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Background: Traumatic brain injury (TBI) is characterized by high mortality and disability rates. Disease-associated microglia (DAM) are a newly discovered subtype of microglia. However, their presence and function in the acute phase of TBI remain unclear. Although glycolysis is important for microglial differentiation, its regulatory role in DAM transformation during the acute phase of TBI is still unclear. In this study, we investigated the functions of DAM-like cells in the acute phase of TBI in mice, as well as the relationship between their transformation and glycolysis. Methods: In this study, a controlled cortical impact model was used to induce TBI in adult male wild-type (WT) C57BL/6 mice and adult male TREM2 knockout mice. Various techniques were used to assess the role of DAM-like cells in TBI and the effects of glycolysis on DAM-like cells, including RT‒qPCR, immunofluorescence assays, behavioural tests, extracellular acidification rate (ECAR) tests, Western blot analysis, cell magnetic sorting and culture, glucose and lactate assays, and flow cytometry. Results: DAM-like cells were observed in the acute phase of TBI in mice, and their transformation depended on TREM2 expression. TREM2 knockout impaired neurological recovery in TBI mice, possibly due in part to their role in clearing debris and secreting VEGFa and BDNF. Moreover, DAM-like cells exhibited significantly increased glycolytic activity. TREM2 regulated the AKT‒mTOR‒HIF-1α pathway and glycolysis in microglia in the acute phase of TBI. The increase in glycolysis in microglia partially contributed to the transformation of DAM-like cells in the acute phase of TBI in mice. Conclusions: Taken together, the results of our study demonstrated that DAM-like cells were present in the acute phase of TBI in mice. TREM2 might influence DAM-like cell transformation by modulating the glycolysis of microglia. Our results provide a new possible pathway for intervening TBI. [ABSTRACT FROM AUTHOR]

Background: White matter injury (WMI) is an important pathological process after traumatic brain injury (TBI). The correlation between white matter functions and the myeloid cells expressing triggering receptor‐2 (TREM2) has been convincingly demonstrated. Moreover, a recent study revealed that microglial sterol metabolism is crucial for early remyelination after demyelinating diseases. However, the potential roles of TREM2 expression and microglial sterol metabolism in WMI after TBI have not yet been explored. Methods: Controlled cortical injury was induced in both wild‐type (WT) and TREM2 depletion (TREM2 KO) mice to simulate clinical TBI. COG1410 was used to upregulate TREM2, while PLX5622 and GSK2033 were used to deplete microglia and inhibit the liver X receptor (LXR), respectively. Immunofluorescence, Luxol fast blue staining, magnetic resonance imaging, transmission electron microscopy, and oil red O staining were employed to assess WMI after TBI. Neurological behaviour tests and electrophysiological recordings were utilized to evaluate cognitive functions following TBI. Microglial cell sorting and transcriptomic sequencing were utilized to identify alterations in microglial sterol metabolism‐related genes, while western blot was conducted to validate the findings. Results: TREM2 expressed highest at 3 days post‐TBI and was predominantly localized to microglial cells within the white matter. Depletion of TREM2 worsened aberrant neurological behaviours, and this phenomenon was mediated by the exacerbation of WMI, reduced renewal of oligodendrocytes, and impaired phagocytosis ability of microglia after TBI. Subsequently, the upregulation of TREM2 alleviated WMI, promoted oligodendrocyte regeneration, and ultimately facilitated the recovery of neurological behaviours after TBI. Finally, the expression of DHCR24 increased in TREM2 KO mice after TBI. Interestingly, TREM2 inhibited DHCR24 and upregulated members of the LXR pathway. Moreover, LXR inhibition could partially reverse the effects of TREM2 upregulation on electrophysiological activities. Conclusions: We demonstrate that TREM2 has the potential to alleviate WMI following TBI, possibly through the DHCR24/LXR pathway in microglia. [ABSTRACT FROM AUTHOR]

