Search

Objective：Traumatic brain injury (TBI) is one of the most serious public health problems in the world. Hydrogen (H2), a flammable, colorless, and odorless gas, has been observed to have preventive and therapeutic effects on brain trauma and other neurological disorders, but its exact mechanism has not been fully clarified. Methods: To further study the mechanism underlying the role of hydrogen gas in alleviating BBB damage after TBI, we performed the scratch injury model on cultured brain microvascular endothelial cells (bEnd.3), which formed the microvascular endothelial barrier – an integral part of the highly specialized BBB. Results: In the case of TBI, hydrogen was able to improve the decline of cell viability induced by TBI. More importantly, inhibition of PI3 K/Akt/GSK3β signal pathway or activation of autophagy reduced the protective effect of hydrogen on cell viability, indicating that such protective effect was regulated by PI3 K/Akt/GSK3β signal pathway and was related to the inhibition of autophagy. Conclusion: So we concluded that hydrogen improved the cell viability in a microvascular endothelial cell model of TBI partly through inhibition of autophagy, and inhibitory effect of hydrogen on autophagy was exerted by activating PI3 K/Akt/GSK3β signal pathway. These findings enriched our knowledge about the mechanism of hydrogen therapy against TBI. [ABSTRACT FROM AUTHOR]

Few studies have explored the effect of hydrogen on neuronal apoptosis or impaired nerve regeneration after traumatic brain injury, and the mechanisms involved in these processes are unclear. In this study, we explored neuroprotection of hydrogen‐rich medium through activation of the miR‐21/PI3K/AKT/GSK‐3β pathway in an in vitro model of traumatic brain injury. Such model adopted PC12 cells with manual scratching. Then, injured cells were cultured in hydrogen‐rich medium for 48 hours. Expression of miR‐21, p‐PI3K, p‐Akt, p‐GSK‐3β, Bax and Bcl‐2 was measured using RT‐qPCR, Western blot analysis and immunofluorescence staining. Rate of apoptosis was determined using TUNEL staining. Neuronal regeneration was assessed using immunofluorescence staining. The results showed that hydrogen‐rich medium improved neurite regeneration and inhibited apoptosis in the injured cells. Scratch injury was accompanied by up‐regulation of miR‐21, p‐PI3K, p‐Akt and p‐GSK‐3β. A miR‐21 antagomir inhibited the expression of these four molecules, while a PI3K blocker only affected the three proteins and not miR‐21. Both the miR‐21 antagomir and PI3K blocker reversed the protective effect of hydrogen. In conclusion, hydrogen exerted a neuroprotective effect against neuronal apoptosis and impaired nerve regeneration through activation of miR‐21/PI3K/AKT/GSK‐3β signalling in this in vitro model of traumatic brain injury. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) are very important regulators of biological processes such as development, cellular differentiation, and tumor generation. MiRNA microarray has been found to be a high throughput global analysis tool for detecting miRNA expression profiling, and miRNA expression profiling will facilitate the study of the biological function of miRNAs. In this report, we describe the miRNA expression level in rat cerebral cortex after traumatic brain injury using microarray method. We choose several time points post brain injury: 6 h, 24 h, 48 h and 72 h, respectively, to reveal differential expression of miRNAs in rat brain cortex compared with control groups. Our research revealed that 136 miRNAs were expressing at 6 h post injury, in which 13 miRNAs were more than 2-fold up-regulated, and 14 miRNAs were more than 2-fold down-regulated; 118 miRNAs were expressing at 24 h post injury, in which 4 miRNAs were more than 2-fold up-regulated, and 23 miRNAs were more than 2-fold down-regulated; 149 miRNAs were expressing at 48 h post injury, in which 16 miRNAs were more than 2-fold up-regulated, and 11 miRNAs were more than 2-fold down-regulated; and 203 miRNAs were expressing at 72 h post injury, in which 19 miRNAs were more than 2-fold up-regulated, and 5 miRNAs were more than 2-fold down-regulated. Furthermore, we revealed global up-regulation of miR-21 expression within all the four time points post injury. Finally, we utilized qRT-PCR methods to verify the microarray results. The qRT-PCR results indicated good consistency with the results of the microarray method. Our microarray based analysis of microRNA expression in rat cerebral cortex after traumatic brain injury has shown that some microRNA such as miR-21 could be involved in the intricate process of TBI course. [Copyright &y& Elsevier]

