RARE DISEASE
Moderate and severe traumatic brain injury
Moderate and severe traumatic brain injury
Moderate and severe traumatic brain injury
Drug discovery
15
drugs
With orphan designations
Overview
Moderate to severe traumatic brain injury (TBI) involves structural brain damage with Glasgow Coma Scale (GCS) scores of 3-12, prolonged unconsciousness (>30 minutes), and post-traumatic amnesia [1][5][16]. These injuries often require acute neurosurgical intervention, multimodal monitoring, and long-term rehabilitation to address cognitive, motor, and behavioral deficits [3][5][13]. Mortality risks increase with severity, while survivors frequently face lifelong disability [6][10][16].
Therapies
Acute care: ICP monitoring, osmotic therapy (mannitol), decompressive craniectomy [5][13][18]
Pharmacologic: Anti-seizure prophylaxis, beta-blockers, amantadine for cognitive recovery [3][8][18]
Rehabilitation: Multidisciplinary programs with cognitive therapy, physiotherapy, and vocational retraining [6][10][15]
Categories: rare neurological diseases
Research Papers
1,737 drug discovery papers about Moderate and severe traumatic brain injury, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,737 drug discovery papers about Moderate and severe traumatic brain injury, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | Effect of early intravenous magnesium sulfate on clinical outcomes in patients with moderate to severe traumatic brain injury: a study protocol for a randomized controlled trial.
Traumatic brain injury (TBI) is associated with substantial mortality and long-term disability worldwide. Acute respiratory distress syndrome (ARDS), as a common complication in moderate-to-severe TBI, further aggravates clinical outcomes and resource utilization. However, effective interventions to prevent TBI-associated ARDS remain limited. This trial aims to evaluate whether early intravenous magnesium sulfate reduces the risk of ARDS and improves clinical outcomes in patients with moderate-to-severe TBI. This protocol outlines a randomized, controlled, double-blind clinical trial involving 164 adults (18-75 years) with moderate-to-severe TBI (Glasgow Coma Scale [GCS] 3-12) within 8 h of injury. Participants will be stratified by baseline GCS (3-8 vs. 9-12) and randomized 1:1 to the intravenous magnesium sulfate group (initial 2 g over 30 min within 8 h, then 2 g daily for 5 days; total 12 g) or an identical placebo group. Both groups will receive guideline-directed standard TBI care. The primary endpoint is a 28-day hierarchical composite (all-cause mortality, then new-onset ARDS within days 1-7, then ≤ 20% increase in PaO₂/FiO₂ AUC from baseline over days 0-5). The hierarchical composite primary endpoint will be analyzed using the win-ratio method. Secondary outcomes include ICU and hospital length of stay, complications, and serial biomarker changes. Follow-up assessments will be conducted on day 28 and at 6 months post-treatment. If effective, this low-cost intervention could be readily incorporated into standard TBI care and help prevent TBI-associated ARDS. Chinese Clinical Trial Registry, identifier ChiCTR2600120684.
2026-09-24 | Outcomes of Older Adults on Anticoagulation Sustaining Ground-Level Falls: A Retrospective Analysis.
Ground-level falls (GLFs) are a leading cause of morbidity and mortality in older adults, a population frequently prescribed anticoagulants. While effective for thromboembolic prevention, the association between anticoagulation and fall-related complications, including traumatic brain injury (TBI), remains mixed, with prior studies reporting inconsistent findings. This study utilized a large national database to evaluate whether preinjury anticoagulation is associated with worse outcomes following GLFs, hypothesizing increased mortality and severe TBI in anticoagulated versus nonanticoagulated older adults. The 2017-2022 Trauma Quality Improvement Program database was queried for older adult trauma patients (OATPs) (≥65 y) presenting after GLFs. Patients were stratified by anticoagulant use. Bivariate analyses and multivariable logistic regression assessed associations with TBI severity and inhospital mortality. Among 1,062,072 OATPs, 300,623 (28.3%) were on anticoagulation. Anticoagulated patients had higher rates of mild (21.1% versus 14.0%, P < 0.001), moderate (13.2% versus 11.9%, P < 0.001), and severe TBI (4.9% versus 2.8%, P < 0.001). They more frequently required the highest-level trauma activation (2.4% versus 1.5%, P < 0.001) and had higher complication (6.4% versus 4.5%, P < 0.001) and mortality rates (4.3% versus 2.5%, P < 0.001). Anticoagulation was independently associated with mortality (OR 1.34, CI 1.31-1.37, P < 0.001) and TBI severity, from mild (OR 1.64, CI 1.62-1.65, P < 0.001) to severe TBI (OR 1.80, CI 1.76-1.84, P < 0.001). Preinjury anticoagulation in OATPs was independently associated with severe TBI and mortality. While anticoagulation remains important for thromboembolic prevention, these findings highlight substantial risk in a fall-prone aging population. Re-evaluation of geriatric anticoagulation guidelines to better balance thromboembolic protection with trauma-related risk appears warranted.
2026-09-19 | Clinical Profile and Association Between Admission Glasgow Coma Scale and In-Hospital Mortality Among Children With Head Injury at a Tertiary Care Centre in Central India.
Introduction Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality in children worldwide, and injury patterns in low- and middle-income countries differ from those reported in high-income settings. Data from tertiary centres in central India remain limited. This study describes the clinical profile, management pattern, and in-hospital outcome of children admitted with head injury at a tertiary care centre and evaluates the association between admission Glasgow Coma Scale (GCS) and in-hospital mortality. Methods This retrospective observational study included 81 children admitted with head injury to the Department of Pediatric Surgery, Gandhi Medical College, Bhopal, India, between January 2026 and June 2026. Demographic details, mechanism of injury, clinical features at presentation, admission GCS, non-contrast computed tomography (NCCT) head findings, management type, length of hospital stay, and outcome were recorded from case records. The association between GCS severity and outcome was assessed using Fisher's exact test, the chi-square test, and the Mann-Whitney U test, with p < 0.05 considered significant. Results The mean age was 5.03 ± 3.31 years, with a male-to-female ratio of 1.53:1. Fall from height was the commonest mechanism (44 of 81, 54.3%), followed by road traffic accidents (17 of 81, 21.0%). Most children presented with mild head injury (GCS 13-15; 61 of 81, 75.3%); eight (9.9%) had severe injury (GCS ≤8). NCCT was performed in 78 of 81 children (96.3%); skull fracture (37 of 78, 47.4%) was the most common finding, followed by extradural hemorrhage (20 of 78, 25.6%) and subdural hemorrhage (18 of 78, 23.1%). Conservative management was employed in 79 of 81 children (97.5%), with two (2.5%) requiring operative intervention. Overall in-hospital mortality was 11.1% (9 of 81). On Fisher's exact test, children with mild GCS had significantly lower odds of death compared with the combined moderate-to-severe group used as the reference category (odds ratio, 0.03; 95% CI, 0.003-0.22; p = 0.00003); seven of eight children with severe GCS died, compared with one of 61 with mild GCS. Mean GCS was significantly lower among children who died than among those discharged (6.1 versus 14.0; Mann-Whitney U = 23.0; p = 0.00000024). Conclusions Pediatric head injury at this centre was predominantly mild and managed conservatively, with fall from height as the leading mechanism, consistent with other Indian series. Lower admission GCS was strongly associated with in-hospital mortality on unadjusted analysis. These findings are descriptive and hypothesis-generating within this cohort; larger, prospective, multicentric studies with multivariable analysis are needed to confirm this association and identify additional factors influencing outcome.
2026-09-03 | Sleep Management and Recovery After TBI in Kids (SMART-Kids): Pilot Trial Using Melatonin.
Sleep disturbances after pediatric traumatic brain injury (TBI) occur in more than 50% of survivors and portend worse cognitive and psychosocial outcomes. We aimed to determine feasibility and acceptability of an early melatonin and sleep education intervention study after TBI. We conducted a pilot randomized, double-blinded placebo-controlled trial of melatonin for 30 days vs placebo in children aged more than 6 to 18 years started within 72 hours of TBI admission. All participants received sleep education handouts with access to short videos. Covariate adaptive randomization was used to balance groups by age and TBI severity. Primary outcomes were feasibility and acceptability. Secondary effectiveness sleep outcomes were explored with the Sleep Disturbances Scale for Children (SDSC) T-scores and actigraphy. Twenty-one (40%) of 53 approached patients consented (median age, 10.7 years), and 19 (91%) completed the study. Fifteen (79%) reported adherence (defined ≥5 of 7 days per week for medication), and 15 provided usable actigraphy data. We found high acceptability with no safety concerns identified. Randomization procedures were successful with no between-group differences observed. A higher frequency of clinically important SDSC scores (T-score ≥60, indicating moderate or greater risk for sleep disorder) at 30 days were found with placebo vs melatonin. Actigraphy showed nonsignificant differences. Melatonin paired with sleep education early during hospitalization and continued for 30 days is feasible and acceptable. Although not powered for effectiveness, results suggest melatonin may reduce sleep disturbances by clinically meaningful margins after TBI hospitalization, and results can be used as effect size estimates for a larger study.
2026-09-02 | Severity-stratified gut microbiome dysbiosis and systemic neuroinflammation in acute traumatic brain injury: a metagenomic and cytokine profiling study.
