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The persistent dysregulation and accumulation of poisonous proteins from destructive neural tissues and cells activate pathological mechanisms after traumatic brain injury (TBI). The lymphatic drainage system of the brain, composed of the glymphatic system and meningeal lymphatic vessels (MLVs), plays an essential role in the clearance of toxic waste after brain injury. The neuroprotective effect of interleukin 33 (IL-33) in TBI mice has been demonstrated; however, its impact on brain lymphatic drainage is unclear. Here, we established a fluid percussion injury model to examine the IL-33 administration effects on neurological function and lymphatic drainage in the acute brain of TBI mice. We verified that exogenous IL-33 could improve the motor and memory skills of TBI mice and demonstrated that in the acute phase, it increased the exchange of cerebrospinal and interstitial fluid, reversed the dysregulation and depolarization of aquaporin-4 in the cortex and hippocampus, improved the drainage of MLVs to deep cervical lymph nodes, and reduced tau accumulation and glial activation. We speculate that the protective effect of exogenous IL-33 on TBI mice's motor and cognitive functions is related to the enhancement of brain lymphatic drainage and toxic metabolite clearance from the cortex and hippocampus in the acute stage. These data further support the notion that IL-33 therapy may be an effective treatment strategy for alleviating acute brain injury after TBI., (© 2023. The Author(s).)

Objective To observe the effects of microRNA-7 (miR-7) on intracerebral hemorrhage-induced brain injury in rats and explore the underlying mechanism. Methods Seventy-five SD rats were used to establish intracerebral hemorrhage model through injection of VII collagenase into the pallidum. These rats were then divided into control, miR-7 agomir, agomir control, miR-7 antagomir and antagomir control groups, containing 15 animals in each group. On day 2 after modeling, rats were injected with 10 μL of physiological saline, miR-7 agomir, agomir control, miR-7 antagomir and antagomir control via the lateral ventricle, respectively. On day 7 after modeling, the neurological function score was evaluated, and then all rats were killed to obtain brain tissue. HE staining was conducted to observe the pathological changes of cerebral tissue. Brain water content was examined by the dried and wet mass. The expressions of miR-7, glial fibrillary acidic protein (GFAP) and epidermal growth factor receptor (EGFR) in the cerebral tissue around hemotomas were detected using real-time quantitative PCR. Western blotting was used to analyze the levels of GFAP, EGFR, signal transducers and activators of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) in the cerebral tissue around hemotomas. In addition, bioinformatics was used to predict the binding of miR-7 to EGFR. Both wild type luciferase reporter gene vector and corresponding mutant vector were constructed and then transfected into HEK293T cells along with miR-7 mimic for detecting the luciferase activity. Results In comparison with control group, miR-7 agomir markedly increased miR-7 level, alleviated the pathological impairment of cerebral tissues, reduced neurological function score and brain water content, and attenuated the expression levels of GFAP and EGFR and p-STAT3/STAT3 ratio in the cerebral tissue around hemotomas. An opposite effect was observed in response to miR-7 antagomir. However, their negative controls had no impact on the above indicators. There was a binding site between 3'-untranslated region within the EGFR and miR-7. Moreover, miR-7 mimic markedly decreased the luciferase activity of the reporter gene of wild type, but not its mutant. Conclusion The miR-7 can inhibit the EGFR/STAT3 signaling pathway to antagonize astrocyte activation, leading to the protection against brain injury after intracerebral hemorrhage in rats.

Objectives: Patients with traumatic brain injury (TBI) often suffer memory and cognitive impairments, and oxiracetam‐like drugs are considered to have a positive impact on these symptoms potentially. However, the efficacy and safety of L‐oxiracetam and oxiracetam in TBI patients have not been sufficiently investigated. Methods: The study adopts a multicenter, randomized, double‐blind, parallel‐group, phase 3 clinical trial design in 74 centers across 51 hospitals in China. A total of 590 TBI patients meeting criteria will be randomly allocated into three groups in a 2:2:1 ratio: L‐oxiracetam group, oxiracetam group, and placebo group. The treatment period is 14 days, with a follow‐up period of 90 days. The primary outcome measure is the change in the Loewenstein Occupational Therapy Cognitive Assessment score at 90 days after treatment. Secondary outcomes include changes in other cognitive assessments, neurological function, activities of daily living, and safety assessments. Discussion: There is no robust evidence to suggest that L‐oxiracetam and oxiracetam can enhance memory and cognitive function in patients with mild to moderate TBI. This study has the potential to answer this crucial clinical question. Trial registration: chinadrugtrials.org.cn, identifier CTR20192539; ClinicalTrials.gov, identifier NCT04205565. [ABSTRACT FROM AUTHOR]

