the elastic material parameters. In light of a recent study (Espindola et al., 2017), which hypothesizes that shear shock formation could play a significant role in Traumatic Brain Injury (TBI), application to brain tissue is considered and it is shown that the size matters in TBI research. Namely, for realistic loadings, smaller brains are less susceptible to formation of shear shocks. Furthermore, given the observed sensitivity to the imparted waveform and the constitutive properties, it is suggested that the non-dimensional maps can guide the design of protective structures by determining the combination of loading parameters, material dimensions, and elastic properties that can avoid shock formation.

Silencing of A20 Aggravates Neuronal Death and Inflammation After Traumatic Brain Injury: A Potential Trigger of Necroptosis.

Programmed cell death is an important biological process that plays an indispensable role in traumatic brain injury (TBI). Inhibition of necroptosis, a type of programmed cell death, is pivotal in neuroprotection and in preventing associated inflammatory responses. Our results showed that necroptosis occurred in human brain tissues after TBI. Necroptosis was also induced by controlled cortical impact (CCI) injury in a rat model of TBI and was accompanied by high translocation of high-mobility group box-1 (HMGB1) to the cytoplasm. HMGB1 was then passed through the impaired cell membrane to upregulate the receptor for advanced glycation end-products (RAGE), nuclear factor (NF)-κB, and inflammatory factors such as interleukin-6 (IL-6), interleukin-1 (IL-1β), as well as NACHT, LRR and PYD domains-containing protein 3 (NLRP3). Necroptosis was alleviated by necrostatin-1 and melatonin but not Z-VAD (a caspase inhibitor), which is consistent with the characteristic of caspase-independent signaling. This study also demonstrated that tumor necrosis factor, alpha-induced protein 3 (TNFAIP3, also known as A20) was indispensable for regulating and controlling necroptosis and inflammation after CCI. We found that a lack of A20 in a CCI model led to aggressive necroptosis and attenuated the anti-necroptotic effects of necrostatin-1 and melatonin.

Progesterone modulates post-traumatic epileptogenesis through regulation of BDNF-TrkB signaling and cell survival-related pathways in the rat hippocampus

Female sex hormone, progesterone, in addition to seizure modifying activity is also known as a potential protective agent against various brain injury conditions. Considering the predisposal role of traumatic brain injury (TBI) on developing post-traumatic epilepsy (PTE), the effect of progesterone on post-traumatic epileptogenesis is not investigated yet. Male Wistar rats were given a moderate focal weight drop injury (500 gr) or sham surgery and then progesterone (16 and 32mg/kg) was given daily for two consecutive weeks. On day 15 of injury, seizures were induced by administration of a GABAA receptor antagonist, pentylenetetrazole (PTZ, 30 mg/kg). Seizures were then assessed over a 1-h period using the Racine clinical rating scale.Traumatized animals that received 32 mg/kg progesterone had reduced score, duration of seizures and almost did not show tonic-clonic seizures during 60 min versus the untreated trauma group. In line with behavioral alterations, 32 mg/kg progesterone enhanced the amount of Nrf2 and HO-1 proteins and decreased the level of NF-kB, BDNF, Caspase 3 and ratio of Bax/Bcl-2 in the ipsilateral hippocampus. Additionally, the number of TUNEL-positive apoptotic cells, as well as injured dark neurons in the parietal cortex and hippocampal CA1 of 32 mg/kg-treated animals showed a significant reduction. Administration of 16 mg/kg progesterone elevated production of BDNF, Bax and Caspase 3 and decreased anti-apoptotic Bcl-2 protein. Taken together, an early administration of 32 mg/kg of progesterone after TBI for two weeks post-injury modified seizure activity.Our findings suggest that post-traumatic anti-epileptogenesis property of a high dose of progesterone partly occurs through the manipulation of BDNF-TrkB axis along with control of cell survival pathways.

Incidence of post-traumatic pneumonia in poly-traumatized patients: identifying the role of traumatic brain injury and chest trauma.