The gut-brain axis has increasingly been implicated in the pathophysiology of traumatic brain injury (TBI). However, few human studies have simultaneously examined gut functional metagenomics and peripheral cytokine profiles across mild to moderate-to-severe TBI, which limits our understanding of how gut health may influence recovery outcomes in TBI patients. This cross-sectional case-control investigation involved the collection of fecal and matched serum samples within 7 days post-injury from 60 mild TBI patients (MT; GCS 13-15), 45 moderate-to-severe TBI patients (MST; GCS ≤ 12), and 113 healthy controls (HC). Shotgun metagenomic sequencing examined gut microbiota. Serum IL-1β, IL-6, IL-8, and TNF-α were measured using a 4-plex Luminex test. Spearman correlation was utilized to construct a hypothesis relating cytokine levels to microbial severity-stratified abundance patterns. TBI was associated with severity-dependent remodeling of the gut microbiota. Alpha diversity decreased from HC to MST (p < 10-6), and community structure varied significantly among all three groups (PERMANOVA, p = 0.001). Serum TNF-α increased in a severity-associated manner (MST vs. HC and MT, p adj < 0.015). Among 332 differentially abundant species, butyrate-producing commensals fell abruptly at MT with no additional decline in MST, suggesting an apparent floor-like pattern rather than confirming a true biological floor effect. For example, Faecalibacterium prausnitzii dropped from 9.02% in HC to 4.29% in MT. In terms of function, metagenomic inference indicated that pathways for fermentative metabolism and short-chain fatty acid (SCFA) biosynthesis were largely suppressed, suggesting a predicted reduction in microbial SCFA production capacity. On the other hand, secondary bile acid synthesis was specifically increased in MST-dominant KOs (85%). Systemically, reduced commensals showed weak, directionally consistent correlations with pro-inflammatory cytokines (|ρ| = 0.16-0.25), although none of the species-cytokine associations survived FDR correction. Acute TBI is associated with severity-specific gut dysbiosis, which is accompanied by systemic neuroinflammation. The early reduction of butyrate-producing taxa in mild TBI suggests that the early post-injury period may represent a potential window for future gut-targeted intervention studies.
proteins
2026-01-10 | Incretin Mimetics as Potential Therapeutics for Concussion and Traumatic Brain Injury: A Narrative Review.
Traumatic brain injury (TBI) represents a significant health concern, with an estimated 70 million annual cases worldwide. Mild brain trauma (concussions) is the most common TBI (81%), followed by moderate (11%) and severe (8%). Cytokine release and neuroinflammation after TBI may cause blood-brain barrier and tissue damage, triggering unfavorable outcomes, including disabilities and mortality. Current TBI treatments, focused on preventing secondary injury, are limited and insufficient. Therefore, new therapeutic approaches are necessary. A growing body of recent literature supports the potential use of incretins: glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and glucagon receptor agonists, as potent neurotrophic/neuroprotective agents. Experiments performed in cellular and animal models, and a limited number of clinical studies, provide evidence that incretins might be a novel and effective treatment for TBI. Incretin-based compounds have already been shown to be safe and efficacious for the treatment of type 2 diabetes mellitus in humans. Therefore, incretins are ideal candidates for rapid evaluation in clinical trials of TBI and might become a novel therapeutic tool for a condition that has very few disease modifying treatments available. Well-designed human clinical trials are urgently needed to determine optimal dosing, timing, and patient selection for effective incretin use in concussion and TBI.
2026-01-01 | Evaluating Quality of Life Effects after Growth Hormone Replacement in Individuals with Moderate-to-Severe Traumatic Brain Injury and Growth Hormone Deficiency
Traumatic brain injury (TBI) is a leading cause of long-term disability, with chronic complications including growth hormone deficiency (GHD). Growth hormone replacement therapy (GHRT) has shown promise in improving these outcomes, but evidence specific to moderate-to-severe TBI (msTBI) populations using TBI-specific quality of life (QoL) measures remains limited. This prospective cohort study evaluated the impact of 1 year of GHRT on QoL in 69 adults with msTBI and GHD, using the QoL after Brain Injury (QOLIBRI) questionnaire. GHD was diagnosed via glucagon stimulation testing at least 1-year postinjury. GHRT was initiated and titrated to achieve therapeutic insulin-like growth factor 1 levels, with QOLIBRI scores collected at baseline, 6 months, and 12 months. Statistical analyses included Friedman tests and multivariate mixed-effects models. Results demonstrated significant improvements in all QOLIBRI domains after 1 year of GHRT. Mixed effects analysis showed a trend toward lower overall QoL after GHRT in severe TBI patients and most model variation existed among individuals by domain of QOLIBRI. These findings suggest that GHRT is associated with improved cognitive, emotional, and physical aspects of QoL in msTBI patients with GHD, as measured by a TBI-specific instrument. The study is limited by its single-center, observational design and lack of a control group. Further research with larger, controlled cohorts is warranted to clarify the long-term benefits of GHRT and optimize management strategies for this population. Enhanced screening and treatment of endocrine dysfunction may improve outcomes for individuals with msTBI.
2025-12-18 | Basophils activate splenic B cells and dendritic cells via IL-13 signaling in acute traumatic brain injury.
Peripheral consequences following traumatic brain injury (TBI) are characterized by both systemic inflammatory responses and autonomic dysregulation. One of the main immune regulatory organs, the spleen, shows high interaction with the brain which is controlled by both circulating mediators as well as autonomic fibers targeting splenic immune cells. The brain-spleen axis does not function as a one-way street, it also shows reciprocal effects where the spleen affects neuroinflammatory and cognitive functions post injury. To date, systemic and splenic inflammatory responses are measured by cells or mediators located in circulation. Nevertheless, most of the signaling and inflammation post injury takes place in the organs. We set out to investigate the early (3 h) signaling landscape in the spleen following a moderate severity closed head injury model to wild-type animals aged p60-90. Using phospho-proteomic signaling approaches, immunofluorescence stainings, Enzyme-Linked Immunosorbent Assay (ELISA), super-resolution microscopy and single mRNA in situ hybridization we investigated novel molecular and cellular players in the spleen involved in immune modulation after a head injury. Based on the signaling signature, we found a rapid influx of basophil granulocytes towards the spleen, via a recruitment mechanism that includes CXCL1 expressed by B-cells and dendritic cells (DCs). The basophils in turn seem to activate B cells and dendritic cells via the IL-13/IL-13Ra1 signaling pathway and enhance protein translation through the long non-coding RNA NORAD. The early recruitment of basophils and subsequent activation of B cells and DCs, is short lived and sets at 3dpi. Interestingly, the rapid recruitment of basophils is inhibited by ethanol intoxication in TBI, with a subsequent prevention of IL-13Ra phosphorylation and NORAD increase in B-cells and DCs. Basophils recruitment to the spleen may serve as an early mediator of systemic inflammatory responses to TBI with potential implications for research on biomarkers and therapeutic targets.
2025-10-02 | A neuroprotective tetrapeptide for treatment of acute traumatic brain injury.
Traumatic brain injury (TBI) is a major clinical problem because of the high incidence and the severity of the subsequent sequelae. Despite extensive efforts, there are no therapeutic drugs clinically approved for treating acute TBI patients. To address this unmet need, we assessed the activity of the tetrapeptide, CAQK, in mice. When administered intravenously shortly after moderate or severe TBI, CAQK accumulates in the injured brain in mice and pigs. CAQK binds to an extracellular matrix glycoprotein complex that is upregulated in injured brain. Treatment of TBI mice with CAQK resulted in reduction in the size of the injury compared to control mice. There was reduced upregulation of the glycoprotein complex, less apoptosis, and lower expression of inflammatory markers in the injured area, indicating that CAQK alleviates neuroinflammation and the ensuing secondary injury. CAQK treatment also improved functional deficit in TBI mice, with no overt toxicity. Our findings suggest that CAQK may have therapeutic applications in TBI.
2025-09-25 | Growth hormone deficiency after moderate traumatic brain injury with normal (or high) IGF-1; a case report demonstrating benefit of replacement therapy and clinical pearls for diagnosis.
Objective: Traumatic brain injury (TBI) is a common cause of acquired pituitary dysfunction in adults. The prevalence of anterior pituitary dysfunction after TBI varies widely, but growth hormone deficiency (GHD) is reported as the most common, ranging from 5-20% after mild to severe TBI. GHD can be difficult to diagnose: 1) its neuropsychological symptoms are nonspecific and overlap with many chronic TBI symptoms; 2) GHD frequently remits if present in the first year after TBI; 3) screening laboratories are not reliable; and 4) validated, easy to administer, confirmatory stimulation tests are not widely available. A diagnosis of GHD is often delayed until 5 years or more after injury. Nonetheless, replacement therapy is associated with improvement in GHD related symptoms, including cognition. This study aims to present a case of GHD after moderate TBI. Methods: We present a case of GHD after a moderate TBI and discuss the chronic effects of GH replacement therapy on his neuropsychological testing and symptoms, as well as clinical pearls for the diagnosis of GHD in persistently symptomatic patients with remote TBI. Results: This case demonstrates that clinical suspicion should supersede inconclusive screening results and prompt referral for definitive provocative testing. Even when diagnosed late, targeted GH replacement therapy can yield significant improvements in debilitating fatigue, metabolic health, and specific domains of neurocognition. Conclusions: Enhanced clinical awareness and a more proactive approach to endocrine surveillance by providers can prevent years of morbidity, reduce diagnostic delays, and offer patients a greater potential for functional recovery.
cell therapies
2025-01-02 | Treatment of severe traumatic brain injury with human bone marrow mesenchymal stem cell extracellular vesicles: a case report.
