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
1,715 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:
1,715 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
2026-08-13 | Gabapentin and cognitive impairment after traumatic brain injury: A multinational cohort of 49,925 patients.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality, and cognitive impairment can be devastating among survivors. The objective was to assess an association between gabapentin and cognitive impairment after TBI. This retrospective cohort study used the multinational TriNetX Research Network (>150 million patients). Adults (≥18 years) with a first TBI and Glasgow Coma Scale (GCS) score recorded on the day of injury were included. Patients with known cognitive impairment or gabapentin exposure were excluded. The cohort (n = 49,925) was stratified into mild (GCS 13-15; n = 34,376), moderate (9-12; n = 4035), and severe (3-8; n = 12,845) TBI. The risk of cognitive impairment and mortality were assessed using Cox proportional hazard models adjusted for known predictors. Secondary analyses examined levetiracetam use (as seizure prophylaxis) and long-term medical and functional outcomes. Among 49,925 included patients w, 3.5% received gabapentin on the day of TBI. After adjustment, gabapentin was associated with a 22% lower risk of cognitive impairment in mild TBI (HR = 0.78; 95% CI, 0.62-0.98; P = .03) and a 46% lower risk of mortality in severe TBI (HR = 0.54; 95% CI, 0.40-0.72; P < .001). Levetiracetam showed no protective association with cognition. Long-term follow-up associated gabapentin use with lower mortality but higher rates of psychiatric/sleep diagnoses, reduced mobility, atrial fibrillation, and pulmonary embolism. Although causality cannot be inferred, these findings suggest gabapentin warrant prospective investigation as a candidate neuroprotective therapy.
2026-08-12 | Scoping review of pharmacological and non-pharmacological management of agitation in post traumatic brain injury patients.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Agitation is a common complication after moderate to severe TBI and managing it in the acute hospital setting can be challenging. Currently, there are no standardised interventions to manage agitation in TBI. This review aims to evaluate contemporary research over the past 10 years which addresses pharmacological and non-pharmacological strategies for managing agitation post-TBI. A scoping review literature search was conducted using PRISMA guidelines. The protocol was pre-registered on PROSPERO (ID 1295903). The literature search used Mesh and Boolean keywords 'traumatic brain injury and 'agitation management' in PubMed, and a free-text search of 'traumatic brain injury and agitation management' with 'map term to subject heading' in Embase (Ovid) and Cochrane, covering studies from 01 January 2015 to 09 March 2026. Findings were analysed and discussed between two reviewers. A total of 65 studies were identified, and after careful review, 13 papers were selected from PubMed and Embase for our Scoping Review. Non-pharmacological strategies highlighted the importance of orienting the patient and the supportive role of family during the acute recovery period. Pharmacological strategies included found that the antipsychotic olanzapine was helpful in managing agitation in moderate to severe TBI. Valproic acid in a small male sample [1] and a separate study using dextromethorphan and quinidine [2] found that these medications were also helpful in managing agitation in TBI. DISCUSSION AND CONCLUSION: Clinicians and health professionals reported that treating the patient holistically, with the medical, social, and psychiatric history was of benefit. Antipsychotic Olanzapine and Valproic acid may have their uses in the short-term, interim acute setting under supervision. Future research with larger sample sizes further investigating these medications would be useful, along with personalisation of medications to the patient's medical history. Most of the studies included in the review are observational and reviews, rather than randomised controlled trials, with a lack of primary evidence which may be a limitation. PROSPERO CRD 1295903.
2026-08-06 | Propranolol attenuates systemic inflammatory response in aged traumatic brain injury patients.