Background and Target: Following brain trauma, blood–brain barrier (BBB) disruption and inflammatory response are critical pathological steps contributing to secondary injury, leading to high mortality and morbidity. Both pathologies are closely associated with endothelial remodeling. In the present study, we concentrated on annexin A1 (ANXA1) as a novel regulator of endothelial function after traumatic brain injury. Methods: After establishing controlled cortical impact (CCI) model in male mice, human recombinant ANXA1 (rANXA1) was administered intravenously, followed by assessments of BBB integrity, brain edema, inflammatory response, and neurological deficits. Result: Animals treated with rANXA1 (1 μg/kg) at 1 h after CCI exhibited optimal BBB protection including alleviated BBB disruption and brain edema, as well as endothelial junction proteins loss. The infiltrated neutrophils and inflammatory cytokines were suppressed by rANXA1, consistent with decreased adhesive and transmigrating molecules from isolated microvessels. Moreover, rANXA1 attenuated the neurological deficits induced by CCI. We further found that the Ras homolog gene family member A (RhoA) inhibition has similar effect as rANXA1 in ameliorating brain injuries after CCI, whereas rANXA1 suppressed CCI-induced RhoA activation. Conclusion: Our findings suggest that the endothelial remodeling by exogenous rANXA1 corrects BBB disruption and inflammatory response through RhoA inhibition, hence improving functional outcomes in CCI mice. [ABSTRACT FROM AUTHOR]

The level of microRNA‐9‐5p (miRNA‐9‐5p) in brain tissues is significantly changed after traumatic brain injury (TBI). However, the effect of miRNA‐9‐5p for brain function in TBI has not been elucidated. In this study, a controlled cortical impact model was used to induce TBI in Sprague–Dawley rats, and an oxygen glucose deprivation model was used to mimic the pathological state in vitro. Brain microvascular endothelial cells (BMECs) and astrocytes were extracted from immature Sprague–Dawley rats and cocultured to reconstruct blood–brain barrier (BBB) in vitro. The results show that the level of miRNA‐9‐5p was significantly increased in brain tissues after TBI, and up‐regulation of miRNA9‐5p contributed to the recovery of neurological function. Up‐regulation of miRNA‐9‐5p with miRNA agomir may significantly alleviate apoptosis, neuroinflammation, and BBB damage in rats after TBI. Moreover, a dual luciferase reporter assay confirmed that miRNA‐9‐5p is a post‐transcriptional modulator of Ptch‐1. In in vitro experiments, the results confirmed that up‐regulation of miRNA‐9‐5p with miRNA mimic alleviates cellular apoptosis, inflammatory response, and BBB damage mainly by inhibiting Ptch‐1. In addition, we found that the activation of Hedgehog pathway was accompanied by inhibition of NF‐κB/MMP‐9 pathway in the BMECs treated with miRNA‐9‐5p mimic. Taken together, these results indicate that up‐regulation of miRNA‐9‐5p alleviates BBB damage and neuroinflammatory responses by activating the Hedgehog pathway and inhibiting NF‐κB/MMP‐9 pathway, which promotes the recovery of neurological function after TBI. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a commonly encountered emergency and severe neurosurgical injury. Previous studies have shown that the presence of the apolipoprotein E ( APOE ) ε4 allele has adverse outcomes across the spectrum of TBI severity. Our objective was to evaluate the effects of APOE alleles on trauma induced early apoptosis via modification of delayed rectifier K + current ( I k(DR) ) in neuronal/glial co-cultures model. An ex vivo neuronal/glial co-cultures model carrying individual APOE alleles ( ε2, ε3, ε4 ) of mechanical injury was developed. Flow cytometry and patch clamp recording were performed to analyze the correlations among APOE genotypes, early apoptosis and I k(DR) . We found that APOEε4 increased early apoptosis at 24 h ( p <0.05) compared to the ones transfected with APOEε3 and APOEε2 . Noticeably, APOEε4 significantly reduced the amplitude of the I k(DR) at 24 h compared to the APOEε3 and APOEε2 ( p <0.05) which exacerbate Ca 2+ influx. This indicates a possible effect of APOEε4 on early apoptosis via inhibiting I k(DR) following injury which may adversely affect the outcome of TBI. [ABSTRACT FROM AUTHOR]