Extracellular vesicles (EVs) derived from regenerative mesenchymal stem cells might safely treat traumatic brain injury (TBI). We evaluated the safety and efficacy of a human bone marrow derived mesenchymal stem cell EVs (hBM-MSC EV) investigational product (IP) in a patient with severe TBI. A single case study employing an IP with a strong safety profile in over 200 patients. The patient was dosed intravenously three times/week in the first week of six successive months. Functional Independence Measure (FIM) and Functional Assessment Measure (FAM) were performed to quantify effects. Safety monitoring was performed every week for nine months. No adverse events occurred. Within eight weeks FIM and FAM scores improved by 48-55% and were sustained for the entire 36 weeks. All specific outcome items assessed by FIM and FAM that were initially low showed sustained improvements ranging from 41% to 233%, with the greatest improvements seen in locomotion, mobility and cognitive function. After moderate improvement with conventional therapy, the substantial improvement observed following introduction of the IP suggests that hBM-MSC EVs may offer a novel and safe means to improve TBI patient outcomes. Appropriate randomized, controlled clinical trials to conclusively evaluate this therapeutic option are indicated.
2024-12-29 | Clinical Outcomes Following Component Therapy Only Versus Whole Blood Plus Component Versus Whole Blood Only in Geriatric Trauma Patients With Isolated Chest or Abdominal Injuries With or Without Traumatic Brain Injury.
This study aims to evaluate clinical outcomes in geriatric trauma patients with isolated chest or abdominal injuries with or without traumatic brain injury (TBI) receiving whole blood (WB), component (COMP), or WB and component therapy (WB + COMP). This retrospective analysis of the American College of Surgeons Trauma Quality Improvement Program Participant Use File dataset from 2017 to 2021 evaluated geriatric (age ≥65) trauma patients with moderate-to-severe isolated chest (abbreviated injury scale (AIS) chest ≥2) or abdominal (AIS abdomen ≥2) injuries with or without TBI (AIS head ≥2) receiving WB, COMP, or WB + COMP. Outcomes included emergency department and 24-h mortality, blood product volume (mL) at 4 hs, and intensive care unit-length of stay. Among non-TBI patients with isolated chest injuries, COMP patients required significantly less plasma (regression coefficient β = -428 mL, 95% confidence interval (CI): 604 mL-249 mL, P < 0.001), and had 48% lower odds of 24-h mortality than WB patients (odds ratio = 0.519, 95% CI: 0.285-0.946, P = 0.032). Among TBI patients with isolated chest injuries, there was no significant association between receiving COMP and plasma volume requirement (β = -166.227, 95% CI: -366.370 to 33.916, P = 0.104) or 24-h mortality (odds ratio = 0.606, 95% CI: 0.301-1.220, P = 0.161) when compared to WB patients. Compared to WB or WB + COMP, COMP therapy significantly reduced transfusion requirements in non-TBI patients. Additionally, COMP therapy was associated with lower 24-h mortality in geriatric patients with isolated chest injuries. TBI patients with isolated chest injuries had no significant differences in clinical outcomes. Further research is warranted to explore the potential benefits of COMP therapy on mortality outcomes in TBI patients.
2024-12-12 | Environmental enrichment-induced cognitive recovery after a moderate pediatric traumatic brain injury is associated with the gut microbiota and neuroinflammation.
Pediatric traumatic brain injury (TBI) is a significant health concern, yet access to rehabilitation therapies for children remains limited. Environmental enrichment (EE) is a preclinical model of neurorehabilitation that promotes behavioral recovery and reduces neuroinflammation after TBI. While the gut microbiota has recently emerged as a potential therapeutic target for treating TBI sequelae in adults, its role in recovery after pediatric TBI remains unclear. Therefore, our aim was to assess the effect of EE on gut microbiota and its correlation with cognition as well as microglial morphology in a preclinical model of pediatric TBI. Male rats underwent a controlled cortical impact of moderate severity or sham injury at postnatal day 21 and were then randomly assigned to either EE or standard (STD) housing. Cognition was evaluated using the Morris water maze (MWM) on post-injury days 14-19. Microglial morphology and caecum microbiota was characterized on post-injury day 21. Cognitive deficits and increased microglial activation in the ipsilateral cortex were observed in the STD-housed TBI rats but not those in EE. TBI decreased microbiota α-diversity, while PERMANOVA analysis showed that both TBI and EE modified microbiota β-diversity. Furthermore, regression models indicated that microglial morphology in the ipsilateral cortex and Lactobacillus reuteri predicted behavioral outcomes, while Prevotellaceae NK3B31 was associated with microglial morphology. The data suggest that EE mitigates TBI-induced alterations in gut microbiota and that there is a complex interplay between EE, microbiota and microglial morphology that predicts behavioral recovery in pediatric rats.
2024-11-28 | Efficacy of restrictive versus liberal transfusion strategies in patients with traumatic brain injury: a systematic review and meta-analysis of randomized controlled trials.
The effects of restrictive versus liberal transfusion strategies in critically ill patients with traumatic brain injury (TBI) and anemia, particularly in adult patients with moderate to severe TBI, remain inconclusive. Therefore, this systematic review and meta-analysis aim to evaluate the comparative impact of restrictive and liberal red blood cell transfusion strategies among critically ill adult patients with moderate to severe TBI. We conducted a search of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from their inception through October 20, 2024, to identify randomized controlled trials that compared restrictive (transfusions at a hemoglobin level of ≤ 7 g/dL) and liberal (transfusions at a hemoglobin level of ≤ 9-10 g/dL) transfusion strategies in adult patients with TBI. The primary outcome was mortality, with secondary outcomes including an unfavorable neurological outcome at six months, as determined by the Glasgow Outcome Scale (GOS < 4; or Glasgow Outcome Scale-Extended [GOSE] < 6), and the number of units of packed red blood cells (pRBCs) transfused. Five randomized controlled trials involving 1,528 patients were included in the analysis. The results showed that restrictive transfusion, compared to liberal transfusion, had no impact on mortality (RR 1.00, 95% CI 0.80 to 1.24, I2 = 0%) or unfavorable neurological outcome at 6 months (RR 1.06, 95% CI 0.94 to 1.20, I2 = 47%). Restrictive transfusion was associated with a reduction in the number of units of pRBCs transfused (MD -2.62, 95% CI -3.33 to -1.90, I2 = 63%). In patients with TBI, a restrictive transfusion strategy did not reduce the risk of mortality or unfavorable neurological outcome compared with a liberal transfusion strategy.
2024-09-04 | Mesenchymal Stromal Cell Implants for Chronic Motor Deficits After Traumatic Brain Injury: Post Hoc Analysis of a Randomized Trial.
Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.
antibodies
2026-09-09 | Natural anti-NMDAR1 autoantibodies are associated with lower risk for depression and PTSD symptoms after traumatic brain injury.
Exposure to a traumatic brain injury (TBI) increases risk of developing psychiatric symptoms including depression, anxiety, and post‑traumatic stress disorder (PTSD). However, biological risk and resiliency factors that help explain the heterogeneity in outcomes are limited. Although ~10% of the population was reported to carry natural autoantibodies to the NMDA receptor, it remains unknown whether carrying anti-NMDAR1 autoantibodies modifies risk for psychiatric outcomes after TBI. Plasma anti-NMDAR1 autoantibody levels were quantified in male active-duty service members before a combat deployment. Outcome measures included post-deployment PTSD (Clinician Administered PTSD Scale-IV), depression (Beck Depression Inventory-2) and anxiety symptoms (Beck Anxiety Inventory). Lifetime TBI was associated with increased predicted depression, PTSD and anxiety symptoms after a combat deployment (N = 606 with TBI, N = 419 without TBI). Higher pre-deployment plasma levels of natural anti-NMDAR1 autoantibodies were modestly but significantly associated with lower predicted post-deployment depression (p = 0.0008) and PTSD symptoms (p = 0.0075), but not anxiety, among individuals with TBI. Within the TBI group, high autoantibody group membership (top quartile) lowered predicted post-deployment CAPS-IV and BDI-II scores by 22% ( ~ 4 points) and 25% ( ~ 2 points), respectively and overall prevalence of psychotropic medication use (p = 0.006). High autoantibody group membership predicted lower odds of reporting post‑deployment moderate-severe depression symptoms (BDI-II > 19) (OR = 0.14, 95% CI 0.01-0.69, p = 0.014). Natural anti-NMDAR1 autoantibodies may be a "resiliency" factor for TBI-associated risk for depression and PTSD symptoms, suggesting potential neuroprotective effects. Future studies should determine if anti-NMDAR1 autoantibodies reach the CNS to suppress glutamate excitotoxicity associated with TBI and if these results generalize across different populations.
2026-03-30 | TREC dynamics as a biomarker of naive T-cell homeostasis in traumatic brain injury: a longitudinal analysis.
Post-traumatic immunosuppression complicates recovery from traumatic brain injury (TBI), increasing susceptibility to infection. Reliable biomarkers to assess immune status are required. We investigated the dynamics of T-cell receptor excision circles (TREC) and B-cell K-deleting recombination excision circles (KREC) as potential markers of immune homeostasis in TBI patients. In this observational study, 51 patients with moderate-to-severe TBI were enrolled. Serial peripheral blood samples were collected for the purpose of quantifying TREC and KREC levels using real-time PCR. Linear mixed-effects models (LMMs) were employed to analyze the longitudinal dynamics and identify clinical predictors. Principal Component Analysis (PCA) was applied to construct a composite severity/inflammation index, and the final model was validated using a cluster bootstrap procedure. In most patients, the baseline TREC level was close to or below the lower age-matched norms. TREC and KREC levels fluctuated greatly, with non-monotonic changes and multi-fold variations. Three patients with decreasing TREC dynamics subsequently succumbed to sepsis. Lower TREC levels were robustly associated with older age and a higher severity/inflammation index (p < 0.001), while KREC dynamics remained independent of the examined clinical and inflammatory parameters. TREC levels restoration was synchronous with neurological improvement (rising GCS) and the resolution of organ dysfunction (declining SOFA). By offering a window into a key, potentially modifiable biological mechanism underlying patient vulnerability, TREC analysis represents a promising new approach for risk stratification and the development of future immunotherapeutic strategies in neurocritical care.