Cardiac injury is a common complication following traumatic brain injury (TBI) that can lead to poor clinical outcomes. Angiotensin II type 2 receptor (AT2R) activation exerts protective roles in the brain and heart, yet its potential impact on TBI or TBI-induced cardiac deficits remains elusive. The goal of this study was to investigate the influence of AT2R activation on recovery after TBI-induced cognitive and cardiac injury using the selective nonpeptide AT2R agonist compound 21 (C21). TBI was induced by cortical impact injury in male adult C57BL/6J mice, and the mice received C21 (0.03 mg/kg, intraperitoneally) starting from 24 h after TBI and continuing once daily. C21 facilitated cognitive function recovery until 1 month after TBI. C21 alleviated blood-brain barrier leakage and brain edema and inhibited the expression of proinflammatory cytokines in the brain after 3 consecutive days of treatment. C21 improved cerebral blood flow after 1 month, although the lesion volume was not affected. C21 also reduced the expression of proinflammatory cytokines in the heart after a 3-day consecutive treatment. Meanwhile, C21 benefited cardiac function, as identified by increased left ventricular ejection fraction 1 month after TBI. In addition, C21 alleviated TBI-induced cardiac hypertrophy and fibrosis; however, blood pressure was not affected. Our results demonstrate that AT2R activation ameliorates TBI-induced neurological and cardiac deficits. [ABSTRACT FROM AUTHOR]

Prognosis evaluation is crucial for the effective management of patients with acute traumatic brain injury (TBI). However, there is still a lack of routinely available blood indicators for mortality risk in clinical practice. To investigate whether blood red cell distribution width to platelet count ratio (RPR) correlates with hospital mortality of TBI, clinical data of 2220 patients with TBI were extracted from two large intensive care unit cohorts (MIMIC-III and eICU Database), and were integratively analyzed using our developed method named MeDICS. We found that higher RPR can be observed among non-survivors than survivors of TBI (p < 0.001). It had a moderately good prognostic performance for mortality with an area under receiver-operating characteristic curve (AUC) of 0.7367, which was greater than that of Glasgow Coma Scale (GCS; AUC = 0.6022). Besides, the nomogram consisting of RPR, GCS, and other risk factors was developed, where 10-fold cross-validation was performed to protect it against overfitting. A Harrell's C-index of 0.8523 was determined, suggesting an improved prognostic value based on RPR. The in vivo experiments further confirmed the association between RPR and neuro-outcome after TBI. It indicated that the continuous change in RPR post-injury is attributed to the development of inflammation, which emphasized the importance of controlling inflammatory response in clinical treatment. Taken together, RPR is a promising routinely available predictor of mortality for acute TBI. The nomogram generated from it can be used in resource-limited settings, thus be proposed as a prognosis evaluation aid for patients with TBI in all levels of medical system. [ABSTRACT FROM AUTHOR]

Pyroptosis is a highly specific type of inflammatory programmed cell death that different from necrosis or apoptosis. It is initiated by cellular detection of acute damage via recognizing pathogen-associated molecular patterns (PAMPs) by NOD-like receptors (NLRs) or AIM2-like receptor (AIM2). NLRs and AIM2 could trigger the formation of a multi-protein complex, known as inflammasome. It also contains apoptotic speck-containing protein (ASC) and pro-Caspase-1, and could process the signals to induce a cascade of inflammatory response. Recently, growing evidence showed that inflammasome-mediated pyroptosis is involved in the pathogenesis of traumatic brain injury (TBI). However, less attention has been paid to their particular roles in regulating blood-brain barrier (BBB) damage, the central pathological change in secondary brain damage of TBI. Thus, we designed this research to explore the impact and mechanism of NLRs and AIM2 inflammasome-mediated pyroptosis in BBB after TBI. We employed the controlled cortical impact (CCI) mice model and manipulated the severity of pyroptosis in BBB using Caspase-1 inhibitor, Ac-YVAD-cmk. We found that TBI led to NLRs and AIM2 inflammasome-mediated pyroptosis in brain microvascular endothelial cells (BMVECs) from injured cerebral cortex. Ac-YVAD-cmk treatment inhibited pyroptosis in injured BMVECs by suppressing the expression of essential inflammasome subunit – Caspase-1 and pivotal downstream pro-inflammatory cytokines (IL-1β and IL-18), as well as hindering GSDMD cleavage and ASC oligomerization. In addition, inhibiting pyroptosis could alleviate TBI-induced BBB leakage, brain edema, loss of tight junction proteins, and the inflammatory response in injured BMVECs. These effects contributed to improving the neurological outcome of CCI mice. In conclusion, NLRs and AIM2 inflammasome-mediated pyroptosis could aggravate BBB damage after TBI. Targeting and controlling pyroptosis in injured BBB would be a promising therapeutic strategy for TBI in the future. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major public health problem with long-term neurobehavioral sequela. The evidences have revealed that TBI is a risk factor for later development of neurodegenerative disease and both the single and repetitive brain injury can lead to the neurodegeneration. But whether the effects of accumulation play an important role in the neurodegenerative disease is still unknown. We utilized the Sprague Dawley (SD) rats to develop the animal models of repetitive mild TBI and single mild TBI in order to detect the neurobehavioral changes. The results of neurobehavioral test revealed that the repetitive mild TBI led to more severe behavioral injuries than the single TBI. There were more activated microglia cells and astrocytes in the repetitive mild TBI group than the single TBI group. In consistent with this, the levels of TNF-α and IL-6 were higher and the expression of IL-10 was lower in the repetitive mild TBI group compared with the single TBI group. The expression of amyloid precursor protein (APP) increased in the repetitive TBI group detected by ELISA and western blot. But the levels of total tau (Tau-5) and P-tau (ser202) seem no different between the two groups in most time point. In conclusion, repetitive mild TBI could lead to more severe neurobehavioral impairments and the effects of accumulation may be associated with the increased inflammation in the brain. [ABSTRACT FROM AUTHOR]

