The Kinetics of Intestinal Permeability in a Mouse Model of Traumatic Brain Injury.

Hippocampal Volume and Mood Disorders After Traumatic Brain Injury

BackgroundThe gut microbiota plays a critical role in regulating brain function through the microbiome-gut-brain axis (MGBA). Dysbiosis of the gut microbiota is associated with neurological impairment in Traumatic brain injury (TBI) patients. Our previous study found that TBI results in a decrease in the abundance of Prevotella copri (P. copri). P. copri has been shown to have antioxidant effects in various diseases. Meanwhile, guanosine (GUO) is a metabolite of intestinal microbiota that can alleviate oxidative stress after TBI by activating the PI3K/Akt pathway. In this study, we investigated the effect of P. copri transplantation on TBI and its relationship with GUO-PI3K/Akt pathway.MethodsIn this study, a controlled cortical impact (CCI) model was used to induce TBI in adult male C57BL/6J mice. Subsequently, P. copri was transplanted by intragastric gavage for 7 consecutive days. To investigate the effect of the GUO-PI3K/Akt pathway in P. copri transplantation therapy, guanosine (GUO) was administered 2 h after TBI for 7 consecutive days, and PI3K inhibitor (LY294002) was administered 30 min before TBI. Various techniques were used to assess the effects of these interventions, including quantitative PCR, neurological behavior tests, metabolite analysis, ELISA, Western blot analysis, immunofluorescence, Evans blue assays, transmission electron microscopy, FITC-dextran permeability assay, gastrointestinal transit assessment, and 16 S rDNA sequencing.ResultsP. copri abundance was significantly reduced after TBI. P. copri transplantation alleviated motor and cognitive deficits tested by the NSS, Morris’s water maze and open field test. P. copri transplantation attenuated oxidative stress and blood-brain barrier damage and reduced neuronal apoptosis after TBI. In addition, P. copri transplantation resulted in the reshaping of the intestinal flora, improved gastrointestinal motility and intestinal permeability. Metabolomics and ELISA analysis revealed a significant increase in GUO levels in feces, serum and injured brain after P. copri transplantation. Furthermore, the expression of p-PI3K and p-Akt was found to be increased after P. copri transplantation and GUO treatment. Notably, PI3K inhibitor LY294002 treatment attenuated the observed improvements.ConclusionsWe demonstrate for the first time that P. copri transplantation can improve GI functions and alter gut microbiota dysbiosis after TBI. Additionally, P. copri transplantation can ameliorate neurological deficits, possibly via the GUO-PI3K/Akt signaling pathway after TBI.

Traumatic brain injury (TBI) is one of the most common causes of neurological damage in young people. It was previously reported that dietary restriction, by either intermittent fasting (IF) or daily caloric restriction (CR), could protect neurons against dysfunction and degeneration in animal models of stroke and Parkinson's disease. Recently, several studies have shown that the protein Sirtuin 1 (SIRT1) plays a significant role in the induced neuroprotection following dietary restriction. In the present study, we found a significant reduction of SIRT1 levels in the cortex and hippocampus in a mouse model of mild weight-drop closed head TBI. This reduction was prevented in mice maintained on IF (alternate day fasting) and CR initiated after the head trauma. Hippocampus-dependent learning and memory (measured using a novel object recognition test) was impaired 30days post-injury in mice fed ad libitum, but not in mice in the IF and CR groups. These results suggest a clinical potential for IF and/or CR as an intervention to reduce brain damage and improve functional outcome in TBI patients.

Workshop on animal models of traumatic brain injury.

Traumatic brain injury results in significant morbidity and mortality and is associated with infectious complications, particularly pneumonia. However, whether traumatic brain injury directly impacts the host response to pneumonia is unknown. The objective of this study was to determine the nature of the relationship between traumatic brain injury and the prevalence of pneumonia in trauma patients and investigate the mechanism of this relationship using a murine model of traumatic brain injury with pneumonia. Data from the National Trauma Data Bank and a murine model of traumatic brain injury with postinjury pneumonia. Academic medical centers in Cincinnati, OH, and Boston, MA. Trauma patients in the National Trauma Data Bank with a hospital length of stay greater than 2 days, age of at least 18 years at admission, and a blunt mechanism of injury. Subjects were female ICR mice 8-10 weeks old. Administration of a substance P receptor antagonist in mice. Pneumonia rates were measured in trauma patients before and after risk adjustment using propensity scoring. In addition, survival and pulmonary inflammation were measured in mice undergoing traumatic brain injury with or without pneumonia. After risk adjustment, we found that traumatic brain injury patients had significantly lower rates of pneumonia compared to blunt trauma patients without traumatic brain injury. A murine model of traumatic brain injury reproduced these clinical findings with mice subjected to traumatic brain injury demonstrating increased bacterial clearance and survival after induction of pneumonia. To determine the mechanisms responsible for this improvement, the substance P receptor was blocked in mice after traumatic brain injury. This treatment abrogated the traumatic brain injury-associated increases in bacterial clearance and survival. The data demonstrate that patients with traumatic brain injury have lower rates of pneumonia compared to non-head-injured trauma patients and suggest that the mechanism of this effect occurs through traumatic brain injury-induced release of substance P, which improves innate immunity to decrease pneumonia.