Aged traumatic brain injury (TBI) patients typically have a worse prognosis than younger individuals, though the underlying mechanisms remain incompletely understood. Secondary neuroinflammation is a key determinant of outcomes following TBI, but how aging reshapes the neuroinflammatory response post-TBI remains poorly understood. Propranolol, a clinically available non-selective beta-adrenergic receptor blocker, has garnered increasing interest for its potential therapeutic value in TBI management. Published clinical studies have shown that early administration of propranolol reduces mortality, shortens hospital stays, and improves outcomes in patients with moderate-to-severe TBI. However, its effects and underlying mechanisms in aged patients remain unclear. Here, we investigated the regulatory mechanisms by which propranolol modulates systemic inflammatory responses in aged TBI mice and conducted a retrospective exposure-based clinical cohort study enrolling aged TBI patients. We found that propranolol significantly reduced the production of peripheral blood-derived neutrophils and classical monocytes, and inhibited their infiltration into the brain. In contrast, both peripheral and brain-infiltrating non-classical monocyte populations were expanded. Mechanistically, propranolol substantially reversed the inflammatory transcriptomic profiles in both the bone marrow and brain of aged TBI mice, as evidenced by the downregulation of myeloid cell differentiation and inflammation-related signaling pathways. Behavioral outcomes of aged TBI mice were also significantly improved. It is worth noting that transcriptomic analysis of patient-derived peripheral blood mononuclear cells (PBMCs) and proteomic analysis of cerebrospinal fluid (CSF) also indicated that systemic inflammatory responses are attenuated in aged TBI patients treated with propranolol. In summary, our study suggests that propranolol holds significant clinical potential for alleviating systemic inflammation and improving outcomes in aged TBI patients.
2026-08-06 | Lacosamide Use After Traumatic Brain Injury: A Scoping Review.
Lacosamide (LCM) is a newer antiepileptic drug that enhances slow inactivation of voltage-gated sodium channels and modulates collapsin response mediator protein-2, suggesting potential roles in seizure control and axonal protection after traumatic brain injury (TBI). However, its role in TBI remains unclear. This scoping review aimed to characterize preclinical and clinical research on LCM use in TBI, focusing on seizure prophylaxis, seizure treatment, and potential neuroprotective effects. A comprehensive search of MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index of Nursing and Allied Health (CINAHL), Web of Science, and ClinicalTrials.gov was conducted. Studies involving human patients or animal TBI models evaluating acute LCM use were included, and data were charted descriptively. Ten studies were included, comprising five preclinical and five clinical investigations. Preclinical studies evaluated seizure-related, electrophysiological, histological, inflammatory, and behavioral outcomes in experimental TBI models. Clinical studies included two randomized trials, two observational cohorts, and one case report involving patients with moderate to severe TBI. LCM was administered for seizure prophylaxis or treatment. Seizure-related and safety outcomes were reported across clinical studies, whereas neurological and functional outcomes were less consistently assessed. Overall, evidence supporting LCM use in acute TBI remains limited, with differences between preclinical and clinical outcome domains.
2026-08-04 | Early versus Late Pharmacologic Thromboprophylaxis in Traumatic Brain Injury: A Propensity-Score Matched Cohort Study.
The optimal timing of pharmacological thromboprophylaxis in traumatic brain injury (TBI) remains uncertain due to competing risks of thrombosis and bleeding. This study evaluated whether early heparin initiation (≤72 hours) reduces vascular occlusive events (VOEs), mortality, and hospital stay without increasing bleeding. We compared early versus late (>72 hours) heparin use via propensity score matching (PSM), subgroup analyses, and multivariable logistic regression. Outcomes included VOEs (deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic stroke), bleeding, 30- and 180-day mortality, and length of stay. After PSM, late heparin was associated with higher VOEs (25.16 vs. 12.24%, p < 0.001), 30-day mortality (20 vs. 11.89%, p = 0.03), 180-day mortality (32.26 vs. 19.58%, p = 0.004), and prolonged hospitalization (median: 15.7 vs. 9.7 days, p < 0.001), without increased bleeding risk (16.77 vs. 22.03%, p = 0.24). Subgroup analyses revealed late heparin as an independent risk factor for VOEs in mild TBI (odds ratio: 2.62, 95% confidence interval: 1.54-4.45; p < 0.001) regardless of fracture status, coagulation profile, or hemorrhagic classification, with nonsignificant associations in nonhemorrhagic and moderate-to-severe TBI subgroups. Multivariable analysis identified late heparin, higher comorbidity index, elevated platelet count, and cranial surgery as independent predictors of VOEs, with late heparin also independently associated with increased mortality. These findings suggest early heparin initiation reduces thromboembolic complications, mortality, and hospital stay without markedly increasing bleeding risk, supporting early anticoagulation in selected patients following individualized risk-benefit assessment.
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
2026-03-30 | 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.
