CD36 deletion prevents white matter injury by modulating microglia polarization through the Traf5-MAPK signal pathway.

BACKGROUND: White matter injury (WMI) represents a significant etiological factor contributing to neurological impairment subsequent to Traumatic Brain Injury (TBI). CD36 receptors are recognized as pivotal participants in the pathogenesis of neurological disorders, including stroke and spinal cord injury. Furthermore, dynamic fluctuations in the phenotypic polarization of microglial cells have been intimately associated with the regenerative processes within the injured tissue following TBI. Nevertheless, there is a paucity of research addressing the impact of CD36 receptors on WMI and microglial polarization. This investigation aims to elucidate the functional role and mechanistic underpinnings of CD36 in modulating microglial polarization and WMI following TBI. METHODS: TBI models were induced in murine subjects via controlled cortical impact (CCI). The spatiotemporal patterns of CD36 expression were examined through quantitative polymerase chain reaction (qPCR), Western blot analysis, and immunofluorescence staining. The extent of white matter injury was assessed via transmission electron microscopy, Luxol Fast Blue (LFB) staining, and immunofluorescence staining. Transcriptome sequencing was employed to dissect the molecular mechanisms underlying CD36 down-regulation and its influence on white matter damage. Microglial polarization status was ascertained using qPCR, Western blot analysis, and immunofluorescence staining. In vitro, a Transwell co-culture system was employed to investigate the impact of CD36-dependent microglial polarization on oligodendrocytes subjected to oxygen-glucose deprivation (OGD). RESULTS: Western blot and qPCR analyses revealed that CD36 expression reached its zenith at 7 days post-TBI and remained sustained at this level thereafter. Immunofluorescence staining exhibited robust CD36 expression in astrocytes and microglia following TBI. Genetic deletion of CD36 ameliorated TBI-induced white matter injury, as evidenced by a reduced SMI-32/MBP ratio and G-ratio. Transcriptome sequencing unveiled differentially expressed genes enriched in processes linked to microglial activation, regulation of neuroinflammation, and the TNF signaling pathway. Additionally, bioinformatics analysis pinpointed the Traf5-p38 axis as a critical signaling pathway. In vivo and in vitro experiments indicated that inhibition of the CD36-Traf5-MAPK axis curtailed microglial polarization toward the pro-inflammatory phenotype. In a Transwell co-culture system, BV2 cells treated with LPS + IFN-γ exacerbated the damage of post-OGD oligodendrocytes, which could be rectified through CD36 knockdown in BV2 cells. CONCLUSIONS: This study illuminates that the suppression of CD36 mitigates WMI by constraining microglial polarization towards the pro-inflammatory phenotype through the down-regulation of the Traf5-MAPK signaling pathway. Our findings present a potential therapeutic strategy for averting neuroinflammatory responses and ensuing WMI damage resulting from TBI.

Neutrophil extracellular traps facilitate sympathetic hyperactivity by polarizing microglia toward M1 phenotype after traumatic brain injury.

Traumatic brain injury (TBI), particularly diffuse axonal injury (DAI), often results in sympathetic hyperactivity, which can exacerbate the prognosis of TBI patients. A key component of this process is the role of neutrophils in causing neuroinflammation after TBI by forming neutrophil extracellular traps (NETs), but the connection between NETs and sympathetic excitation following TBI remains unclear. Utilizing a DAI rat model, the current investigation examined the role of NETs and the HMGB1/JNK/AP1 signaling pathway in this process. The findings revealed that sympathetic excitability intensifies and peaks 3 days post-injury, a pattern mirrored by the activation of microglia, and the escalated NETs and HMGB1 levels. Subsequent in vitro exploration validated that HMGB1 fosters microglial activation via the JNK/AP1 pathway. Moreover, in vivo experimentation revealed that the application of anti-HMGB1 and AP1 inhibitors can mitigate microglial M1 polarization post-DAI, effectively curtailing sympathetic hyperactivity. Therefore, this research elucidates that post-TBI, NETs within the PVN may precipitate sympathetic hyperactivity by stimulating M1 microglial polarization through the HMGB1/JNK/AP1 pathway.