Background: Severe traumatic brain injuries (TBIs) are an important health issue worldwide, which are associated with harmful side effects. This meta-analysis investigates the cognitive and functional outcomes in severe brain trauma cases. It assesses the impact on memory, verbal and visual abilities, attention, learning, and the presence of depression. The study provides a comprehensive overview of the consequences of severe brain trauma injury on cognitive and functional domains. Objective: The main objective of the current comprehensive meta-analysis study is to assess and analyze the impact of severe TBI on functional and cognitive outcomes, including verbal, visual, attention, learning, memory, and emotional stability. Methods: We collected data from three online databases, including PubMed, Cochrane Library, and Embase. Case-control trials related to severe TBI association with cognitive and functional outcomes were included. Verbal strength, visual functions, learning abilities, attention, memory, and depression were considered primary outcomes. Results: We have included 13 case-control studies with 1,442 subjects in this meta-analysis, which provide adequate data to determine the pooled effect size for targeted outcomes. The effect of severe TBI on the inducement of depression and impairment of memory, verbal, visual, attention, and learning abilities compared to the control group showed statistically significant outcomes (p < 0.05). Conclusion: Severe TBI is strongly associated with impaired cognitive and functional abilities, including visual and verbal disabilities, impaired memory, depression inducement, attention deficits, and learning disabilities. [ABSTRACT FROM AUTHOR]

Aim: We aim to identify the specific CD4+ T‐cell subtype influenced by brain‐to‐CLN signaling and explore their role during the acute phase of traumatic brain injury (TBI). Method: Cervical lymphadenectomy or cervical afferent lymphatic ligation was performed before TBI. Cytokine array and western blot were used to detect cytokines, while the motor function was assessed using mNss and rotarod test. CD4+ T‐cell subtypes in blood, brain, and CLNs were analyzed with Cytometry by time‐of‐flight analysis (CyTOF) or fluorescence‐activated cell sorting (FACS). Brain edema and volume changes were measured by 9.4T MRI. Neuronal apoptosis was evaluated by terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling (TUNEL) staining. Results: Cervical lymphadenectomy and ligation of cervical lymphatic vessels resulted in a decreased infiltration of CD4+ T cells, specifically CD11b‐positive CD4+ T cells, within the affected region. The population of CD4+CD11b+ T cells increased in ligated CLNs, accompanied by a decrease in the average fluorescence intensity of sphingosine‐1‐phosphate receptor‐1 (S1PR1) on these cells. Administration of CD4+CD11b+ T cells sorted from CLNs into the lateral ventricle reversed the attenuated neurologic deficits, brain edema, and lesion volume following cervical lymphadenectomy. Conclusion: The infiltration of CD4+CD11b+ T cells exacerbates secondary brain damage in TBI, and this process is modulated by brain‐to‐CLN signaling. [ABSTRACT FROM AUTHOR]

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]

The early stages of brain injury can induce acute liver injury, which can be recovered in the short term. Continued medication treatment during hospitalization for brain injury alleviates the prognosis and contributes to a high incidence of drug-induced liver injury (DILI). We hypothesize that there is an interaction between changes in the hepatic environment after brain injury and liver injury produced by intensive drug administration, leading to an upregulation of the organism's sensitivity to DILI. In this study, mice models of TBI were established by controlled cortical impact (CCI) and models of DILI were constructed by acetaminophen (APAP). All mice were divided into four groups: Sham, TBI, APAP, and TBI+APAP, and related liver injury indicators in liver and serum were detected by Western blot, Quantitative real-time PCR (qRT-PCR), and immunohistochemical staining. The results suggested that liver injury induced in the early stages of brain injury recovered in 3 days, but this state could still significantly aggravate DILI, represented by higher liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), oxidative stress (increase in malondialdehyde [MDA] concentration and deregulation of glutathione [GSH] and superoxide dismutase [SOD] activities), inflammatory response (activation of the HMGB1/TLR4/NF-κB signaling pathway, and increased messenger RNA [mRNA] and protein levels of pro-inflammatory cytokines including tumor necrosis factor alpha [TNF-α], interleukin [IL]-6, and IL-1β), and apoptosis (TUNEL assay, upregulation of Bax protein and deregulation of Bcl-2 protein). In summary, our results suggested that TBI is a potential susceptibility factor for DILI and exacerbates DILI. [ABSTRACT FROM AUTHOR]