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Traumatic brain injury（TBI） is one of the major causes of death and disability worldwide.No effective treatment has been identified from clinical trials.Compelling evidence exists that treatment with mesenchymal stem cells（MSCs） exerts a substantial therapeutic effect after experimental brain injury.In addition to their soluble factors,therapeutic effects of MSCs may be attributed to their generation and release of exosomes.Exosomes are endosomal origin small-membrane nano-sized vesicles generated by almost all cell types.Exosomes play a pivotal role in intercellular communication.Intravenous delivery of MSC-derived exosomes improves functional recovery and promotes neuroplasticity in rats after TBI.Therapeutic effects of exosomes derive from the exosome content,especially micro RNAs（mi RNAs）.mi RNAs are small non-coding regulatory RNAs and play an important role in posttranscriptional regulation of genes.Compared with their parent cells,exosomes are more stable and can cross the blood-brain barrier.They have reduced the safety risks inherent in administering viable cells such as the risk of occlusion in microvasculature or unregulated growth of transplanted cells.Developing a cell-free exosome-based therapy may open up a novel approach to enhancing multifaceted aspects of neuroplasticity and to amplifying neurological recovery,potentially for a variety of neural injuries and neurodegenerative diseases.This review discusses the most recent knowledge of exosome therapies for TBI,their associated challenges and opportunities.

Traumatic brain injury （TBI） is a major cause of disability and death in patients who experience a traumatic injury. Mitochondrial dysfunction is one of the main factors contributing to secondary injury in TBI-associated brain damage. Evidence of compromised mitochondrial function after TBI has been, but the molecular mechanisms underlying the pathogenesis of TBI are not well understood Silent information regulator family protein 1 （SlRT1）, a member of the NAD~-dependent protein deacetylases, has been shown to exhibit neuroprotective activities in animal models of various pathologies, including ischemic brain injury, subarachnoid hemorrhage and several neurodegenerative diseases. In this study, we investigated whether SIRT1 also exert neuroprotective effect post-TBI, and further explored the possible regulatory mechanisms involved in TBI pathogenesi6. A lateral fluid-percussion （LFP） brain injury model was established in rats to mimic the insults of TBI. The expression levels of SIRT1, p-p38, cleaved caspase-9 and cleaved easpase-3 were all markedly increased and reached a maximum at 12 h post-TBI. In addition, mitochondrial function was impaired, evidenced by the presence of swollen and irregularly shaped mitochondria with disrupted and poorly defined cristae, a relative increase of the percentage of neurons with low ALPm, the opening of mPTP, and a decrease in neuronal ATP content, especially at 12 h post- TBI. Pretreatment with the SIRT1 inhibitor sirtinol （10 mg/kg, ip） induced p-p38 activation, exacerbated mitochondrial damage, and promoted the activation of the mitochondrial apoptosis pathway. In contrast, pretreatment with the p38 inhibitor SB203580 （200 pg/kg, ip） significantly attenuated post-TBI-induced expression of both cleaved caspase-9 and cleaved caspase-3 and rnitochondrial damage, whereas it had no effects on SlRT1 expression. Together, these results reveal that the 12 h after TBI may be a crucial time at which secondary damage occurs; the activation of SIRT1 expression and inhibition of the p38 MAPK pathway may play a neuroprotective role in preventing secondary damage post-TBI. For this reason, both SIRT1 and p38 are likely to be important targets to prevent secondary damage post-TBI.

Traumatic brain injury is the leading cause of morbidity and mortality in young adults. The secondary injury in traumatic brain injury consists of a complex cascade of processes that simultaneously react to the primary injury to the brain. This cascade has been the target of numerous therapeutic agents investigated over the last 30 years, but no neuroprotective treatment option is currently available that improve neurological outcome after traumatic brain injury. Progesterone has long been considered merely a female reproductive hormone. Numerous studies, however, show that progesterone has substantial pleiotropic properties as a neuroprotective agent in both animal models and humans. Here, we review the increasing evidence that progesterone can act as a neuroprotective agent to treat traumatic brain injury and the mechanisms underlying these effects. Additionally, we discuss the current progress of clinical studies on the application of progesterone in the treatment of traumatic brain injuries.