NETs Lead to Sympathetic Hyperactivity After Traumatic Brain Injury Through the LL37-Hippo/MST1 Pathway.

Background: Paroxysmal sympathetic hyperactivity (PSH) is one of the important reasons for the high mortality and morbidity of traumatic brain injury (TBI). We aim to explore the role of the neutrophil extracellular traps (NETs) in the pathogenesis of sympathetic hyperexcitability after TBI and the underlying mechanisms, providing evidence for clinical treatment. Methods: Enzyme-linked immunosorbent assay was used to assess the plasma metanephrine and normetanephrine levels which represented the variation of the sympathetic system after TBI with rat diffuse axonal injury (DAI) model. NETs in the paraventricular nucleus (PVN) and circulating blood were examined using immunofluorescence and flow cytometry. Neutrophils-microglia co-culture system was established to further explore the effect of NETs on PSH and its mechanisms. Results: After TBI, metanephrine and normetanephrine levels began to increase at 9 h and peaked at 72 h. After the injury, the level of NETs kept increasing at 24 and 72 h in the PVN. A positive correlation was found between the concentration of the PVN NETs and blood catecholamine. Flow cytometry of peripheral blood cells revealed that NETs level in the injury group was higher than that in the control group. Immunofluorescence results confirmed the presence of NETs in the PVN after TBI. The positive result of immunoprecipitation suggested a correlation effect between LL37 and P2 × 7. Peptidyl arginine deiminase-4 (PAD4) inhibitor could inhibit the expression levels of MST1, YAP, and IL-1ß. The hippo/MST1 pathway inhibitor could inhibit the expression levels of YAP and IL-1ß. Conclusion: NETs formation in the PVN might be associated with sympathetic hyperactivity after TBI, which might relate to the activation of microglia cells and increased secretion of IL-1ß via the hippo/MST1 pathway.

Histone Demethylase KDM4A Inhibition Represses Neuroinflammation and Improves Functional Recovery in Ischemic Stroke.

BACKGROUND: Epigenetic regulation concerning histone lysine methylation and demethylation play a crucial role in cerebral ischemic injury. Dysregulation of histone methylation modifiers has been identified in cerebral ischemia. However, the function and the underlying mechanisms of histone demethylase KDM4A on neuroinflammation and functional recovery in ischemic stroke remains unclear. METHODS: In the present study, the rat model of transient middle cerebral artery occlusion (MCAO) was established, and the expression level of KDM4A was assessed in brain tissues. KDM4A inhibition was carried out by intrathecal injection with Lv-shKDM4A, and then pro-inflammatory cytokines and neurological functional tests were assessed. RESULTS: We demonstrated that rats subjected to MCAO showed a markedly increased expression of KDM4A, pro-inflammatory cytokines IL-1ß and TNF-α, and vascular endothelial growth factor (VEGF), whereas KDM4A inhibition repressed the expression of IL-1ß, TNF-α and VEGF both in MCAO and oxygen-glucose deprivation (OGD) models. Furthermore, KDM4A inhibition showed a marked improvement in spatial learning and sensorimotor function, as suggested by mNSS and foot-fault test, respectively. Mechanistically, KDM4A inhibition repressed NF-κB signaling activation in microglia as indicated by decreased expression and nuclear translocation of p65 in vitro and in vivo. The effects of KDM4A overexpression on exacerbating neuroinflammation was inhibited by additional treatment of NF-κB inhibitor (JSH-23). CONCLUSION: The current results demonstrated KDM4A inhibition improves functional recovery in ischemic stroke by repressing NF-κB activation and subsequent neuroinflammation.