How to improve the outcome of patients with traumatic brain injury in China

Background Traumatic brain injury (TBI) continues to be a leading cause of morbidity and mortality. Nutraceuticals and supplements have emerged as potential therapeutics to enhance brain recovery post-injury. Objective To review the current evidence on the efficacy of various nutraceuticals and supplements in TBI management. Methods A comprehensive search of PubMed, Scopus, and Google Scholar databases for studies published from January 2000 to December 2023 was conducted. Results Omega-3 fatty acids, play a crucial role in neuronal integrity and function, aiding TBI recovery by reducing oxidative stress and inflammation. Curcumin, known for its antioxidant and anti-inflammatory properties, reduces oxidative stress, increases brain-derived neurotrophic factor (BDNF), and suppresses inflammatory markers, enhancing cognitive recovery in TBI models. Fisetin, a flavonoid, reduces oxidative damage and inflammation by upregulating Nrf2 pathways and suppressing NF-kB, showing potential in TBI models. Vitamin D supplementation improves cognitive function, reduces inflammation, and correlates with better recovery outcomes in TBI patients. B vitamins, especially B2, B3, and B6, exhibit neuroprotective properties by reducing lesion volume, oxidative stress, and neuronal damage post-TBI. Vitamin E, an antioxidant, protects against TBI-induced oxidative stress and improves neurocognitive outcomes. These agents modulate various pro- and anti-inflammatory pathways to abrogate neuroinflammation, stabilize mitochondria, decrease oxidative stress, and promote neuronal recovery. Creatine, Coenzyme Q10, magnesium, and zinc also show promise in reducing inflammation, and enhancing recovery in TBI models, although further clinical research is needed. Conclusion Nutraceuticals and supplements show promising potential in the management of TBI. Trial registration: ClinicalTrials.gov identifier: NCT01814527. Trial registration: ClinicalTrials.gov identifier: NCT03032302.

The authors present two studies that investigate the biochemical and histologic effects of the nonimmunosuppressive neuroimmunophilin (NIMM) ligand V-10,367 in a mouse model of traumatic brain injury (TBI). In study 1, the authors examined the effect of V-10,367 (50 mg/kg x 2 per day, by mouth) on neurofilament M (NFM) protein levels and on alpha-spectrin breakdown products (SBDPs) when dosed for 2 days, starting 24 hours after TBI and killed on day 3. In study 2, V-10,367 was given for 10 days, starting 24 hours after TBI and the mice killed 6 weeks after TBI, to measure the extent of neurodegeneration (amino CuAg stain). The results in study 1 revealed that V-10,367-treatment significantly increased NFM protein levels in both sham and TBI mice. In addition, V-10,367 attenuated SBDP 150 levels in the cortex, striatum, and hippocampus. The results of study 2 indicated that TBI mice treated with V-10,367 demonstrated significantly less neurodegeneration compared to injured, vehicle-treated mice. In summary, these results suggest that NIMMs may be neuroprotective indirectly through inhibition of calpain-mediated cytoskeletal damage and perhaps via maintenance of neuronal plasticity. In the context of this mouse model of TBI, the therapeutic window for V-10,367's positive effects is at least 24 hours after injury, which, in the case of TBI models, is largely unprecedented for a neuroprotective compound.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, and is indiscriminate in who it affects, including children. Although there are currently no Food and Drug Administration-approved therapeutics, promising results from recent induced pluripotent stem cell-derived neural stem cell (iNSC) studies have demonstrated decreased tissue damage and functional deficits in pre-clinical TBI models. Moreover, while the rest has been traditionally identified as the standard of care following TBI, research now suggests that physical activity postinjury may significantly enhance neuroprotective and regenerative signaling in patients. Combining these two therapies may therefore synergistically improve recovery outcomes in TBI patients. In this study, we evaluated the combined therapeutic efficacy of iNSCs and structured treadmill walking on cellular, tissue, and functional recovery in a translational pediatric pig TBI model. One-month-old piglets received a controlled cortical impact-induced TBI and were randomly assigned to either a PBS (n = 4), PBS + treadmill (n = 4), iNSC (n = 4), or iNSC + treadmill (n = 4) treatment group. Piglets received intraparenchymal transplantations of either iNSCs or PBS 5 days post-TBI. At 1-week post-transplantation, piglets assigned to the treadmill treatment groups began a 12-week progressive walking regimen. Motor function and open field behavior assessments were performed pre-TBI and 12 weeks post-transplantation. Magnetic resonance imaging (MRI) and histological evaluation of collected brain tissue were performed 12 weeks post-transplantation. Immunohistochemistry revealed long-term survival, engraftment, and differentiation of transplanted iNSCs into neurons, astrocytes, and oligodendrocytes in treated piglets. Furthermore, iNSC + treadmill treatment showed increased endogenous neuron and oligodendrocyte survival, increased proliferation of neuroblasts, and decreased populations of reactive astrocytes and immune cells in TBI brain tissue. MRI analysis revealed a significant reduction in lesion volume, midline shift, and white matter degradation with preserved cerebral blood flow following both iNSC and iNSC + treadmill interventions. These cellular and tissue-level effects corresponded with significant motor function recovery as seen through increased step and stride length with decreased stance percentage and time. During open field behavioral assessments, iNSC and iNSC + treadmill-treated piglets demonstrated improved exploratory behaviors. These findings suggest that the combination of iNSCs with structured treadmill walking significantly enhanced TBI recovery beyond the therapeutic potential of iNSCs or exercise alone. Therefore, this novel combination therapy needs to be further explored as a potential transformative treatment option for pediatric TBI patients.