Our recent researches have identified increased expression of miR-21-5p in rats brain following traumatic brain injury (TBI), which protected against blood-brain barrier (BBB) damage. To further study the mechanism underlying the role of miR-21-5p on alleviating BBB damage after TBI, we performed the scratch injury model on cultured brain microvascular endothelial cells (BMVECs), which formed the microvascular endothelial barrier – an integral part of the highly specialized BBB. The expression level of miR-21-5p in BMVECs was observed to be increased after scratch injury, and could be further up-regulated by transfecting miR-21-5p mimics. We found that up-regulation of miR-21-5p level in BMVECs can alleviate endothelial barrier damage and loss of tight junction proteins. To further investigate the mechanism of this protective effect, we evaluated the impact of miR-21-5p on inflammation and apoptosis in injured BMVECs. On one hand, miR-21-5p suppressed inflammation by regulating the expression of inflammatory cytokines and NF-kB signaling. On the other hand, miR-21-5p inhibited cellular apoptosis by regulating the expression of apoptosis factors and Akt signaling. In addition, we also detected the activity of Ang-1/Tie-2 axis (associated with BBB stabilization) in BMVECs after scratch injury, and found that miR-21-5p can promote its activation. Taken together, miR-21-5p alleviates leakage of injured brain microvascular endothelial barrier through suppressing inflammation and apoptosis, while impacting the activities of NF-kB, Akt and Ang-1/Tie-2 signaling. Thus, miR-21-5p could be a potential therapeutic target for interventions of BBB damage after TBI. [ABSTRACT FROM AUTHOR]

Our recent studies have identified increased expression of miR-21 in brain following traumatic brain injury (TBI), which alleviated brain edema that related to the blood–brain barrier (BBB) leakage. To analyze the potential effect of miR-21 on secondary BBB damage after TBI, we employed the fluid percussion injury rat model and manipulated the expression level of miR-21 in brain. We found that miR-21 level in brain microvascular endothelial cells (BMVECs) in lesioned cerebral cortex can be upregulated or downregulated by intracerebroventricular infusion of miR-21 agomir or antagomir. Upregulated miR-21 level conferred a better neurological outcome of TBI, and alleviated TBI-induced secondary BBB damage and loss of tight junction proteins. To explore the molecular mechanism underlying this protective effect, we detected the impact of miR-21 on the expression of Angiopoietin-1(Ang-1) and Tie-2, which can promote the expression of tight junction proteins and amplify BBB stabilization. We found that miR-21 exerts the protective effect on BBB by activating the Ang-1/Tie-2 axis in BMVECs. Thus, miR-21 could be a potential therapeutic target for interventions of secondary BBB damage after TBI. [ABSTRACT FROM AUTHOR]

Abstract: Emerging evidence demonstrates that severe illness could induce critical illness-related corticosteroid insufficiency (CIRCI) and cause poor prognosis. The purpose of this study was to test the hypothesis that methylprednisolone (MP), a synthetic glucocorticoid, promotes post-traumatic apoptosis in both the hypothalamus and pituitary, resulting in acute CIRCI and increased mortality in the acute phase of traumatic brain injury (TBI). We tested this hypothesis by measuring acute CIRCI in rats subjected to fluid percussion injury (FPI) and treated with MP (5–30mg/kg). The corticosteroid response to TBI was evaluated using the corticosterone increase index (CII), where values less than 2.5 were considered indicative of acute CIRCI. The CII of MP treated rats was comparable to that of saline treated control rats before injury but was significantly decreased in injured rats receiving high-dose MP on post-injury day 7. Similarly, the incidence of acute CIRCI was significantly higher in the high-dose MP group on post-injury day 7. Furthermore, the CII of rats that did not survive post-injury was significantly lower compared to that of survival and was indicative of acute CIRCI. We also examined apoptosis in the paraventricular nucleus (PVN) of the hypothalamus and the adenohypophysis of the pituitary, using a TUNEL assay and transmission electron microscopy (TEM). The number of TUNEL-positive cells was significantly higher in injured rats treated with high-dose MP. No TUNEL-positive cells were detected in the adenohypophysis across experimental groups at either 7 or 14days after TBI. However, autopsies performed on rats that did not survive post-injury revealed obvious apoptotic cells in the adenohypophysis. Moreover, TEM revealed morphological changes characteristic of apoptosis in both the PVN and adenohypophysis of high-dose MP treated rats. These data suggest that MP therapy for TBI could increase neuronal apoptosis in both the hypothalamus and pituitary and consequently exacerbate acute CIRCI and mortality induced by TBI. [Copyright &y& Elsevier]