Risk factors and clinical features of paroxysmal sympathetic hyperactivity after spontaneous intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Paroxysmal sympathetic hyperactivity (PSH) is a rare complication of spontaneous intracerebral hemorrhage (ICH).We aimed to evaluate the risk factors and clinical features for PSH after ICH. METHODS: From January 1, 2013 to April 1, 2018, patients with ICH were consecutively included in this observational study. Baseline characteristics were compared in patients with and without PSH. Multivariate logistic regression analysis was used to determine the risk factors associated with PSH development. Clinical features of patients with PSH were also analyzed. RESULTS: There were 548 patients with ICH included and a total of 15 (2.7%) patients were identified with PSH. In univariate analysis, PSH development was associated with the following: previous hemorrhagic stroke, pupils abnormity, admission Glasgow Coma Scale (GCS) score, hematoma volume, liver function abnormity, neutrophil count and early tracheostomy. Multivariate logistic regression analysis showed that a significantly increased risk of PSH was found in patients with previous hemorrhagic stroke (odds ratio [OR], 4.176; 95% confidence interval [CI], 1.111-15.698), admission GCS score (OR, 0.703; 95% CI, 0.548-0.902) and early tracheostomy (OR, 8.317; 95%CI, 1.755-39.412).The most common symptoms of PSH were hyperthermia (80%) and hyperhidrosis (80%).The median Intensive Care Unit stays and Glasgow Outcome Scale at discharge were 34 (19-46) and 2 (1.5-3), respectively. CONCLUSIONS: PSH is characterized by a cluster of symptoms and abnormal vital signs, which may lead to poor outcomes in ICH. The present study suggests that previous hemorrhagic stroke, admission GCS score and early tracheostomy may be the significant risk factors for PSH after ICH.

Effect of oxidative stress in rostral ventrolateral medulla on sympathetic hyperactivity after traumatic brain injury.

Sympathetic hyperactivity occurs in a subgroup of patients after traumatic brain injury (TBI). The rostral ventrolateral medulla (RVLM) is a key region for the activity of sympathetic nervous system. Oxidative stress in the RVLM is proved to be responsible for the increased level of sympathetic activity in animal models of hypertension and heart failure. In this study, we investigated whether oxidative stress in the RVLM contributed to the development of sympathetic hyperactivity after TBI in rats. Model of diffuse axonal injury was induced using Sprague-Dawley rats, and level of mean arterial pressure (MAP) and plasma Norepinephrine (NE) was measured to evaluate the sympathetic activity. For the assessment of oxidative stress, expression of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) in the RVLM was determined. Microinjection of Tempol into the RVLM was performed to determine the effect of oxidative stress on sympathetic hyperactivity. According to the results, TBI led to elevated MAP and plasma NE in rats. It also induced a significantly increased level of ROS, MDA production and decreased level of SOD in the RVLM. The sympathetic activity, ROS, and MDA in the RVLM decreased significantly after microinjection of Tempol. Therefore, the present results suggested that oxidative stress in the RVLM was involved in the development of sympathetic hyperactivity following TBI.

Tracheostomy as a Risk Factor for Paroxysmal Sympathetic Hyperactivity in Severe Traumatic Brain Injury.

BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) is an uncommon complication of severe traumatic brain injury (sTBI). The clinical risk factors for PSH have not been fully characterized, especially regarding tracheostomy, which has usually been recommended for patients with sTBI to facilitate treatment. We examined the effects of tracheostomy on PSH incidence in patients with sTBI. METHODS: The present single-center, retrospective study included consecutive patients with sTBI who had been admitted to the Shanghai Changzheng Hospital from January 1, 2013 to March 31, 2018. The potential risk factors related to the occurrence of PSH was explored by univariate analysis. Multivariate logistic regression analysis was conducted to determine the independence of the factors associated with PSH development. RESULTS: Of the 120 patients with sTBI, 17 with PSH were identified (14.16%). We found 3 risk factors were significantly associated with PSH on univariate and multivariate analyses: 1) tracheostomy (odds ratio [OR], 5.368; 95% confidence interval [CI], 1.102-26.151; P = 0.038); 2) age (OR, 0.916; 95% CI, 0.874-0.960; P < 0.001); and 3) hydrocephalus (OR, 6.715; 95% CI, 1.708-26.408; P = 0.006). CONCLUSIONS: Our results suggest that tracheostomy is independently associated with an increased incidence of PSH.

miR-448-3p controls intracranial aneurysm by regulating KLF5 expression.