2026-02-13 | From Traumatic Brain Injury to Alzheimer's Disease: Multilevel Biomechanical, Neurovascular, and Molecular Mechanisms with Emerging Therapeutic Directions.
Traumatic brain injury (TBI) is being increasingly recognized as a major risk factor for chronic neurodegenerative disease, including chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Biomechanical forces during head trauma, particularly rotational acceleration and angular deformation, produce diffuse axonal injury (DAI) and widespread white matter damage that trigger persistent neurobiological cascades. These include axonal transport failure, blood-brain barrier (BBB) disruption, neuroinflammation, neurovascular and mitochondrial dysfunction, and pathological protein aggregation, closely paralleling core AD features. Epidemiological data support a dose-response relationship between TBI severity or repetition and subsequent dementia risk, moderated by genetic factors such as apolipoprotein E4 (ApoE4). Converging experimental and early clinical studies have begun to target shared injury and neurodegenerative pathways through acute neuroprotection, stem cell-based strategies for BBB restoration and neural repair, transcriptional and hormonal modulation, mitochondrial stabilization, and immunomodulation of chronic inflammation. This review synthesizes evidence linking biomechanical injury to molecular and neurovascular pathways of neurodegeneration and summarizes emerging temporally targeted interventions. By integrating mechanistic and therapeutic perspectives, we aim to narrow the translational gap between TBI and AD, refine identification of at-risk populations, and inform priorities for prevention and development of disease-modifying therapies.
2026-01-16 | Potential Neuroprotective Effects of Natural Anti-NMDAR1 Autoantibodies Against Psychiatric Symptoms Associated with Traumatic Brain Injuries.
Traumatic brain injury (TBI) increases the risk of developing psychiatric symptoms such as post-traumatic stress disorder (PTSD), depression and anxiety, however biological risk and resiliency factors that explain the significant heterogeneity in outcomes are limited. Although 5-10% of the population carries natural autoantibodies to the NMDA receptor (anti-NMDAR1) it is unknown if carrying anti-NMDAR1 autoantibodies modifies risk for psychiatric outcomes after TBI. Since TBI facilitates infiltration of circulating natural anti-NMDAR1 autoantibodies into the brain, we tested the hypothesis that natural anti-NMDAR1 autoantibody levels in plasma may modify risk for development of psychiatric symptoms after TBI. Data were analyzed from 1025 Marine Resiliency Study-II participants, a longitudinal study that included plasma collection and assessments for TBI, PTSD (Clinician Administered PTSD Scale-IV), depression (Beck Depression Inventory-2) and anxiety symptoms (Beck Anxiety Inventory) before and after a combat deployment to Afghanistan (2010-2013). Plasma anti-NMDAR1 autoantibody levels were quantified using a luciferase-based immunnoassay. Outcomes were post-deployment symptoms and the predictor was a continuous or dichotomous measure of anti-NMDAR1 autoantibody level. Covariates included pre-deployment symptoms, deployment history and experiences. TBI (606 with TBI, 419 without TBI) was associated with significantly greater depression, PTSD and anxiety symptoms post-deployment. In individuals with no TBI history, anti-NMDAR1 autoantibody levels were not associated with symptoms. In individuals that endorsed a TBI however, higher pre-deployment plasma levels of natural anti-NMDAR1 autoantibodies were significantly associated with lower predicted post-deployment depression and PTSD symptoms, but not anxiety. In the TBI group, high autoantibody group membership lowered predicted post-deployment CAPS-IV and BDI-2 scores by 22 and 25% respectively (Cohen's d=0.25-0.32). After deployment, prevalence of moderate-severe depression was significantly lower in participants with high anti-NMDAR1 autoantibodies (.8% [2/256 participants]) compared with participants with low anti-NMDAR1 autoantibodies (3.5% [27/763 participants]), as was prevalence of taking psychotropic medications. Natural anti-NMDAR1 autoantibodies may be a "resilience" factor for TBI-associated increases in depression and PTSD symptoms, supporting the hypothesis that natural anti-NMDAR1 autoantibodies could have neuroprotective effects. Mechanistic studies are warranted to understand if plasma natural anti-NMDAR1 autoantibodies reach the CNS to suppress glutamate excitotoxicity associated with TBI.
2025-02-12 | GPX3 as a Novel and Potential Therapeutic Target in the Shared Molecular Mechanisms of Traumatic Brain Injury and Parkinson's Disease.
Traumatic brain injury (TBI) is a prevalent neurological disorder associated with significant public health burdens and long-term risks, including neurodegenerative diseases such as Parkinson's disease (PD). Emerging evidence suggests a strong link between moderate to severe TBI and an elevated risk of PD, though the underlying mechanisms remain poorly understood. Common differentially expressed genes (DEGs) were identified in GEO datasets of patients with traumatic brain injury (TBI) and Parkinson's disease (PD). Further analyses, including GO and KEGG pathway enrichment, protein-protein interaction (PPI) network construction, hub gene identification, as well as miRNA and transcription factor prediction and drug candidate screening, were conducted. Subsequently, the expression of hub genes was validated using additional TBI- and PD-related GEO datasets and the Comparative Toxicogenomics Database (CTD). Finally, the expression of hub genes was further validated in a mouse model of TBI induced by controlled cortical impact (CCI). Shared transcriptional signatures between TBI and PD were uncovered, highlighting overlapping molecular networks and pathways. The glutathione peroxidase 3 (GPX3) gene emerged as a pivotal hub gene, with its expression significantly altered in both TBI and PD datasets. This study underscores the critical role of GPX3 in the molecular intersection of TBI and PD, suggesting it as a novel and potential therapeutic target, offering new insights into potential therapeutic strategies.
other
2022-06-03 | Downregulation of microRNA-124-3p promotes subventricular zone neural stem cell activation by enhancing the function of BDNF downstream pathways after traumatic brain injury in adult rats.
In this study, the effect of intracerebral ventricle injection with a miR-124-3p agomir or antagomir on prognosis and on subventricular zone (SVZ) neural stem cells (NSCs) in adult rats with moderate traumatic brain injury (TBI) was investigated. Model rats with moderate controlled cortical impact (CCI) were established and verified as described previously. The dynamic changes in miR-124-3p and the status of NSCs in the SVZ were analyzed. To evaluate the effect of lateral ventricle injection with miR-124-3p analogs and inhibitors after TBI, modified neurological severity scores (mNSSs) and rotarod tests were used to assess motor function prognosis. The variation in SVZ NSC marker expression was also explored. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of predicted miR-124-3p targets was performed to infer miR-124-3p functions, and miR-124-3p effects on pivotal predicted targets were further explored. Administration of miR-124 inhibitors enhanced SVZ NSC proliferation and improved the motor function of TBI rats. Functional analysis of miR-124 targets revealed high correlations between miR-124 and neurotrophin signaling pathways, especially the TrkB downstream pathway. PI3K, Akt3, and Ras were found to be crucial miR-124 targets and to be involved in most predicted functional pathways. Interference with miR-124 expression in the lateral ventricle affected the PI3K/Akt3 and Ras pathways in the SVZ, and miR-124 inhibitors intensified the potency of brain-derived neurotrophic factor (BDNF) in SVZ NSC proliferation after TBI. Disrupting miR-124 expression through lateral ventricle injection has beneficial effects on neuroregeneration and TBI prognosis. Moreover, the combined use of BDNF and miR-124 inhibitors might lead to better outcomes in TBI than BDNF treatment alone.
2022-05-19 | circHtra1/miR-3960/GRB10 Axis Promotes Neuronal Loss and Immune Deficiency in Traumatic Brain Injury.
Circular RNAs (circRNAs) are abundant in the brain and contribute to central nervous system diseases; however, the exact roles of circRNAs in human traumatic brain injury (TBI) have not been established. In this study, we used a competing endogenous RNA (ceRNA) chipset as well as in vitro and in vivo assays to characterize differentially expressed circRNAs in TBI. We detected 3035 differentially expressed circRNAs in the severe TBI group, 2362 in the moderate group, and 433 in the mild group. A ceRNA network was constructed. The circRNA has_circ_0020269 (circHtra1) was significantly upregulated after brain insults and was correlated with the severity of injury. circHtra1 inhibited cell proliferation and promoted apoptosis, and its knockdown reversed these effects. Further analyses revealed that circHtra1 functions as a miR-3960 sponge and increases the expression of GRB10, which is involved in NK cell infiltration after TBI. circHtra1 was identified as a target of the IGF-1/ADAR1 axis. Reduced expression of ADAR1 (involved in A-to-I editing) after brain insults upregulated circHtra1. Our results show that circHtra1 promotes neuronal loss by sponging miR-3960 and regulating GRB10 and apoptosis during brain insults. In addition, A-to-I editing could regulate circRNA expression profiles after TBI, and circHtra1 is a potential therapeutic target.
small molecules
2026-09-30 | Effect of early intravenous magnesium sulfate on clinical outcomes in patients with moderate to severe traumatic brain injury: a study protocol for a randomized controlled trial.