PurposeTraumatic brain injury (TBI) and chest trauma are common injuries in severely injured patients. Both entities are well known to be associated with severe post-traumatic complications, including pneumonia, a common complication with a significant impact on the further clinical course. However, the relevance of TBI, chest trauma and particularly their combination as risk factors for the development of pneumonia and its impact on outcomes are not fully elucidated.MethodsA retrospective analysis of poly-traumatized patients treated between 2010 and 2015 at a level I trauma centre was performed. Inclusion criteria were: Injury Severity Score ≥ 16 and age ≥ 18 years. TBI and chest trauma were classified according to the Abbreviated Injury Scale. Complications (i.e. acute respiratory distress syndrome (ARDS), multi-organ dysfunction syndrome (MODS) and pneumonia) were documented by a review of the medical records. The primary outcome parameter was in-hospital mortality.ResultsOver the clinical course, 19.9% of all patients developed pneumonia, and in-hospital mortality was 25.3%. Pneumonia (OR 5.142, p = 0.001) represented the strongest independent predictor of in-hospital mortality, followed by the combination of chest injury and TBI (OR 3.784, p = 0.008) and TBI (OR 3.028, p = 0.010). Chest injury alone, the combination of chest injury and TBI, and duration of ventilation were independent predictors of pneumonia [resp. OR 4.711 (p = 0.004), OR 4.193 (p = 0.004), OR 1.002 (p < 0.001)].ConclusionsChest trauma alone and especially its combination with TBI represent high-risk injury patterns for the development of pneumonia, which forms the strongest predictor of mortality in poly-traumatized patients.

Treating Alcohol Use Disorder in U.S. Veterans: The Role of Traumatic Brain Injury.

The authors examined the efficacy of valproate to reduce relapse to heavy drinking among veterans with alcohol use disorder (AUD) and neuropsychiatric comorbidities and whether antecedent traumatic brain injury (TBI) or posttraumatic stress disorder (PTSD) affected treatment response. Participants were male veterans 18-60 years old with an AUD and no other substance use besides nicotine or cannabis. Sixty-two patients were randomly assigned to receive either valproate or naltrexone. Participants were evaluated at baseline and followed weekly for 24 weeks. All participants received standardized psychosocial interventions as well as treatment for coexistent psychiatric conditions. During the follow-up period, nine study subjects in the naltrexone group and 14 in the valproate group relapsed to heavy drinking, but the difference did not reach statistical significance. Participants with a history of moderate to severe TBI were more likely to relapse to heavy drinking compared with those with no TBI (hazard ratio=4.834, 95% CI=1.103-21.194, p=0.033). PTSD status did not significantly affect outcome. Intensive outpatient programs are efficacious alternatives to treat AUD in veterans, although the role of pharmacological treatment is not completely elucidated. Glutamatergic agents appear to be less effective than opiate antagonists to prevent relapse to heavy drinking and to increase cumulative abstinence. Future studies should examine novel pharmacological and nonpharmacological options.

When a Slice Is Not Enough! Comparison of Whole-Brain versus Standard Limited-Slice Perfusion Computed Tomography in Patients with Severe Traumatic Brain Injury.

Introduction: Cerebral perfusion computed tomography (PCT) provides crucial information in acute stroke and has an increasing role in traumatic brain injury (TBI) management. Most studies on TBI patients utilize 64-slice scanners, which are limited to four brain slices (limited-brain PCT, LBPCT). Newer 320-slice scanners depict the whole brain perfusion status (WBPCT). We aimed to identify the additional information gained with WBPCT when compared to LBPCT. Patients and methods: Forty-nine patients with severe TBI were investigated within 48 h from admission with WBPCT. Findings from LBPCT were compared with findings from WBPCT. Results: A perfusion abnormality was identified in 39 (80%) and 37 (76%) patients by WBPCT and LBPCT, respectively (p = 0.8). There were 90 and 68 perfusion abnormalities identified by WBPCT and LBPCT, respectively (p < 0.001). In the 39 patients with a perfusion abnormality detected by WBPCT, 15 (38%) had further perfusion abnormalities outside the LBPCT area of coverage. Thirty-six (92%) patients had a larger perfusion abnormality upon WBPCT compared with LBPCT. Additional information gained showed some statistically significant correlation with clinical outcome. Conclusions: In severe TBI patients, WBPCT provides extra information compared to LBPC. The limitations of LBPCT should be considered when evaluating studies reporting on PCT findings and their association with outcomes.