Abstract: To investigate the relationship between apolipoprotein E (APOE) polymorphisms and the severity of traumatic brain injury (TBI) in acute stage in the cohort of mainland Chinese patients. We prospectively identified admissions to the two neurosurgical departments for head injury. A total of 110 subjects with TBI (80 males and 30 females, with mean age of 43.87 years) were enrolled from December 2003 to May 2004, and demographic and clinical data were collected. Venous blood was collected from patients with TBI on admission to determine the APOE genotype polymorphisms. The APOE genotyping was performed by means of PCR-RFLP. The deterioration of patients’ condition in acute stage (<7 days after TBI) was judged by either of following criteria: decrease of GCS, increase in hematoma volume or delayed hematoma both detected by repeated CT scanning. χ 2-test and logistic regression analyses were done by SPSS. The distributions of APOE genotypes and alleles matched Hardy–Weinberg law. In 110 Chinese patients, 19 subjects presented with deteriorated clinical condition after hospitalization, and seven of 17 patients with APOE ɛ4 (41.2%) had a deteriorated condition which was significantly different from those without APOE ɛ4 (12 of 93 patients, 12.9%, P =0.01). However, neither the presence of ɛ2 nor of ɛ3 was significantly different from those absent of it (P >0.05). Logistic regression analyses showed that APOE ɛ4 was a risk factor (OR=4.836, P =0.011, 95% CI 1.443–16.208) to predispose to clinical deterioration after adjusting for patient age, sex, smoking or not, alcohol-drinking or not, injury severity, injury mechanisms, treatments, and pattern of TBI. This finding suggests that the patients with APOE ɛ4 predispose to clinical deterioration in acute phase after TBI and APOE polymorphisms play a role in early responses to TBI. [Copyright &y& Elsevier]

Recently, increasing evidence has shown that cell cycle activation is a key factor of neuronal death and neurological dysfunction after traumatic brain injury (TBI). This study aims to investigate the effects of Honokiol, a cell cycle inhibitor, on attenuating the neuronal damage and facilitating functional recovery after TBI in rats, in an attempt to unveil its underlying molecular mechanisms in TBI. This study suggested that delayed intravenous administration of Honokiol could effectively ameliorate TBI-induced sensorimotor and cognitive dysfunctions. Meanwhile, Honokiol treatment could also reduce the lesion volume and increase the neuronal survival in the cortex and hippocampus. The neuronal degeneration and apoptosis in the cortex and hippocampus were further significantly attenuated by Honokiol treatment. In addition, the expression of cell cycle-related proteins, including cyclin D1, CDK4, pRb and E2F1, was significantly increased and endogenous cell cycle inhibitor p27 was markedly decreased at different time points after TBI. And these changes were significantly reversed by post-injury Honokiol treatment. Furthermore, the expression of some of the key cell cycle proteins such as cyclin D1 and E2F1 and the associated apoptosis in neurons were both remarkably attenuated by Honokiol treatment. These results show that delayed intravenous administration of Honokiol could effectively improve the functional recovery and attenuate the neuronal cell death, which is probably, at least in part, attributed to its role as a cell cycle inhibitior. This might give clues to developing attractive therapies for future clinical trials. [ABSTRACT FROM AUTHOR]

• For the first time, we find lnc RNA MALAT1 is neuroprotective in TBI. • It is a study involving Lnc RNA and diseases. • This study associates angiogenesis with neurogenesis. • It benefits for the translation from bench to bed. As a highly evolutionary conserved lncRNA, MALAT1 was first demonstrated to associate with metastasis of lung tumor by promoting angiogenesis. Activated vasculature was recently indicated to assist neurogenesis by secreting neurotrophic factor Ang1 (Angiopoietin-1). The purpose of this study is to investigate the potential role of MALAT1 in angiogenesis following traumatic brain injury (TBI). Adult male mice were subjected to controlled cortical impact (CCI) and brain microvascular endothelial cells were exposed to oxygen-glucose deprivation (OGD). MALAT1 RNA levels were quantified by qRT-PCR in different cells of CNS and located by RNA-FISH. Angiogenesis were measured by cell viability, migration assay, tube formation assay in vitro, and immunohistochemistry in vivo. Expression of Angiopoietin-1 was assessed by Western blot. Neurological functions were performed by NSS, Wire grip and MWM tests. Our results indicated that 1) MALAT1 RNA was localized in cerebral endothelium, enhanced by OGD stimuli. 