Traumatic brain injury (TBI) is associated with substantial mortality and long-term disability worldwide. Acute respiratory distress syndrome (ARDS), as a common complication in moderate-to-severe TBI, further aggravates clinical outcomes and resource utilization. However, effective interventions to prevent TBI-associated ARDS remain limited. This trial aims to evaluate whether early intravenous magnesium sulfate reduces the risk of ARDS and improves clinical outcomes in patients with moderate-to-severe TBI. This protocol outlines a randomized, controlled, double-blind clinical trial involving 164 adults (18-75 years) with moderate-to-severe TBI (Glasgow Coma Scale [GCS] 3-12) within 8 h of injury. Participants will be stratified by baseline GCS (3-8 vs. 9-12) and randomized 1:1 to the intravenous magnesium sulfate group (initial 2 g over 30 min within 8 h, then 2 g daily for 5 days; total 12 g) or an identical placebo group. Both groups will receive guideline-directed standard TBI care. The primary endpoint is a 28-day hierarchical composite (all-cause mortality, then new-onset ARDS within days 1-7, then ≤ 20% increase in PaO₂/FiO₂ AUC from baseline over days 0-5). The hierarchical composite primary endpoint will be analyzed using the win-ratio method. Secondary outcomes include ICU and hospital length of stay, complications, and serial biomarker changes. Follow-up assessments will be conducted on day 28 and at 6 months post-treatment. If effective, this low-cost intervention could be readily incorporated into standard TBI care and help prevent TBI-associated ARDS. Chinese Clinical Trial Registry, identifier ChiCTR2600120684.
2026-09-24 | Outcomes of Older Adults on Anticoagulation Sustaining Ground-Level Falls: A Retrospective Analysis.
Ground-level falls (GLFs) are a leading cause of morbidity and mortality in older adults, a population frequently prescribed anticoagulants. While effective for thromboembolic prevention, the association between anticoagulation and fall-related complications, including traumatic brain injury (TBI), remains mixed, with prior studies reporting inconsistent findings. This study utilized a large national database to evaluate whether preinjury anticoagulation is associated with worse outcomes following GLFs, hypothesizing increased mortality and severe TBI in anticoagulated versus nonanticoagulated older adults. The 2017-2022 Trauma Quality Improvement Program database was queried for older adult trauma patients (OATPs) (≥65 y) presenting after GLFs. Patients were stratified by anticoagulant use. Bivariate analyses and multivariable logistic regression assessed associations with TBI severity and inhospital mortality. Among 1,062,072 OATPs, 300,623 (28.3%) were on anticoagulation. Anticoagulated patients had higher rates of mild (21.1% versus 14.0%, P < 0.001), moderate (13.2% versus 11.9%, P < 0.001), and severe TBI (4.9% versus 2.8%, P < 0.001). They more frequently required the highest-level trauma activation (2.4% versus 1.5%, P < 0.001) and had higher complication (6.4% versus 4.5%, P < 0.001) and mortality rates (4.3% versus 2.5%, P < 0.001). Anticoagulation was independently associated with mortality (OR 1.34, CI 1.31-1.37, P < 0.001) and TBI severity, from mild (OR 1.64, CI 1.62-1.65, P < 0.001) to severe TBI (OR 1.80, CI 1.76-1.84, P < 0.001). Preinjury anticoagulation in OATPs was independently associated with severe TBI and mortality. While anticoagulation remains important for thromboembolic prevention, these findings highlight substantial risk in a fall-prone aging population. Re-evaluation of geriatric anticoagulation guidelines to better balance thromboembolic protection with trauma-related risk appears warranted.
2026-09-19 | Clinical Profile and Association Between Admission Glasgow Coma Scale and In-Hospital Mortality Among Children With Head Injury at a Tertiary Care Centre in Central India.
Introduction Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality in children worldwide, and injury patterns in low- and middle-income countries differ from those reported in high-income settings. Data from tertiary centres in central India remain limited. This study describes the clinical profile, management pattern, and in-hospital outcome of children admitted with head injury at a tertiary care centre and evaluates the association between admission Glasgow Coma Scale (GCS) and in-hospital mortality. Methods This retrospective observational study included 81 children admitted with head injury to the Department of Pediatric Surgery, Gandhi Medical College, Bhopal, India, between January 2026 and June 2026. Demographic details, mechanism of injury, clinical features at presentation, admission GCS, non-contrast computed tomography (NCCT) head findings, management type, length of hospital stay, and outcome were recorded from case records. The association between GCS severity and outcome was assessed using Fisher's exact test, the chi-square test, and the Mann-Whitney U test, with p < 0.05 considered significant. Results The mean age was 5.03 ± 3.31 years, with a male-to-female ratio of 1.53:1. Fall from height was the commonest mechanism (44 of 81, 54.3%), followed by road traffic accidents (17 of 81, 21.0%). Most children presented with mild head injury (GCS 13-15; 61 of 81, 75.3%); eight (9.9%) had severe injury (GCS ≤8). NCCT was performed in 78 of 81 children (96.3%); skull fracture (37 of 78, 47.4%) was the most common finding, followed by extradural hemorrhage (20 of 78, 25.6%) and subdural hemorrhage (18 of 78, 23.1%). Conservative management was employed in 79 of 81 children (97.5%), with two (2.5%) requiring operative intervention. Overall in-hospital mortality was 11.1% (9 of 81). On Fisher's exact test, children with mild GCS had significantly lower odds of death compared with the combined moderate-to-severe group used as the reference category (odds ratio, 0.03; 95% CI, 0.003-0.22; p = 0.00003); seven of eight children with severe GCS died, compared with one of 61 with mild GCS. Mean GCS was significantly lower among children who died than among those discharged (6.1 versus 14.0; Mann-Whitney U = 23.0; p = 0.00000024). Conclusions Pediatric head injury at this centre was predominantly mild and managed conservatively, with fall from height as the leading mechanism, consistent with other Indian series. Lower admission GCS was strongly associated with in-hospital mortality on unadjusted analysis. These findings are descriptive and hypothesis-generating within this cohort; larger, prospective, multicentric studies with multivariable analysis are needed to confirm this association and identify additional factors influencing outcome.
2026-09-03 | Sleep Management and Recovery After TBI in Kids (SMART-Kids): Pilot Trial Using Melatonin.
Sleep disturbances after pediatric traumatic brain injury (TBI) occur in more than 50% of survivors and portend worse cognitive and psychosocial outcomes. We aimed to determine feasibility and acceptability of an early melatonin and sleep education intervention study after TBI. We conducted a pilot randomized, double-blinded placebo-controlled trial of melatonin for 30 days vs placebo in children aged more than 6 to 18 years started within 72 hours of TBI admission. All participants received sleep education handouts with access to short videos. Covariate adaptive randomization was used to balance groups by age and TBI severity. Primary outcomes were feasibility and acceptability. Secondary effectiveness sleep outcomes were explored with the Sleep Disturbances Scale for Children (SDSC) T-scores and actigraphy. Twenty-one (40%) of 53 approached patients consented (median age, 10.7 years), and 19 (91%) completed the study. Fifteen (79%) reported adherence (defined ≥5 of 7 days per week for medication), and 15 provided usable actigraphy data. We found high acceptability with no safety concerns identified. Randomization procedures were successful with no between-group differences observed. A higher frequency of clinically important SDSC scores (T-score ≥60, indicating moderate or greater risk for sleep disorder) at 30 days were found with placebo vs melatonin. Actigraphy showed nonsignificant differences. Melatonin paired with sleep education early during hospitalization and continued for 30 days is feasible and acceptable. Although not powered for effectiveness, results suggest melatonin may reduce sleep disturbances by clinically meaningful margins after TBI hospitalization, and results can be used as effect size estimates for a larger study.
2026-09-02 | Severity-stratified gut microbiome dysbiosis and systemic neuroinflammation in acute traumatic brain injury: a metagenomic and cytokine profiling study.
The gut-brain axis has increasingly been implicated in the pathophysiology of traumatic brain injury (TBI). However, few human studies have simultaneously examined gut functional metagenomics and peripheral cytokine profiles across mild to moderate-to-severe TBI, which limits our understanding of how gut health may influence recovery outcomes in TBI patients. This cross-sectional case-control investigation involved the collection of fecal and matched serum samples within 7 days post-injury from 60 mild TBI patients (MT; GCS 13-15), 45 moderate-to-severe TBI patients (MST; GCS ≤ 12), and 113 healthy controls (HC). Shotgun metagenomic sequencing examined gut microbiota. Serum IL-1β, IL-6, IL-8, and TNF-α were measured using a 4-plex Luminex test. Spearman correlation was utilized to construct a hypothesis relating cytokine levels to microbial severity-stratified abundance patterns. TBI was associated with severity-dependent remodeling of the gut microbiota. Alpha diversity decreased from HC to MST (p < 10-6), and community structure varied significantly among all three groups (PERMANOVA, p = 0.001). Serum TNF-α increased in a severity-associated manner (MST vs. HC and MT, p adj < 0.015). Among 332 differentially abundant species, butyrate-producing commensals fell abruptly at MT with no additional decline in MST, suggesting an apparent floor-like pattern rather than confirming a true biological floor effect. For example, Faecalibacterium prausnitzii dropped from 9.02% in HC to 4.29% in MT. In terms of function, metagenomic inference indicated that pathways for fermentative metabolism and short-chain fatty acid (SCFA) biosynthesis were largely suppressed, suggesting a predicted reduction in microbial SCFA production capacity. On the other hand, secondary bile acid synthesis was specifically increased in MST-dominant KOs (85%). Systemically, reduced commensals showed weak, directionally consistent correlations with pro-inflammatory cytokines (|ρ| = 0.16-0.25), although none of the species-cytokine associations survived FDR correction. Acute TBI is associated with severity-specific gut dysbiosis, which is accompanied by systemic neuroinflammation. The early reduction of butyrate-producing taxa in mild TBI suggests that the early post-injury period may represent a potential window for future gut-targeted intervention studies.
proteins
2026-01-10 | Incretin Mimetics as Potential Therapeutics for Concussion and Traumatic Brain Injury: A Narrative Review.