2024-09-19 | Parsimonious immune-response endotypes and global outcome in patients with traumatic brain injury.
The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.
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
2026-08-13 | Gabapentin and cognitive impairment after traumatic brain injury: A multinational cohort of 49,925 patients.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality, and cognitive impairment can be devastating among survivors. The objective was to assess an association between gabapentin and cognitive impairment after TBI. This retrospective cohort study used the multinational TriNetX Research Network (>150 million patients). Adults (≥18 years) with a first TBI and Glasgow Coma Scale (GCS) score recorded on the day of injury were included. Patients with known cognitive impairment or gabapentin exposure were excluded. The cohort (n = 49,925) was stratified into mild (GCS 13-15; n = 34,376), moderate (9-12; n = 4035), and severe (3-8; n = 12,845) TBI. The risk of cognitive impairment and mortality were assessed using Cox proportional hazard models adjusted for known predictors. Secondary analyses examined levetiracetam use (as seizure prophylaxis) and long-term medical and functional outcomes. Among 49,925 included patients w, 3.5% received gabapentin on the day of TBI. After adjustment, gabapentin was associated with a 22% lower risk of cognitive impairment in mild TBI (HR = 0.78; 95% CI, 0.62-0.98; P = .03) and a 46% lower risk of mortality in severe TBI (HR = 0.54; 95% CI, 0.40-0.72; P < .001). Levetiracetam showed no protective association with cognition. Long-term follow-up associated gabapentin use with lower mortality but higher rates of psychiatric/sleep diagnoses, reduced mobility, atrial fibrillation, and pulmonary embolism. Although causality cannot be inferred, these findings suggest gabapentin warrant prospective investigation as a candidate neuroprotective therapy.
2026-08-12 | Scoping review of pharmacological and non-pharmacological management of agitation in post traumatic brain injury patients.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Agitation is a common complication after moderate to severe TBI and managing it in the acute hospital setting can be challenging. Currently, there are no standardised interventions to manage agitation in TBI. This review aims to evaluate contemporary research over the past 10 years which addresses pharmacological and non-pharmacological strategies for managing agitation post-TBI. A scoping review literature search was conducted using PRISMA guidelines. The protocol was pre-registered on PROSPERO (ID 1295903). The literature search used Mesh and Boolean keywords 'traumatic brain injury and 'agitation management' in PubMed, and a free-text search of 'traumatic brain injury and agitation management' with 'map term to subject heading' in Embase (Ovid) and Cochrane, covering studies from 01 January 2015 to 09 March 2026. Findings were analysed and discussed between two reviewers. A total of 65 studies were identified, and after careful review, 13 papers were selected from PubMed and Embase for our Scoping Review. Non-pharmacological strategies highlighted the importance of orienting the patient and the supportive role of family during the acute recovery period. Pharmacological strategies included found that the antipsychotic olanzapine was helpful in managing agitation in moderate to severe TBI. Valproic acid in a small male sample [1] and a separate study using dextromethorphan and quinidine [2] found that these medications were also helpful in managing agitation in TBI. DISCUSSION AND CONCLUSION: Clinicians and health professionals reported that treating the patient holistically, with the medical, social, and psychiatric history was of benefit. Antipsychotic Olanzapine and Valproic acid may have their uses in the short-term, interim acute setting under supervision. Future research with larger sample sizes further investigating these medications would be useful, along with personalisation of medications to the patient's medical history. Most of the studies included in the review are observational and reviews, rather than randomised controlled trials, with a lack of primary evidence which may be a limitation. PROSPERO CRD 1295903.
2026-08-06 | Propranolol attenuates systemic inflammatory response in aged traumatic brain injury patients.