Objectives. The Brain Trauma Foundation (BTF) Guidelines for Prehospital Management of Traumatic Brain Injury (TBI) are intended to standardize treatment and improve outcomes in severe TBI patients. The key guideline components focus on airway management, blood pressure support, Glasgow Coma Score assessment, and transport. The purposes of this study were to determine if providers could learn and retain the guidelines (education), assess if providers would use the guidelines in practice (implementation), and evaluate the effect of guideline implementation on patients (outcomes). Methods. Data were collected prospectively on all trauma patients for five months. Providers were then educated on the TBI guidelines over two months, and five additional months of data were collected. A knowledge test was given before and after the course and three months later to assess education. To assess implementation, data were analyzed to determine whether providers were using the key interventions more consistently after education. The clinical courses of TBI patients before and after guideline implementation were measured to assess outcomes. Results. Knowledge of TBI care improved significantly after education and remained elevated at three months (62% vs. 82% vs. 79%, p < 0.001). For the 1,044 patients seen, providers demonstrated higher rates of appropriate care, resulting in lower rates of hypoxia (2.8% vs. 1.1%, p = 0.010) and hypotension (4.8% vs. 2.0%, p = 0.018). Mortality was significantly decreased (34.6% vs. 17.0%, p = 0.039), and rates of patients with maximum functional scores at 14 days significantly increased (Glasgow Outcome Score 44.2% vs. 66.0%, p = 0.025; Rancho Los Amigos Scale 55.9% vs. 77.3%, p = 0.045). Conclusion. Providers were able to learn and implement the BTF guidelines, and outcomes in TBI patients were significantly improved. All emergency medical services providers should be trained in these potentially lifesaving guidelines.

P033 Transcranial direct current stimulation in a mouse model of traumatic brain injury

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Identification of endogenous neuroprotective mechanisms after TBI and the development of therapeutic targets to improve TBI outcomes are areas of intense scientific research. In this review, we summarize genetically modified TBI mouse models and highlight the recent scientific findings from using such models, including mediators of inflammation, programmed cell death and metabolism, modulators of vascular tone and membrane channel proteins. A deeper understanding of the complex biochemical processes and genetic pathways in TBI could offer personalized genomic-based therapies for and improve clinical outcomes in TBI patients.

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are a recently established family of regulatory small non-coding RNAs that modulate diverse biological processes. Growing evidence indicates that tsRNAs are involved in neurological disorders and play a role in the pathogenesis of neurodegenerative disease. However, whether tsRNAs are involved in traumatic brain injury-induced secondary injury remains poorly understood. In this study, a mouse controlled cortical impact model of traumatic brain injury was established, and integrated tsRNA and messenger RNA (mRNA) transcriptome sequencing were used. The results revealed that 103 tsRNAs were differentially expressed in the mouse model of traumatic brain injury at 72 hours, of which 56 tsRNAs were upregulated and 47 tsRNAs were downregulated. Based on microRNA-like seed matching and Pearson correlation analysis, 57 differentially expressed tsRNA-mRNA interaction pairs were identified, including 29 tsRNAs and 26 mRNAs. Moreover, Gene Ontology annotation of target genes revealed that the significantly enriched terms were primarily associated with inflammation and synaptic function. Collectively, our findings suggest that tsRNAs may be associated with traumatic brain injury-induced secondary brain injury, and are thus a potential therapeutic target for traumatic brain injury. The study was approved by the Beijing Neurosurgical Institute Animal Care and Use Committee (approval No. 20190411) on April 11, 2019.

Factor Analysis of the Rivermead Post-Concussion Symptoms Questionnaire in Mild-to-Moderate Traumatic Brain Injury Patients

Is the Silent Epidemic Keeping Patients Awake?