Gene expression profile of the hippocampus of rats subjected to traumatic brain injury.

Traumatic brain injury (TBI) is a serious public health problem as well as a leading cause of severe posttraumatic disability. Numerous studies indicate that the differentially expressed genes (DEGs) of neural signaling pathways are strongly correlated with brain injury. To further analyze the roles of the DGEs in the central nervous system, here we systematically investigated TBI on the hippocampus and its injury mechanism at the whole genome level. On the basis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes Analyses, we revealed that the DEGs were involved in many signaling pathways related to the nervous system, especially neuronal survival-related pathways. Finally, we verified the microarray results and detected the gene expression of neuronal survival-related genes in the hippocampus by using real-time quantitative polymerase chain reaction. With Western blot and axon growth assay, the expression of P2rx3 was upregulated in rats subjected to TBI, and overexpression of P2rx3 promoted neurite growth of NG108 cells. Our results suggested that the DEGs (especially P2rx3) and several signaling pathways might play a pivotal role in TBI. We also provided several targeted genes related to TBI for future investigation.

Potential Roles of NIX/BNIP3L Pathway in Rat Traumatic Brain Injury

NIX/BNIP3L is known as a proapoptotic protein that is also related to mitophagy. Previous reports have shown that NIX could be involved in neuronal apoptosis after intracerebral hemorrhage, but it also plays a protective role in mitophagy in ischemic brain injury. How NIX works in traumatic brain injury (TBI) is unclear. Thus, this study was designed to observe the expression of NIX and perform a preliminary exploration of the possible effects of NIX in a rat TBI model. The results showed that NIX expression decreased after damage, and colocalized with neuronal cells in cortical areas. Moreover, when we induced upregulation of NIX, autophagy was increased, while neuronal apoptosis and brain water content decreased along with neurological deficits. These findings remind us that NIX probably plays a neuroprotective role in TBI through autophagy and apoptosis pathways.

Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury

BackgroundStudies have shown that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) protects against brain damage. However, the low survival number of transplanted BMSCs remains a pertinent challenge and can be attributed to the unfavorable microenvironment of the injured brain. It is well known that calpain activation plays a critical role in traumatic brain injury (TBI)-mediated inflammation and cell death; previous studies showed that inhibiting calpain activation is neuroprotective after TBI. Thus, we investigated whether preconditioning with the calpain inhibitor, MDL28170, could enhance the survival of BMSCs transplanted at 24 h post TBI to improve neurological function.MethodsTBI rat model was induced by the weight-drop method, using the gravitational forces of a free falling weight to produce a focal brain injury. MDL28170 was injected intracranially at the lesion site at 30 min post TBI, and the secretion levels of neuroinflammatory factors were assessed 24 h later. BMSCs labeled with green fluorescent protein (GFP) were locally administrated into the lesion site of TBI rat brains at 24 h post TBI. Immunofluorescence and histopathology were performed to evaluate the BMSC survival and the TBI lesion volume. Modified neurological severity scores were chosen to evaluate the functional recovery. The potential mechanisms by which MDL28170 is involved in the regulation of inflammation signaling pathway and cell apoptosis were determined by western blot and immunofluorescence staining.ResultsOverall, we found that a single dose of MDL28170 at acute phase of TBI improved the microenvironment by inhibiting the inflammation, facilitated the survival of grafted GFP-BMSCs, and reduced the grafted cell apoptosis, leading to the reduction of lesion cavity. Furthermore, a significant neurological function improvement was observed when BMSCs were transplanted into a MDL28170-preconditioned TBI brains compared with the one without MDL28170-precondition group.ConclusionsTaken together, our data suggest that MDL28170 improves BMSC transplantation microenvironment and enhances the neurological function restoration after TBI via increased survival rate of BMSCs. We suggest that the calpain inhibitor, MDL28170, could be pursued as a new combination therapeutic strategy to advance the effects of transplanted BMSCs in cell-based regenerative medicine.