microRNAs (miRNAs) control several processes known to be involved in progression of aneurysm. Here, intracranial aneurysms (IAs) were surgically induced in Sprague-Dawley rats, and we found that miR-448-3p was downregulated and KLF5 was upregulated in IA rats. We identified Klf5 as a direct target of miR-448-3p in smooth muscle cells (SMCs). In addition, aneurysms size and the lumen area of the aneurysms were smaller 4 weeks after IA induction in the miR-448-3p-treated group. miR-448-3p treatment protected the wall thickness ratio and suppressed macrophage infiltration after IA induction. IAs caused a significant increase in KLF5 expression and were alleviated by miR-448-3p. Moreover, the anti-inflammatory effect of miR-448-3p was verified in lipopolysaccharide -stimulated RAW 264.7 macrophage cells. The expression levels of KLF5, MMP2, and MMP9 levels were elevated by LPS, and were attenuated by miR-448-3p. These data suggest that miR-448-3p plays the inhibitory role in IA progression, indicating that miR-448-3p overexpression is crucial for preventing the development of IA through downregulation of macrophage-mediated inflammation.

CCNG2 Overexpression Mediated by AKT Inhibits Tumor Cell Proliferation in Human Astrocytoma Cells.

The cyclin family protein CCNG2 has an important inhibitory role in cancer initiation and progression, but the exact mechanism is still unknown. In this study, we examined the relationship between CCNG2 and the malignancy of astrocytomas and whether the AKT pathway, which is upregulated in astrocytomas, may inhibit CCNG2 expression. CCNG2 expression was found to be negatively associated with the pathological grade and proliferative activity of astrocytomas, as the highest expression was found in control brain tissue (N = 31), whereas the lowest expression was in high-grade glioma tissue (N = 31). Additionally, CCNG2 overexpression in glioma cell lines, T98G and U251 inhibited proliferation and arrested cells in the G0/G1 phase. Moreover, CCNG2 overexpression could increase glioma cells apoptosis. In contrast, AKT activity increased in glioma cells that had low CCNG2 expression. Expression of CCNG2 was higher in cells treated with the AKT kinase inhibitor MK-2206 indicating that the presence of phosphorylated AKT may inhibit the expression of CCNG2. Inhibition of AKT also led to decreased colony formation in T98G and U251 cells and knocked down of CCNG2 reversed the result. Finally, overexpression of CCNG2 in glioma cells reduced tumor volume in a murine model. To conclude, low expression of CCNG2 correlated with the severity astrocytoma and CCNG2 overexpression could induce apoptosis and inhibit proliferation. Inhibition of AKT activity increased the expression of CCNG2. The present study highlights the regulatory consequences of CCNG2 expression and AKT activity in astrocytoma tumorigenesis and the potential use of CCNG2 in anticancer treatment.

Clinical management of traumatic superior orbital fissure and orbital apex syndromes.

OBJECTIVES: Both traumatic orbital apex syndrome (OAS) and traumatic superior orbital fissure syndrome (SFOS) are rare conditions after craniofacial injury. Few types of researches investigate the difference in clinical characteristics and outcome between them. We describe clinical features and cranial nerves functional recovery of traumatic OAS or SOFS and to discuss surgical decompression of these patients. PATIENTS AND METHODS: A retrospective study was performed of 15 patients diagnosed with traumatic OAS and 39 patients with traumatic SOFS from July 2010 to July 2017 in our hospital. The initial status and functional recovery of cranial nerve were evaluated based on visual perception and extraocular muscle movement. The average follow-up period was 11.8 months. RESULTS: 41 males' and 13 females' patients with a mean age of 38.3 years were included. 12 patients were diagnosed with internal carotid artery injury. In the OAS group, there is no visual recovery of those 10 totally blindness patients and only 5 functional recovery patients at 6-months follow up. No visual dysfunction occurred in the SOFS group. Cranial nerves Ⅲ, Ⅳ, and Ⅵ function recovery were better in the SOFS group than in the OAS group. CONCLUSION: Patients with OAS might undergo more severe cranial nerves injury and worse functional recovery. Due to the occurrence of internal carotid artery injury, CTA or DSA are recommended. Surgical decompression should be considered when there is evidence of optical canal fracture or bone fragment impingement of the superior orbital fissure.