Traumatic brain injury (TBI) represents a significant health concern, with an estimated 70 million annual cases worldwide. Mild brain trauma (concussions) is the most common TBI (81%), followed by moderate (11%) and severe (8%). Cytokine release and neuroinflammation after TBI may cause blood-brain barrier and tissue damage, triggering unfavorable outcomes, including disabilities and mortality. Current TBI treatments, focused on preventing secondary injury, are limited and insufficient. Therefore, new therapeutic approaches are necessary. A growing body of recent literature supports the potential use of incretins: glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and glucagon receptor agonists, as potent neurotrophic/neuroprotective agents. Experiments performed in cellular and animal models, and a limited number of clinical studies, provide evidence that incretins might be a novel and effective treatment for TBI. Incretin-based compounds have already been shown to be safe and efficacious for the treatment of type 2 diabetes mellitus in humans. Therefore, incretins are ideal candidates for rapid evaluation in clinical trials of TBI and might become a novel therapeutic tool for a condition that has very few disease modifying treatments available. Well-designed human clinical trials are urgently needed to determine optimal dosing, timing, and patient selection for effective incretin use in concussion and TBI.
2026-01-01 | Evaluating Quality of Life Effects after Growth Hormone Replacement in Individuals with Moderate-to-Severe Traumatic Brain Injury and Growth Hormone Deficiency
Traumatic brain injury (TBI) is a leading cause of long-term disability, with chronic complications including growth hormone deficiency (GHD). Growth hormone replacement therapy (GHRT) has shown promise in improving these outcomes, but evidence specific to moderate-to-severe TBI (msTBI) populations using TBI-specific quality of life (QoL) measures remains limited. This prospective cohort study evaluated the impact of 1 year of GHRT on QoL in 69 adults with msTBI and GHD, using the QoL after Brain Injury (QOLIBRI) questionnaire. GHD was diagnosed via glucagon stimulation testing at least 1-year postinjury. GHRT was initiated and titrated to achieve therapeutic insulin-like growth factor 1 levels, with QOLIBRI scores collected at baseline, 6 months, and 12 months. Statistical analyses included Friedman tests and multivariate mixed-effects models. Results demonstrated significant improvements in all QOLIBRI domains after 1 year of GHRT. Mixed effects analysis showed a trend toward lower overall QoL after GHRT in severe TBI patients and most model variation existed among individuals by domain of QOLIBRI. These findings suggest that GHRT is associated with improved cognitive, emotional, and physical aspects of QoL in msTBI patients with GHD, as measured by a TBI-specific instrument. The study is limited by its single-center, observational design and lack of a control group. Further research with larger, controlled cohorts is warranted to clarify the long-term benefits of GHRT and optimize management strategies for this population. Enhanced screening and treatment of endocrine dysfunction may improve outcomes for individuals with msTBI.
2025-12-18 | Basophils activate splenic B cells and dendritic cells via IL-13 signaling in acute traumatic brain injury.
Peripheral consequences following traumatic brain injury (TBI) are characterized by both systemic inflammatory responses and autonomic dysregulation. One of the main immune regulatory organs, the spleen, shows high interaction with the brain which is controlled by both circulating mediators as well as autonomic fibers targeting splenic immune cells. The brain-spleen axis does not function as a one-way street, it also shows reciprocal effects where the spleen affects neuroinflammatory and cognitive functions post injury. To date, systemic and splenic inflammatory responses are measured by cells or mediators located in circulation. Nevertheless, most of the signaling and inflammation post injury takes place in the organs. We set out to investigate the early (3 h) signaling landscape in the spleen following a moderate severity closed head injury model to wild-type animals aged p60-90. Using phospho-proteomic signaling approaches, immunofluorescence stainings, Enzyme-Linked Immunosorbent Assay (ELISA), super-resolution microscopy and single mRNA in situ hybridization we investigated novel molecular and cellular players in the spleen involved in immune modulation after a head injury. Based on the signaling signature, we found a rapid influx of basophil granulocytes towards the spleen, via a recruitment mechanism that includes CXCL1 expressed by B-cells and dendritic cells (DCs). The basophils in turn seem to activate B cells and dendritic cells via the IL-13/IL-13Ra1 signaling pathway and enhance protein translation through the long non-coding RNA NORAD. The early recruitment of basophils and subsequent activation of B cells and DCs, is short lived and sets at 3dpi. Interestingly, the rapid recruitment of basophils is inhibited by ethanol intoxication in TBI, with a subsequent prevention of IL-13Ra phosphorylation and NORAD increase in B-cells and DCs. Basophils recruitment to the spleen may serve as an early mediator of systemic inflammatory responses to TBI with potential implications for research on biomarkers and therapeutic targets.
2025-10-02 | A neuroprotective tetrapeptide for treatment of acute traumatic brain injury.
Traumatic brain injury (TBI) is a major clinical problem because of the high incidence and the severity of the subsequent sequelae. Despite extensive efforts, there are no therapeutic drugs clinically approved for treating acute TBI patients. To address this unmet need, we assessed the activity of the tetrapeptide, CAQK, in mice. When administered intravenously shortly after moderate or severe TBI, CAQK accumulates in the injured brain in mice and pigs. CAQK binds to an extracellular matrix glycoprotein complex that is upregulated in injured brain. Treatment of TBI mice with CAQK resulted in reduction in the size of the injury compared to control mice. There was reduced upregulation of the glycoprotein complex, less apoptosis, and lower expression of inflammatory markers in the injured area, indicating that CAQK alleviates neuroinflammation and the ensuing secondary injury. CAQK treatment also improved functional deficit in TBI mice, with no overt toxicity. Our findings suggest that CAQK may have therapeutic applications in TBI.
2025-09-25 | Growth hormone deficiency after moderate traumatic brain injury with normal (or high) IGF-1; a case report demonstrating benefit of replacement therapy and clinical pearls for diagnosis.
Objective: Traumatic brain injury (TBI) is a common cause of acquired pituitary dysfunction in adults. The prevalence of anterior pituitary dysfunction after TBI varies widely, but growth hormone deficiency (GHD) is reported as the most common, ranging from 5-20% after mild to severe TBI. GHD can be difficult to diagnose: 1) its neuropsychological symptoms are nonspecific and overlap with many chronic TBI symptoms; 2) GHD frequently remits if present in the first year after TBI; 3) screening laboratories are not reliable; and 4) validated, easy to administer, confirmatory stimulation tests are not widely available. A diagnosis of GHD is often delayed until 5 years or more after injury. Nonetheless, replacement therapy is associated with improvement in GHD related symptoms, including cognition. This study aims to present a case of GHD after moderate TBI. Methods: We present a case of GHD after a moderate TBI and discuss the chronic effects of GH replacement therapy on his neuropsychological testing and symptoms, as well as clinical pearls for the diagnosis of GHD in persistently symptomatic patients with remote TBI. Results: This case demonstrates that clinical suspicion should supersede inconclusive screening results and prompt referral for definitive provocative testing. Even when diagnosed late, targeted GH replacement therapy can yield significant improvements in debilitating fatigue, metabolic health, and specific domains of neurocognition. Conclusions: Enhanced clinical awareness and a more proactive approach to endocrine surveillance by providers can prevent years of morbidity, reduce diagnostic delays, and offer patients a greater potential for functional recovery.
cell therapies
2025-01-02 | Treatment of severe traumatic brain injury with human bone marrow mesenchymal stem cell extracellular vesicles: a case report.
Extracellular vesicles (EVs) derived from regenerative mesenchymal stem cells might safely treat traumatic brain injury (TBI). We evaluated the safety and efficacy of a human bone marrow derived mesenchymal stem cell EVs (hBM-MSC EV) investigational product (IP) in a patient with severe TBI. A single case study employing an IP with a strong safety profile in over 200 patients. The patient was dosed intravenously three times/week in the first week of six successive months. Functional Independence Measure (FIM) and Functional Assessment Measure (FAM) were performed to quantify effects. Safety monitoring was performed every week for nine months. No adverse events occurred. Within eight weeks FIM and FAM scores improved by 48-55% and were sustained for the entire 36 weeks. All specific outcome items assessed by FIM and FAM that were initially low showed sustained improvements ranging from 41% to 233%, with the greatest improvements seen in locomotion, mobility and cognitive function. After moderate improvement with conventional therapy, the substantial improvement observed following introduction of the IP suggests that hBM-MSC EVs may offer a novel and safe means to improve TBI patient outcomes. Appropriate randomized, controlled clinical trials to conclusively evaluate this therapeutic option are indicated.
2024-12-29 | Clinical Outcomes Following Component Therapy Only Versus Whole Blood Plus Component Versus Whole Blood Only in Geriatric Trauma Patients With Isolated Chest or Abdominal Injuries With or Without Traumatic Brain Injury.