Previous neuropathological studies regarding traumatic brain injury have primarily focused on changes in large structures, for example, the clinical prognosis after cerebral contusion, intrace- rebral hematoma, and epidural and subdural hematoma. In fact, many smaller injuries can also lead to severe neurological disorders. For example, cerebral microbleeds result in the dysfunc- tion of adjacent neurons and the disassociation between cortex and subcortical structures. These tiny changes cannot be adequately visualized on CT or conventional MRI. In contrast, gradient echo sequence-based susceptibility-weighted imaging is very sensitive to blood metabolites and microbleeds, and can be used to evaluate traumatic cerebral microbleeds with high sensitivity and accuracy. Cerebral microbleed can be considered as an important imaging marker for dif- fuse axonal injury with potential relevance for prognosis. For this reason, based on experimental and clinical studies, this study reviews the role of imaging data showing traumatic cerebral microbleeds in the evaluation of cerebral neuronal injury and neurofunctional loss.

Traumatic brain injury （TBI） is the leading cause of death and disability of persons under 45 years old in the United States, affecting over 1.5 million individtials each year. It had been th ought that recovery from such injuries is severely limited due to the inability of the adult bra in to replace damaged neurons. However, recent studies indicate that the mature mammalian central nervous system （CNS） has the potential to replenish damaged neurons by proliferation and neuronal differentiation of adult neural stem/progenitor cells residing in the neurogenic regions in the brain. Furthermore, increasing evidence indicates that these endogenous stem/ progenitor cells may play regenerative and reparative roles in response to CNS injuries or diseases. In support of this notion, heightened levels of cell proliferation and neurogenesis have been ob- served in response to brain trauma or insults suggesting that the brain has the inherent potential to restore populations of damaged or destroyed neurons. This review will discuss the potential functions of adult neurogenesis and recent development of strategies aiming at harnessing this neurogenic capacity in order to repopulate and repair the injured brain.

Background： The ability to predict posttraumatic stress disorder （PTSD） is a critical issue in the management of patients with mild traumatic brain injury （mTBI）, as early medical and rehabilitative interventions may reduce the risks of long-term cognitive changes. The aim of the present study was to investigate how diffusion tensor imaging （DTI） metrics changed in the transition from acute to chronic phases in patients with mTBI and whether the alteration relates to the development of PTSD. Methods： Forty-three patients with mTBI and 22 healthy volunteers were investigated. The patients were divided into two groups： successful recovery （SR, n = 22） and poor recovery （PR, n = 21）, based on neurocognitive evaluation at 1 or 6 months after injury. All patients underwent magnetic resonance imaging investigation at acute （within 3 days）, subacute （10-20 days）, and chronic （1-6 months） phases after injury. Group differences of fractional anisotropy （FA） and mean diffusivity （MD） were analyzed using tract-based spatial statistics （TBSS）. The accuracy of DTI metrics for classifying PTSD was estimated using Bayesian discrimination analysis. Results： TBSS showed white matter （WM） abnormalities in various brain regions. In the acute phase, FA values were higher for PR and SR patients than controls （all P 〈 0.05）. In subacute phase, PR patients have higher mean MD than SR and controls （all P 〈 0.05）. In the chronic phase, lower FA and higher MD were observed in PR compared with both SR and control groups （all P 〈 0.05）. PR and SR groups could be discriminated with a sensitivity of 73%, specificity of 78%, and accuracy of 75.56%, in terms of MD value in subacute phase. Conclusions： Patients with mTBI have multiple abnormalities in various WM regions. DTI metrics change over time and provide a potential indicator at subacute stage for PTSD following mTBI.