2) Inhibition of MALAT1 by siRNA suppressed angiogenesis, as indicated by endothelial viability, tube formation, migration, and functional vessel density. 3) MALAT1 inhibition further decreased Ang1 expression in the endothelium. 4) Mice with MALAT1 inhibition exhibited worse behavioral performances (NSS, wire grip, Morris water maze), as compared to control. MALAT1 could promote angiogenesis, subsequently contributing to the Ang1 synthesis from active vasculature. It may eventually benefit to functional recovery following TBI. [ABSTRACT FROM AUTHOR]

• Increasing of microRNA-9-5p activates Hedgehog pathway. • Activation of Hedgehog pathway by increasing microRNA-9-5p enhances angiogenesis in vitro and in vivo. • Increasing of microRNA-9-5p improves neurological outcomes after traumatic brain injury. MicroRNA-9-5p (miRNA-9-5p) is an important regulator of angiogenesis in many pathological states. However, the effect of miRNA-9-5p on angiogenesis after traumatic brain injury (TBI) has not been elucidated. In this study, a controlled cortical impact (CCI) model was used to induce TBI in Sprague-Dawley rats, and an oxygen glucose deprivation (OGD) model was used to mimic the pathological state in vitro. Brain microvascular endothelial cells (BMECs) were extracted from immature rats. The results showed that the level of miRNA-9-5p was significantly increased in the traumatic foci after TBI, and the upregulation of miRNA9-5p promoted the recovery of neurological function. Moreover, the upregulation of miRNA-9-5p with miRNA agomir significantly increased the density of the microvascular and neurons around the traumatic foci in rats after TBI. The results of the in vitro experiments confirmed that the upregulation of miRNA-9-5p with a miRNA mimic improved cellular viability and alleviated cellular apoptosis. Dual luciferase reporter assay validated that miRNA-9-5p was a posttranscriptional modulator of Ptch-1. Activation of the Hedgehog pathway by increasing the level of miRNA-9-5p promoted the migration and tube formation of BMECs in vitro. In addition, we found that the upregulation of miRNA-9-5p activated the Hedgehog pathway and increased the phosphorylation of AKT, which promoted the expression of cyclin D1, MMP-9 and VEGF in BMECs. All these results indicate that the upregulation of miRNA-9-5p promotes angiogenesis and improves neurological functional recovery after TBI, mainly by activating the Hedgehog pathway. MiRNA-9-5p may be a potential new therapeutic target for TBI. [ABSTRACT FROM AUTHOR]

Highlights • For the first time, we explored how cortical blood flow is pathological altered following TBI using a newly developed technique, laser speckle imaging techniques. • We have used a controlled cortical impact brain trauma model that is widely used to mimic a range of human contusion injuries. • The novel approach for cerebral blood flow monitoring by laser speckle imaging, may be extended from bench to bed for TBI. Abstract The role of the cerebrovascular network during the acute and chronic phases after traumatic brain injury (TBI) is poorly defined and emerging evidence suggests that cerebral perfusion is altered. The purpose of this study is to explore how the cortical blood flow is pathologically altered following TBI using a newly developed technique, laser speckle imaging. The controlled cortical impact (CCI) model was established in mice. Then, cerebral blood flow was monitored in vivo laser speckle imaging and vessel painting was labeled by Lectin in the peri-contusional cortex. Lastly, mice were assessed for lesion size and neurological functions. Our results indicated that: 1) In the acute phase of TBI, cerebral blood flow and microvessel counts decreased significantly (P < 0.05) 2) In the chronic phase of TBI, cerebral blood flow and microvessel counts recovered gradually (P < 0.05) 3) Cortical lesion volume reduced significantly in the chronic phase of TBI (P < 0.05) 4) Spontaneous neurocognitive recovery occurred following CCI in mice (P < 0.05). In the acute phase of TBI, there is a reduction in cerebral perfusion at the lesion site. However, this reduction recovers in the chronic phase of TBI ultimately, followed by an improvement of ameliorated neurobehavioral functions and a decrease in the lesion size. The novel approach for cerebral blood flow monitoring by laser speckle imaging can be extended from bench to bedside and provide potential therapeutic strategies for TBI patients. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) causes a high rate of mortality and disability worldwide, and there exists almost none effective drugs to protect against TBI. Neurotoxicity occurring after TBI can be derived from microglia and astrocytes, and causes neuronal death and synapse loss. Bexarotene has been demonstrated to protect neurons in CNS diseases. In the present study, we aimed to investigate the potential role of bexarotene in protecting against neurotoxicity after TBI, as well as the underlying mechanism. The controlled cortical impact (CCI) model was established on adult C57BL/6 mice, followed by intraperitoneal administration of bexarotene for 14 consecutive days. We found that bexarotene improved sensorimotor function and cognitive recovery in CCI mice. In addition, bexarotene decreased neuronal death and synapse loss, as well as inhibited apoptotic cascade. Moreover, bexarotene treatment reduced M1 microglia polarization, microglia-derived pro-inflammatory cytokines, and the number of A1 astrocytes after CCI. These effects of bexarotene were partially abolished by T0070907, an antagonist of peroxisome proliferator–activated receptor gamma (PPARγ). Additionally, bexarotene enhanced nuclear translocation and transcriptional activity of PPARγ. These findings show that bexarotene inhibits neurotoxicity in mice after TBI, at least in part through a PPARγ-dependent mechanism. [ABSTRACT FROM AUTHOR]

Bexarotene has been proved to have neuroprotective effects in many animal models of neurological diseases. However, its neuroprotection in traumatic brain injury (TBI) is still unknown. This study aims to explore the neuroprotective effects of bexarotene on TBI and its possible mechanism. Controlled cortical impact (CCI) model was used to simulate TBI in C57BL/6 mice as well as APOE gene knockout ( APOE-KO ) mice. After CCI, mice were daily dosed with bexarotene or vehicle solution intraperitoneally. The motor function, learning and memory, inflammatory factors, microglia amount, apoptosis condition around injury site and main side-effects were all measured. The results showed that, after CCI, bexarotene treatment markedly improved the motor function and spatial memory in C57BL/6 compare to APOE-KO mice which showed no improvement. The inflammatory cytokines, microglia amount, cell apoptosis rate, and protein of cleaved caspase-3 around the injury site were markedly upregulated after TBI in both C57BL/6 and APOE-KO mice, and all these upregulation were significantly mitigated by bexarotene treatment in C57BL/6 mice, but not in APOE-KO mice. No side-effects were detected after consecutive administration. Taken together, bexarotene inhibits the inflammatory response as well as cell apoptosis and improves the neurological function of mice after TBI partially through apolipoprotein E. This may make it a promising candidate for the therapeutic treatment after TBI. [ABSTRACT FROM AUTHOR]

Background and objective The present study aims to detect the altered lncRNA expression in the mouse cortex after traumatic brain injury (TBI). We also simultaneously detected the altered mRNA profile to further analyze the possible function of lncRNA. Method C57BL/6 mice (n=18) were used to construct a controlled cortical impact model. At 24 h post-TBI, the cortex around injury site was collected and the total RNA was extracted to construct the cDNA library. RNA sequencing (RNA-seq) was carried out followed by RT-PCR for confirmation. Bioinformatic analysis (including GO analysis, KEGG pathway and co-expression analysis) also were performed. Results A total of 64,530 transcripts were detected in the current sequencing study, in which 27,457 transcripts were identified as mRNA and 37,073 transcripts as lncRNA. A total of 1580 mRNAs (1430 up-regulated and 150 down-regulated) and 823 lncRNAs (667 