This study aims to evaluate clinical outcomes in geriatric trauma patients with isolated chest or abdominal injuries with or without traumatic brain injury (TBI) receiving whole blood (WB), component (COMP), or WB and component therapy (WB + COMP). This retrospective analysis of the American College of Surgeons Trauma Quality Improvement Program Participant Use File dataset from 2017 to 2021 evaluated geriatric (age ≥65) trauma patients with moderate-to-severe isolated chest (abbreviated injury scale (AIS) chest ≥2) or abdominal (AIS abdomen ≥2) injuries with or without TBI (AIS head ≥2) receiving WB, COMP, or WB + COMP. Outcomes included emergency department and 24-h mortality, blood product volume (mL) at 4 hs, and intensive care unit-length of stay. Among non-TBI patients with isolated chest injuries, COMP patients required significantly less plasma (regression coefficient β = -428 mL, 95% confidence interval (CI): 604 mL-249 mL, P < 0.001), and had 48% lower odds of 24-h mortality than WB patients (odds ratio = 0.519, 95% CI: 0.285-0.946, P = 0.032). Among TBI patients with isolated chest injuries, there was no significant association between receiving COMP and plasma volume requirement (β = -166.227, 95% CI: -366.370 to 33.916, P = 0.104) or 24-h mortality (odds ratio = 0.606, 95% CI: 0.301-1.220, P = 0.161) when compared to WB patients. Compared to WB or WB + COMP, COMP therapy significantly reduced transfusion requirements in non-TBI patients. Additionally, COMP therapy was associated with lower 24-h mortality in geriatric patients with isolated chest injuries. TBI patients with isolated chest injuries had no significant differences in clinical outcomes. Further research is warranted to explore the potential benefits of COMP therapy on mortality outcomes in TBI patients.
2024-12-12 | Environmental enrichment-induced cognitive recovery after a moderate pediatric traumatic brain injury is associated with the gut microbiota and neuroinflammation.
Pediatric traumatic brain injury (TBI) is a significant health concern, yet access to rehabilitation therapies for children remains limited. Environmental enrichment (EE) is a preclinical model of neurorehabilitation that promotes behavioral recovery and reduces neuroinflammation after TBI. While the gut microbiota has recently emerged as a potential therapeutic target for treating TBI sequelae in adults, its role in recovery after pediatric TBI remains unclear. Therefore, our aim was to assess the effect of EE on gut microbiota and its correlation with cognition as well as microglial morphology in a preclinical model of pediatric TBI. Male rats underwent a controlled cortical impact of moderate severity or sham injury at postnatal day 21 and were then randomly assigned to either EE or standard (STD) housing. Cognition was evaluated using the Morris water maze (MWM) on post-injury days 14-19. Microglial morphology and caecum microbiota was characterized on post-injury day 21. Cognitive deficits and increased microglial activation in the ipsilateral cortex were observed in the STD-housed TBI rats but not those in EE. TBI decreased microbiota α-diversity, while PERMANOVA analysis showed that both TBI and EE modified microbiota β-diversity. Furthermore, regression models indicated that microglial morphology in the ipsilateral cortex and Lactobacillus reuteri predicted behavioral outcomes, while Prevotellaceae NK3B31 was associated with microglial morphology. The data suggest that EE mitigates TBI-induced alterations in gut microbiota and that there is a complex interplay between EE, microbiota and microglial morphology that predicts behavioral recovery in pediatric rats.
2024-11-28 | Efficacy of restrictive versus liberal transfusion strategies in patients with traumatic brain injury: a systematic review and meta-analysis of randomized controlled trials.
The effects of restrictive versus liberal transfusion strategies in critically ill patients with traumatic brain injury (TBI) and anemia, particularly in adult patients with moderate to severe TBI, remain inconclusive. Therefore, this systematic review and meta-analysis aim to evaluate the comparative impact of restrictive and liberal red blood cell transfusion strategies among critically ill adult patients with moderate to severe TBI. We conducted a search of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from their inception through October 20, 2024, to identify randomized controlled trials that compared restrictive (transfusions at a hemoglobin level of ≤ 7 g/dL) and liberal (transfusions at a hemoglobin level of ≤ 9-10 g/dL) transfusion strategies in adult patients with TBI. The primary outcome was mortality, with secondary outcomes including an unfavorable neurological outcome at six months, as determined by the Glasgow Outcome Scale (GOS < 4; or Glasgow Outcome Scale-Extended [GOSE] < 6), and the number of units of packed red blood cells (pRBCs) transfused. Five randomized controlled trials involving 1,528 patients were included in the analysis. The results showed that restrictive transfusion, compared to liberal transfusion, had no impact on mortality (RR 1.00, 95% CI 0.80 to 1.24, I2 = 0%) or unfavorable neurological outcome at 6 months (RR 1.06, 95% CI 0.94 to 1.20, I2 = 47%). Restrictive transfusion was associated with a reduction in the number of units of pRBCs transfused (MD -2.62, 95% CI -3.33 to -1.90, I2 = 63%). In patients with TBI, a restrictive transfusion strategy did not reduce the risk of mortality or unfavorable neurological outcome compared with a liberal transfusion strategy.
2024-09-04 | Mesenchymal Stromal Cell Implants for Chronic Motor Deficits After Traumatic Brain Injury: Post Hoc Analysis of a Randomized Trial.
Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.
antibodies
2026-09-09 | Natural anti-NMDAR1 autoantibodies are associated with lower risk for depression and PTSD symptoms after traumatic brain injury.
Exposure to a traumatic brain injury (TBI) increases risk of developing psychiatric symptoms including depression, anxiety, and post‑traumatic stress disorder (PTSD). However, biological risk and resiliency factors that help explain the heterogeneity in outcomes are limited. Although ~10% of the population was reported to carry natural autoantibodies to the NMDA receptor, it remains unknown whether carrying anti-NMDAR1 autoantibodies modifies risk for psychiatric outcomes after TBI. Plasma anti-NMDAR1 autoantibody levels were quantified in male active-duty service members before a combat deployment. Outcome measures included post-deployment PTSD (Clinician Administered PTSD Scale-IV), depression (Beck Depression Inventory-2) and anxiety symptoms (Beck Anxiety Inventory). Lifetime TBI was associated with increased predicted depression, PTSD and anxiety symptoms after a combat deployment (N = 606 with TBI, N = 419 without TBI). Higher pre-deployment plasma levels of natural anti-NMDAR1 autoantibodies were modestly but significantly associated with lower predicted post-deployment depression (p = 0.0008) and PTSD symptoms (p = 0.0075), but not anxiety, among individuals with TBI. Within the TBI group, high autoantibody group membership (top quartile) lowered predicted post-deployment CAPS-IV and BDI-II scores by 22% ( ~ 4 points) and 25% ( ~ 2 points), respectively and overall prevalence of psychotropic medication use (p = 0.006). High autoantibody group membership predicted lower odds of reporting post‑deployment moderate-severe depression symptoms (BDI-II > 19) (OR = 0.14, 95% CI 0.01-0.69, p = 0.014). Natural anti-NMDAR1 autoantibodies may be a "resiliency" factor for TBI-associated risk for depression and PTSD symptoms, suggesting potential neuroprotective effects. Future studies should determine if anti-NMDAR1 autoantibodies reach the CNS to suppress glutamate excitotoxicity associated with TBI and if these results generalize across different populations.
2026-03-30 | TREC dynamics as a biomarker of naive T-cell homeostasis in traumatic brain injury: a longitudinal analysis.
Post-traumatic immunosuppression complicates recovery from traumatic brain injury (TBI), increasing susceptibility to infection. Reliable biomarkers to assess immune status are required. We investigated the dynamics of T-cell receptor excision circles (TREC) and B-cell K-deleting recombination excision circles (KREC) as potential markers of immune homeostasis in TBI patients. In this observational study, 51 patients with moderate-to-severe TBI were enrolled. Serial peripheral blood samples were collected for the purpose of quantifying TREC and KREC levels using real-time PCR. Linear mixed-effects models (LMMs) were employed to analyze the longitudinal dynamics and identify clinical predictors. Principal Component Analysis (PCA) was applied to construct a composite severity/inflammation index, and the final model was validated using a cluster bootstrap procedure. In most patients, the baseline TREC level was close to or below the lower age-matched norms. TREC and KREC levels fluctuated greatly, with non-monotonic changes and multi-fold variations. Three patients with decreasing TREC dynamics subsequently succumbed to sepsis. Lower TREC levels were robustly associated with older age and a higher severity/inflammation index (p < 0.001), while KREC dynamics remained independent of the examined clinical and inflammatory parameters. TREC levels restoration was synchronous with neurological improvement (rising GCS) and the resolution of organ dysfunction (declining SOFA). By offering a window into a key, potentially modifiable biological mechanism underlying patient vulnerability, TREC analysis represents a promising new approach for risk stratification and the development of future immunotherapeutic strategies in neurocritical care.
2026-02-13 | From Traumatic Brain Injury to Alzheimer's Disease: Multilevel Biomechanical, Neurovascular, and Molecular Mechanisms with Emerging Therapeutic Directions.
Traumatic brain injury (TBI) is being increasingly recognized as a major risk factor for chronic neurodegenerative disease, including chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Biomechanical forces during head trauma, particularly rotational acceleration and angular deformation, produce diffuse axonal injury (DAI) and widespread white matter damage that trigger persistent neurobiological cascades. These include axonal transport failure, blood-brain barrier (BBB) disruption, neuroinflammation, neurovascular and mitochondrial dysfunction, and pathological protein aggregation, closely paralleling core AD features. Epidemiological data support a dose-response relationship between TBI severity or repetition and subsequent dementia risk, moderated by genetic factors such as apolipoprotein E4 (ApoE4). Converging experimental and early clinical studies have begun to target shared injury and neurodegenerative pathways through acute neuroprotection, stem cell-based strategies for BBB restoration and neural repair, transcriptional and hormonal modulation, mitochondrial stabilization, and immunomodulation of chronic inflammation. This review synthesizes evidence linking biomechanical injury to molecular and neurovascular pathways of neurodegeneration and summarizes emerging temporally targeted interventions. By integrating mechanistic and therapeutic perspectives, we aim to narrow the translational gap between TBI and AD, refine identification of at-risk populations, and inform priorities for prevention and development of disease-modifying therapies.