Background： Traumatic brain injury （TBI） is a life-threatening disease worldwide. Regulatory T cells （Treg ceils） were involved in the immunological system in central nervous system. It is defined as a subpopulation of CD4＋ cells that express CD25 and transcription lactor forkhead box P3. The level of circulating Treg cells increases in a variety of pathologic conditions. The purpose of this study was to uncover the role of circulating Treg cells in TBI. Methods： A clinical study was conducted in two neurosurgical intensive care units of Tianjin Medical University General Hospital and Second Hospital of Tianjin Medical University （Tianjin, China）. Forty patients and 30 healthy controls were recruited t＇rom August 2013 to November 2013. Circulating Treg cells was detected on the follow-up period of 1,4, 7, 14, and 21 days alter TBI. Blood sample （ 1 ml） was withdrawn in the morning and processed within 2 h. Results： There was no significant difference in the level of circulating Treg cells between TBI patients and normal controls during follow-up. TBI patients exhibited higher circulating Treg level than normal controls on the 1st day after TBI. Treg level was decreased on the 4th day, climbed tip on the 7th day and peaked on 14th day after TBI. Treg cells declined to the normal level on 21th day alter TBI. The level of circulating Treg cells was significantly higher in survival TBI patients when compared to nonsurvival TBI patients. TBI patients with improved conditions exhibited significantly higher circulating Treg level when compared to those with deteriorated conditions. The circulating Treg level was correlated with neurologic recovery after TBI. A better neural recovery and lower hospital mortality were found in TBI patients with circulating Treg cells more than 4.91% in total CD4＋ inononuclear cells as compared to those with circulating Treg cells less than 4.91% in total CD4 mononuclear cells in the first 14 days. Conclusions： The level of circulating Treg cells is positively correlated with clinical outcome of TBI. The level of Treg cells predicts the progress for TBI patients and may be a target in TBI treatment.

To investigate the supplement of lost nerve cells in rats with traumatic brain injury by intravenous administration of allogenic bone marrow mesenchymal stem cells, this study established a Wistar rat model of traumatic brain injury by weight drop impact acceleration method and administered 3 × 106 rat bone marrow mesenchymal stem cells via the lateral tail vein. At 14 days after cell transplantation, bone marrow mesenchymal stem cells differentiated into neurons and astrocytes in injured rat cerebral cortex and rat neurological function was improved significantly. These findings suggest that intravenously administered bone marrow mesenchymal stem cells can promote nerve cell regeneration in injured cerebral cortex, which supplement the lost nerve cells.

Traumatic brain injury（TBI） is a leading cause of death and disability in individuals worldwide.Producing a clinically relevant TBI model in small-sized animals remains fairly challenging.For good screening of potential therapeutics,which are effective in the treatment of TBI,animal models of TBI should be established and standardized.In this study,we established mouse models of closed head injury using the Shohami weight-drop method with some modifications concerning cognitive deficiency assessment and provided a detailed description of the severe TBI animal model.We found that 250 g falling weight from 2 cm height produced severe closed head injury in C57BL/6 male mice.Cognitive disorders in mice with severe closed head injury could be detected using passive avoidance test on day 7 after injury.Findings from this study indicate that weight-drop injury animal models are suitable for further screening of brain neuroprotectants and potentially are similar to those seen in human TBI.

Traumatic brain injury survivors often experience cognitive deficits and neuropsychiatric symptoms.However,the neurobiological mechanisms underlying specific impairments are not fully understood.Advances in neuroimaging techniques（such as diffusion tensor imaging and functional MRI）have given us new insights on structural and functional connectivity patterns of the human brain in both health and disease.The connectome derived from connectivity maps reflects the entire constellation of distributed brain networks.Using these powerful neuroimaging approaches,changes at the microstructural level can be detected through regional and global properties of neuronal networks.Here we will review recent developments in the study of brain network abnormalities in traumatic brain injury,mainly focusing on structural and functional connectivity.Some connectomic studies have provided interesting insights into the neurological dysfunction that occurs following traumatic brain injury.These techniques could eventually be helpful in developing imaging biomarkers of cognitive and neurobehavioral sequelae,as well as predicting outcome and prognosis.