Functional Recovery of Cranial Nerves in Patients with Traumatic Orbital Apex Syndrome.

OBJECTIVE: Traumatic orbital apex syndrome (TOAS) is a rare disease characterized by the damage of cranial nerves (CNs) II, III, IV, and VI. The aim of our study was to analyze the functional recovery of CNs in TOAS and discuss the management of these patients. METHODS: We retrospectively reviewed 28 patients with TOAS treated in the Department of Neurosurgery, Shanghai Changzheng Hospital from February 2006 to February 2016. Functional recovery of CNs was evaluated based on extraocular muscle movement and visual perception. Follow-up duration was at least 6 months. RESULTS: There were 26 males and 2 females with a mean age of 35.3 years. The most common cause of TOAS was traffic accident. CN IV suffered the lightest injury among CNs III, IV, and VI. CN II achieved obvious improvement at 3-month follow-up, while other CNs enjoyed evident improvement at 6-month follow-up. There was no significant difference between conservative treatment and surgical decompression. CONCLUSION: CNs passing through orbital apex region might recover to different degrees several months after proper management. Clinical decision should be individualized and surgical decompression could be considered with evidence of fracture, hematoma, or deformation.

Analysis of the embolization spinal dural arteriovenous fistula and surgical treatments on 52 cases of the patients.

BACKGROUND: Spinal dural arteriovenous fistula (SDAVF) highly threatens people's life and health. Effective methods for the diagnosis and treatment of the disease are badly needed in clinical application. OBJECTIVE: The objective of the present study was to sum up the diagnosis and treatment method of SDAVF to improve the diagnosis and treatment effect of the disease. METHODS: The epidemiological data, imaging data, therapeutic methods and postoperative follow-up data of 52 cases of patients with SDAVF received in our hospital in recent 6 years were collected and retrospectively analyzed. RESULTS: There were 43 male patients and 9 female patients with ages of 39-77 years and average age of 59.6 years. The course of disease was 1 to 48 months with an average disease course of 14.4 months. All the patients had syndromes of lower limb numbness, pain, weakness and other sensory and movement disorders mostly accompanied with defecation dysfunction. Magnetic resonance imaging (MRI) results demonstrated that spinal cord abnormalities were found in spinal cord, which could be diagnosed by digital subtraction angiography (DSA) examination. There were 40 cases received surgical treatment and there was no recurrence in the follow-up. There were 12 patients received embolotherapy, of whom 3 patients were operated the second time and 2 patients had embolization again. After 0.5-6 years of follow-up, postoperative symptoms of the 40 patients were improved in different degrees. The modified Aminoff-Logue function scoring was significantly decreased after treatment. CONCLUSION: SDAVF is the easily diagnosed and delayed spinal cord vascular lesions in clinical applications. The diagnosis relies mainly on MRI and DSA examinations. The surgical treatment effect is good and is not easily relapsed. The trauma of the interventional embolization treatment is small, but the recurrence rate is high.

Clinical features and functional recovery of traumatic isolated oculomotor nerve palsy in mild head injury with sphenoid fracture.

OBJECT: The aim of this study was to provide information about long-term functional outcome in patients with isolated oculomotor nerve palsy following minor head injury and to discuss surgical treatment of these patients, especially those with accompanying sphenoid fracture. METHODS: A retrospective analysis was made of 26 patients with traumatic isolated oculomotor nerve palsy. The severity of oculomotor nerve palsy and the functional recovery were evaluated based on extraocular muscle movement, eyelid movement, and pupil size. On average, patients were evaluated 3.6 days after the initial injury, and the average follow-up period was 14.2 months (range 3 months-2 years). RESULTS: Twenty men and six women were enrolled in this study. The most common cause of trauma was motor vehicle accident in 17 (65.4%) of 26. Among all the recorded symptoms, internal ophthalmoplegia was most frequently seen. The recovery rates of ptosis, external ophthalmoplegia, and internal ophthalmoplegia were 95% (19 of 20 patients), 83.3% (15 of 18 patients), and 50% (13 of 26 patients), respectively. The 6 patients with sphenoid fracture underwent surgical decompression of the superior orbital fissure, after which all patients experienced recovery from ptosis and external ophthalmoplegia and 66.7% (4 of 6 patients) recovered from internal ophthalmoplegia. CONCLUSIONS: Limited eye movement may be a major factor that negatively affects functional recovery after mild head injury. Sphenoid fracture might be one of the potential mechanisms involved in traumatic isolated oculomotor nerve palsy after mild head injury. Surgical decompression should be considered when there is evidence of bone compression of the superior orbital fissure.