Tachykinin NK1 receptor antagonist L-733,060 and substance P deletion exert neuroprotection through inhibiting oxidative stress and cell death after traumatic brain injury in mice.

Substance P (SP) is believed to play a role in traumatic brain injury (TBI), and the inhibition of binding of SP to the tachykinin neurokinin-1 receptor (NK1R) using NK1R antagonists had made favorable effects on TBI. Our current study addresses the functional roles and underlying mechanisms of SP and NK1R antagonist L-733,060 following TBI. Adult male wild type C57BL/6 J and SP knock out (SPKO) mice received a controlled cortical impact and outcome parameters were assessed. The results showed that TBI-induced motor and spatial memory deficits, lesion volume, brain water content and blood-brain barrier disruption were alleviated both in L-733,060-treated C57BL/6 J mice and vehicle-treated SPKO mice. L-733,060 treatment and SP deletion inhibited TBI-induced the release of cytochrome c from mitochondria to cytoplasm, activation of caspase-3, oxidative stress and neuroinflammation. Higher SP levels in serum and cortex were observed in wild type mice undergoing TBI relative to wild type sham group, but very little expression of cortical SP was detected in the SP-/- mice either TBI or not. Upregulation of NK1R expression after TBI was observed, and there was no significant difference between wild type and SPKO groups. in vitro, L-733,060 and SP deletion inhibited scratch injury-induced cell death, loss of mitochondrial membrane potential and reactive oxygen species (ROS) production following TBI. Together, the results of this study implicate a functional role for NK1-R antagonist L-733,060 and deletion of SP in TBI-induced neurological outcome, oxidative damage, neuroinflammation and cell death. Upregulation of NK1R maybe a consequence of TBI, independent of the levels of substance P. This study raises the possibility that targeting SP through its receptor NK1R or genetic deletion may have therapeutic efficacy in TBI.

Retracted: Knockdown of long noncoding RNA GAS5 attenuates H2 O2 -induced damage in retinal ganglion cells through upregulating miR-124: Potential role in traumatic brain injury.

Optic nerve injury is one of the most common and serious complications in traumatic brain injury (TBI). Alleviating degree of optic nerve injury is important to cure of TBI. This study explored the role of long noncoding RNA (lncRNA) GAS5 in mice retinal ganglion cells (RGCs) suffered to H2 O 2 injury. Primary RGC (PRGCs) were treated with H2 O 2 to simulate an in vitro oxidation stress model. LncRNA GAS5 and miR-124 expressions were knocked down by cell transfection with short-hairpin RNA against GAS5 and miR-124 inhibitor, and the transfection efficiency was determined by qRT-PCR. Cell viability, apoptotic cell rate, and production of reactive oxygen species (ROS) was analyzed by CCK-8 assay, PI/FITC-Annexin V method, and DCFH-DA fluorometric assay. Cell apoptosis-associated proteins as well as activations of JAK/STAT3 signaling and JNK signaling were analyzed by Western blot. H2 O 2 treatment-induced cell injury was inhibited by lncRNA GAS5 silence. Specifically, knockdown of GAS5 improved viability of primary PRGCs, inhibited apoptosis, decreased ROS expression, increased antiapoptosis proteins' expressions, and decreased proapoptosis proteins' expressions. It was also found that miR-124 inhibitor treatment impaired the cell protective effect of GAS5 silence, indicating low level of GAS5 protected PRGCs via upregulating miR-124. GAS5 silence might exert cytoprotection effect via activating JAK/STAT3 signaling pathway and inhibiting activation of JNK signaling pathway. Knocking down lncRNA GAS5 alleviated H2 O 2 -induced injury in PRGCs via upregulation of miR-124, which might dependent on activation of JAK/STAT3 signaling pathway and inhibition of JNK signaling pathway.