up-regulated and 156 down-regulated) were significantly changed according to the criteria ( | log 2 (fold change) |>1 and P <0.05). These altered mRNAs were mainly related to inflammatory and immunological activity, metabolism, neuronal and vascular network. The expression of single lncRNA may be related with several mRNAs, and so was the mRNA. Also, a total of 360 new mRNAs and 8041 new lncRNAs were identified. The good reproducibility and reliability of RNA-seq were confirmed by RT-PCR. Conclusion Numerous lncRNAs and mRNAs were significantly altered in mouse cortex around the injury site 24 h after TBI. Our present data may provide a promising approach for further study about TBI. [ABSTRACT FROM AUTHOR]

The degree of post-traumatic brain edema and dysfunction of the blood-brain barrier (BBB) influences the neurofunctional outcome after a traumatic brain injury (TBI). Previous studies have demonstrated that the administration of apolipoprotein E-mimetic peptide COG1410 reduces the brain water content after subarachnoid hemorrhage, intra-cerebral hemorrhage, and focal brain ischemia. However, the effects of COG1410 on vasogenic edema following TBI are not known. The current study evaluated the effects of 1 mg/kg daily COG1410 versus saline administered intravenously after a controlled cortical impact (CCI) injury on BBB dysfunction and vasogenic edema at an acute stage in mice. The results demonstrated that treatment with COG1410 suppressed the activity of matrix metalloproteinase-9, reduced the disruption of the BBB and Evans Blue dye extravasation, reduced the TBI lesion volume and vasogenic edema, and decreased the functional deficits compared with mice treated with vehicle, at an acute stage after CCI. These findings suggest that COG1410 is a promising preclinical therapeutic agent for the treatment of traumatic brain injury. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) destroys white matter, and this destruction is aggravated by secondary neuroinflammatory reactions. Although white matter injury (WMI) is strongly correlated with poor neurological function, understanding of white matter integrity maintenance is limited, and no available therapies can effectively protect white matter. One candidate approach that may fulfill this goal is cannabinoid receptor 2 (CB2) agonist treatment. Here, we confirmed that a selective CB2 agonist, JWH133, protected white matter after TBI. The motor evoked potentials (MEPs), open field test, and Morris water maze test were used to assess neurobehavioral outcomes. Brain tissue loss, WM damage, Endoplasmic reticulum stress (ER stress), microglia responses were evaluated after TBI. The functional integrity of WM was measured by diffusion tensor imaging (DTI) and transmission electron microscopy (TEM). Primary microglia and oligodendrocyte cocultures were used for additional mechanistic studies. JWH133 increased myelin basic protein (MBP) and neurofilament heavy chain (NF200) levels and anatomic preservation of myelinated axons revealed by DTI and TEM. JWH133 also increased the numbers of oligodendrocyte precursor cells and mature oligodendrocytes. Furthermore, JWH133 drove microglial polarization toward the protective M2 phenotype and modulated the redistribution of microglia in the striatum. Further investigation of the underlying mechanism revealed that JWH133 downregulated phosphorylation of the protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) signaling pathway and its downstream signals eukaryotic translation initiation factor 2 α (eIF2α), activating transcription factor 4 (ATF4) and Growth arrest and DNA damage-inducible protein (GADD34); this downregulation was followed by p-Protein kinase B(p-Akt) upregulation. In primary cocultures of microglia and oligodendrocytes, JWH133 decreased phosphorylated PERK expression in microglia stimulated with tunicamycin and facilitated oligodendrocyte survival. These data reveal that JWH133 ultimately alleviates WMI and improves neurological behavior following TBI. However, these effects were prevented by SR144528, a selective CB2 antagonist. This work illustrates the PERK-mediated interaction between microglia and oligodendrocytes. In addition, the results are consistent with recent findings that microglial polarization switching accelerates WMI, highlighting a previously unexplored role for CB2 agonists. Thus, CB2 agonists are potential therapeutic agents for TBI and other neurological conditions involving white matter destruction. • JWH133 alleviates white matter injury following TBI. • JWH133 regulates the interaction between microglia and oligodendrocytes through PERK pathway in vivo and vitro. • Illustrating the neuroprotective effect of JWH133 after TBI further. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) has been regarded as one of the leading cause of injury-related death and disability. White matter injury after TBI is characterized by axon damage and demyelination, resulting in neural network impairment and neurological deficit. Brain-derived neurotrophic factor (BDNF) can promote white matter repair. The activation of peroxisome proliferator–activated receptor gamma (PPARγ) has been reported to promote microglia/macrophages towards anti-inflammatory state and therefore to promote axon regeneration. Bexarotene, an agonist of retinoid X receptor (RXR), can activate RXR/PPARγ heterodimers. The aim of the present study was to identify the effect of bexarotene on BDNF in microglia/macrophages and axon sprouting after TBI in mice. Bexarotene was administered intraperitoneally in C57BL/6 mice undergoing controlled cortical impact (CCI). PPARγ dependency was determined by intraperitoneal administration of a PPARγ antagonist T0070907. We found that bexarotene promoted axon regeneration indicated by increased growth associated protein 43 (GAP43) expression, myelin basic protein (MBP) expression, and biotinylated dextran amine (BDA)+ axon sprouting. Bexarotene also increased microglia/macrophages-specific brain derived neurotrophic factor (BDNF) expression after TBI. In addition, bexarotene reduced the number of pro-inflammatory microglia/macrophages while increased the number of anti-inflammatory microglia/macrophages after TBI. Moreover, bexaortene inhibited pro-inflammatory cytokine secretion. In addition, bexarotene treatment improved neurological scores and cognitive function of CCI-injured mice. These effects of bexarotene were partially abolished by T0070907. In conclusion, bexarotene promotes axon sprouting, increases microglia/macrophages-specific BDNF expression, and induces microglia/macrophages from a pro-inflammatory state towards an anti-inflammatory one after TBI at least partially in a PPARγ-dependent manner. • Bexarotene promotes axon sprouting after traumatic brain injury in mice. • Bexarotene increases microglia/macrophages - specific brain - derived neuroptrophic factor expression after traumatic brain injury. • Bexarotene promotes microglia towards anti-iflammatory state after traumatic brain injury in mice. [ABSTRACT FROM AUTHOR]

Background Literature about traumatic brain injury caused by missile wounds is scanty. We shed some light on this field. Methods This retrospective study was carried out, between September 2000 and September 2010, on 520 civilian patients who sustained traumatic brain injury from missiles in the north of Palestine. Thorough detailed analyses were made of patients' admission Glasgow Coma Scale (GCS) scores, pupillary reactivity to light, site and mode of injuries, type of injurious agents, missile trajectory, method of treatment, radiologic manifestations, complications, and outcome. The GCS score was used to assess the level of consciousness, whereas the Glasgow Outcome Scale score was used to evaluate the outcome. Results Patients' age ranged from 6 months to 75 years. Only 50 (9.6%) patients were female. Patients injured by metallic bullets, rubber bullets, and shrapnel from bomb explosions numbered 351, 139, and 30, respectively. Of 384 patients who were treated conservatively, no mortality was detected, whereas of 136 surgically treated patients, 66 (48.5%) died of their injuries. Although our management of patients was not optimal because of many factors, the overall mortality was 12.7% ( n = 66). Conclusions The promptness of transport to hospital was a decisive factor with a major bearing on decreasing mortality. Brain computed tomography was invaluable in the diagnosis and follow-up of our patients. In addition, age, pupillary reactivity, admission GCS score, missile trajectory, ventricular involvement, and site and mode of injury were important prognostic factors. [ABSTRACT FROM AUTHOR]