Hyperbaric oxygen therapy in the management of paroxysmal sympathetic hyperactivity after severe traumatic brain injury: a report of 6 cases.

Paroxysmal sympathetic hyperactivity (PSH) after severe brain injury is detrimental to the recovery of patients. Pharmacologic management of PSH is difficult and efficacy is unpredictable or incomplete. This report presents 6 cases of PSH after extremely severe traumatic brain injury in which hyperbaric oxygen therapy (HBOT) controlled paroxysmal autonomic changes and posturing in the early subacute phase after limited success with conventional medication regimens. Thus, HBOT may present an option for the management of PSH in addition to pharmacologic therapy. Potential mechanisms for these effects are discussed.

Risk factors related to dysautonomia after severe traumatic brain injury.

BACKGROUND: Dysautonomia after severe traumatic brain injury (TBI) is a clinical syndrome affecting a subgroup of survivors and is characterized by episodes of autonomic dysregulation and muscle overactivity. The purpose of this study was to determine the incidence of dysautonomia after severe TBI in an intensive care unit setting and analyze the risk factors for developing dysautonomia. METHODS: A consecutive series of 101 patients with severe TBI admitted in a major trauma hospital during a 2-year period were prospectively observed to determine the effects of age, sex, mode of injury, hypertension history, admission systolic blood pressure, fracture, lung injury, admission Glasgow Coma Scale (GCS) score, injury severity score, emergency craniotomy, sedation or analgesia, diffuse axonal injury (DAI), magnetic resonance imaging (MRI) scales, and hydrocephalus on the development of dysautonomia. Risk factors for dysautonomia were evaluated by using logistic regression analysis. RESULTS: Seventy-nine of the 101 patients met inclusion criteria, and dysautonomia was observed in 16 (20.3%) of these patients. Univariate analysis revealed significant correlations between the occurrence of dysautonomia and patient age, admission GCS score, DAI, MRI scales, and hydrocephalus. Sex, mode of injury, hypertension history, admission systolic blood pressure, fracture, lung injury, injury severity score, sedation or analgesia, and emergency craniotomy did not influence the development of dysautonomia. Multivariate logistic regression revealed that patient age and DAI were two independent predictors of dysautonomia. There was no independent association between dysautonomia and admission GCS score, MRI scales, or hydrocephalus. CONCLUSIONS: Dysautonomia frequently occurs in patients with severe TBI. A younger age and DAI could be risk factors for facilitating the development of dysautonomia.

Prognostic influence and magnetic resonance imaging findings in paroxysmal sympathetic hyperactivity after severe traumatic brain injury.

Paroxysmal sympathetic hyperactivity (PSH) is a clinical syndrome affecting a subgroup of survivors of severe brain injury. In this study, the prevalence, magnetic resonance imaging (MRI) presentation, influence on the clinical course in the intensive care unit (ICU), and effect on neurological recovery of PSH were prospectively surveyed in 87 patients with severe traumatic brain injury (TBI). Cranial MRI was performed during the first 30 days after injury. The outcome was assessed according to the Glasgow Outcome Scale (GOS). PSH occurred in 18.4% of patients, with a greater incidence among younger patients and those with lower Glasgow Coma Scale (GCS) scores. Patients with PSH had more deep lesions as shown on cranial MRI, significantly longer ICU stays, and worse outcomes. PSH was shown to be common among patients with severe TBI who also had deep intraparenchymal lesions. The mechanism by which PSH influences patient outcomes has yet to be defined, but we believe that it may be mediated by diencephalic-mesencephalic dysfunction or disconnection.