2026-01-16 | Potential Neuroprotective Effects of Natural Anti-NMDAR1 Autoantibodies Against Psychiatric Symptoms Associated with Traumatic Brain Injuries.
Traumatic brain injury (TBI) increases the risk of developing psychiatric symptoms such as post-traumatic stress disorder (PTSD), depression and anxiety, however biological risk and resiliency factors that explain the significant heterogeneity in outcomes are limited. Although 5-10% of the population carries natural autoantibodies to the NMDA receptor (anti-NMDAR1) it is unknown if carrying anti-NMDAR1 autoantibodies modifies risk for psychiatric outcomes after TBI. Since TBI facilitates infiltration of circulating natural anti-NMDAR1 autoantibodies into the brain, we tested the hypothesis that natural anti-NMDAR1 autoantibody levels in plasma may modify risk for development of psychiatric symptoms after TBI. Data were analyzed from 1025 Marine Resiliency Study-II participants, a longitudinal study that included plasma collection and assessments for TBI, PTSD (Clinician Administered PTSD Scale-IV), depression (Beck Depression Inventory-2) and anxiety symptoms (Beck Anxiety Inventory) before and after a combat deployment to Afghanistan (2010-2013). Plasma anti-NMDAR1 autoantibody levels were quantified using a luciferase-based immunnoassay. Outcomes were post-deployment symptoms and the predictor was a continuous or dichotomous measure of anti-NMDAR1 autoantibody level. Covariates included pre-deployment symptoms, deployment history and experiences. TBI (606 with TBI, 419 without TBI) was associated with significantly greater depression, PTSD and anxiety symptoms post-deployment. In individuals with no TBI history, anti-NMDAR1 autoantibody levels were not associated with symptoms. In individuals that endorsed a TBI however, higher pre-deployment plasma levels of natural anti-NMDAR1 autoantibodies were significantly associated with lower predicted post-deployment depression and PTSD symptoms, but not anxiety. In the TBI group, high autoantibody group membership lowered predicted post-deployment CAPS-IV and BDI-2 scores by 22 and 25% respectively (Cohen's d=0.25-0.32). After deployment, prevalence of moderate-severe depression was significantly lower in participants with high anti-NMDAR1 autoantibodies (.8% [2/256 participants]) compared with participants with low anti-NMDAR1 autoantibodies (3.5% [27/763 participants]), as was prevalence of taking psychotropic medications. Natural anti-NMDAR1 autoantibodies may be a "resilience" factor for TBI-associated increases in depression and PTSD symptoms, supporting the hypothesis that natural anti-NMDAR1 autoantibodies could have neuroprotective effects. Mechanistic studies are warranted to understand if plasma natural anti-NMDAR1 autoantibodies reach the CNS to suppress glutamate excitotoxicity associated with TBI.
2025-02-12 | GPX3 as a Novel and Potential Therapeutic Target in the Shared Molecular Mechanisms of Traumatic Brain Injury and Parkinson's Disease.
Traumatic brain injury (TBI) is a prevalent neurological disorder associated with significant public health burdens and long-term risks, including neurodegenerative diseases such as Parkinson's disease (PD). Emerging evidence suggests a strong link between moderate to severe TBI and an elevated risk of PD, though the underlying mechanisms remain poorly understood. Common differentially expressed genes (DEGs) were identified in GEO datasets of patients with traumatic brain injury (TBI) and Parkinson's disease (PD). Further analyses, including GO and KEGG pathway enrichment, protein-protein interaction (PPI) network construction, hub gene identification, as well as miRNA and transcription factor prediction and drug candidate screening, were conducted. Subsequently, the expression of hub genes was validated using additional TBI- and PD-related GEO datasets and the Comparative Toxicogenomics Database (CTD). Finally, the expression of hub genes was further validated in a mouse model of TBI induced by controlled cortical impact (CCI). Shared transcriptional signatures between TBI and PD were uncovered, highlighting overlapping molecular networks and pathways. The glutathione peroxidase 3 (GPX3) gene emerged as a pivotal hub gene, with its expression significantly altered in both TBI and PD datasets. This study underscores the critical role of GPX3 in the molecular intersection of TBI and PD, suggesting it as a novel and potential therapeutic target, offering new insights into potential therapeutic strategies.
other
2022-06-03 | Downregulation of microRNA-124-3p promotes subventricular zone neural stem cell activation by enhancing the function of BDNF downstream pathways after traumatic brain injury in adult rats.
In this study, the effect of intracerebral ventricle injection with a miR-124-3p agomir or antagomir on prognosis and on subventricular zone (SVZ) neural stem cells (NSCs) in adult rats with moderate traumatic brain injury (TBI) was investigated. Model rats with moderate controlled cortical impact (CCI) were established and verified as described previously. The dynamic changes in miR-124-3p and the status of NSCs in the SVZ were analyzed. To evaluate the effect of lateral ventricle injection with miR-124-3p analogs and inhibitors after TBI, modified neurological severity scores (mNSSs) and rotarod tests were used to assess motor function prognosis. The variation in SVZ NSC marker expression was also explored. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of predicted miR-124-3p targets was performed to infer miR-124-3p functions, and miR-124-3p effects on pivotal predicted targets were further explored. Administration of miR-124 inhibitors enhanced SVZ NSC proliferation and improved the motor function of TBI rats. Functional analysis of miR-124 targets revealed high correlations between miR-124 and neurotrophin signaling pathways, especially the TrkB downstream pathway. PI3K, Akt3, and Ras were found to be crucial miR-124 targets and to be involved in most predicted functional pathways. Interference with miR-124 expression in the lateral ventricle affected the PI3K/Akt3 and Ras pathways in the SVZ, and miR-124 inhibitors intensified the potency of brain-derived neurotrophic factor (BDNF) in SVZ NSC proliferation after TBI. Disrupting miR-124 expression through lateral ventricle injection has beneficial effects on neuroregeneration and TBI prognosis. Moreover, the combined use of BDNF and miR-124 inhibitors might lead to better outcomes in TBI than BDNF treatment alone.
2022-05-19 | circHtra1/miR-3960/GRB10 Axis Promotes Neuronal Loss and Immune Deficiency in Traumatic Brain Injury.
Circular RNAs (circRNAs) are abundant in the brain and contribute to central nervous system diseases; however, the exact roles of circRNAs in human traumatic brain injury (TBI) have not been established. In this study, we used a competing endogenous RNA (ceRNA) chipset as well as in vitro and in vivo assays to characterize differentially expressed circRNAs in TBI. We detected 3035 differentially expressed circRNAs in the severe TBI group, 2362 in the moderate group, and 433 in the mild group. A ceRNA network was constructed. The circRNA has_circ_0020269 (circHtra1) was significantly upregulated after brain insults and was correlated with the severity of injury. circHtra1 inhibited cell proliferation and promoted apoptosis, and its knockdown reversed these effects. Further analyses revealed that circHtra1 functions as a miR-3960 sponge and increases the expression of GRB10, which is involved in NK cell infiltration after TBI. circHtra1 was identified as a target of the IGF-1/ADAR1 axis. Reduced expression of ADAR1 (involved in A-to-I editing) after brain insults upregulated circHtra1. Our results show that circHtra1 promotes neuronal loss by sponging miR-3960 and regulating GRB10 and apoptosis during brain insults. In addition, A-to-I editing could regulate circRNA expression profiles after TBI, and circHtra1 is a potential therapeutic target.
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Drug Discovery Landscape
15 orphan drug designations for Moderate and severe traumatic brain injury.
15 orphan drug designations for Moderate and severe traumatic brain injury.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Exenatide | peptides | EMA | — | Boyd Consultants Limited |
Progesterone [BHR-100] | small molecules | EMA | [INACTIVE] Bhr Pharma Belgium | |
Apomorphine hydrochloride | small molecules | EMA | Dr Elkan Raphael Gamzu | |
cyclosporine; ciclosporin | small molecules | FDA | Owl Therapeutics | |
Ciclosporin | small molecules | EMA | ICON Clinical Research Limited | |
progesterone | small molecules | FDA | BHR Pharma, LLC | |
(-)-(2R)-3-(2-hydroxymethylindanyl-4-oxy)-phenyl-4,4,4-trifluorobutane-1-sulfonate | small molecules | EMA | KeyNeurotek Pharmaceuticals AG | |
4-amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride | small molecules | EMA | veriNOS operations GmbH | |
Apomorphine hydrochloride | small molecules | FDA | NeuroHealing Pharmaceuticals, Inc. | |
dimethyl sulfoxide | small molecules | EMA | — | Aop Orphan Pharmaceuticals GmbH |
dexanabinol | small molecules | FDA | Pharmos Corporation | |
N-3[[4(aminoiminomethyl)benzoyl]amino]propyl]-1-[[2,4-dichloro-3-[[2,4-dimethyl-8-quinolinyl) oxy]methyl] phenyl]sulphonyl]-(2S)-2-pyrrolidinecarboxamide, di(methanesulfonate) | small molecules | EMA | Xytis Pharmaceuticals Limited | |
Sodium dichloroacetate | small molecules | FDA | — | Questcor Pharmaceuticals, Inc. |
Enadoline hydrochloride | small molecules | FDA | — | Warner-Lambert Company |
Dimethyl sulfoxide | small molecules | FDA | Abela Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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