Aged traumatic brain injury (TBI) patients typically have a worse prognosis than younger individuals, though the underlying mechanisms remain incompletely understood. Secondary neuroinflammation is a key determinant of outcomes following TBI, but how aging reshapes the neuroinflammatory response post-TBI remains poorly understood. Propranolol, a clinically available non-selective beta-adrenergic receptor blocker, has garnered increasing interest for its potential therapeutic value in TBI management. Published clinical studies have shown that early administration of propranolol reduces mortality, shortens hospital stays, and improves outcomes in patients with moderate-to-severe TBI. However, its effects and underlying mechanisms in aged patients remain unclear. Here, we investigated the regulatory mechanisms by which propranolol modulates systemic inflammatory responses in aged TBI mice and conducted a retrospective exposure-based clinical cohort study enrolling aged TBI patients. We found that propranolol significantly reduced the production of peripheral blood-derived neutrophils and classical monocytes, and inhibited their infiltration into the brain. In contrast, both peripheral and brain-infiltrating non-classical monocyte populations were expanded. Mechanistically, propranolol substantially reversed the inflammatory transcriptomic profiles in both the bone marrow and brain of aged TBI mice, as evidenced by the downregulation of myeloid cell differentiation and inflammation-related signaling pathways. Behavioral outcomes of aged TBI mice were also significantly improved. It is worth noting that transcriptomic analysis of patient-derived peripheral blood mononuclear cells (PBMCs) and proteomic analysis of cerebrospinal fluid (CSF) also indicated that systemic inflammatory responses are attenuated in aged TBI patients treated with propranolol. In summary, our study suggests that propranolol holds significant clinical potential for alleviating systemic inflammation and improving outcomes in aged TBI patients.
2026-08-06 | Lacosamide Use After Traumatic Brain Injury: A Scoping Review.
Lacosamide (LCM) is a newer antiepileptic drug that enhances slow inactivation of voltage-gated sodium channels and modulates collapsin response mediator protein-2, suggesting potential roles in seizure control and axonal protection after traumatic brain injury (TBI). However, its role in TBI remains unclear. This scoping review aimed to characterize preclinical and clinical research on LCM use in TBI, focusing on seizure prophylaxis, seizure treatment, and potential neuroprotective effects. A comprehensive search of MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index of Nursing and Allied Health (CINAHL), Web of Science, and ClinicalTrials.gov was conducted. Studies involving human patients or animal TBI models evaluating acute LCM use were included, and data were charted descriptively. Ten studies were included, comprising five preclinical and five clinical investigations. Preclinical studies evaluated seizure-related, electrophysiological, histological, inflammatory, and behavioral outcomes in experimental TBI models. Clinical studies included two randomized trials, two observational cohorts, and one case report involving patients with moderate to severe TBI. LCM was administered for seizure prophylaxis or treatment. Seizure-related and safety outcomes were reported across clinical studies, whereas neurological and functional outcomes were less consistently assessed. Overall, evidence supporting LCM use in acute TBI remains limited, with differences between preclinical and clinical outcome domains.
2026-08-04 | Early versus Late Pharmacologic Thromboprophylaxis in Traumatic Brain Injury: A Propensity-Score Matched Cohort Study.
The optimal timing of pharmacological thromboprophylaxis in traumatic brain injury (TBI) remains uncertain due to competing risks of thrombosis and bleeding. This study evaluated whether early heparin initiation (≤72 hours) reduces vascular occlusive events (VOEs), mortality, and hospital stay without increasing bleeding. We compared early versus late (>72 hours) heparin use via propensity score matching (PSM), subgroup analyses, and multivariable logistic regression. Outcomes included VOEs (deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic stroke), bleeding, 30- and 180-day mortality, and length of stay. After PSM, late heparin was associated with higher VOEs (25.16 vs. 12.24%, p < 0.001), 30-day mortality (20 vs. 11.89%, p = 0.03), 180-day mortality (32.26 vs. 19.58%, p = 0.004), and prolonged hospitalization (median: 15.7 vs. 9.7 days, p < 0.001), without increased bleeding risk (16.77 vs. 22.03%, p = 0.24). Subgroup analyses revealed late heparin as an independent risk factor for VOEs in mild TBI (odds ratio: 2.62, 95% confidence interval: 1.54-4.45; p < 0.001) regardless of fracture status, coagulation profile, or hemorrhagic classification, with nonsignificant associations in nonhemorrhagic and moderate-to-severe TBI subgroups. Multivariable analysis identified late heparin, higher comorbidity index, elevated platelet count, and cranial surgery as independent predictors of VOEs, with late heparin also independently associated with increased mortality. These findings suggest early heparin initiation reduces thromboembolic complications, mortality, and hospital stay without markedly increasing bleeding risk, supporting early anticoagulation in selected patients following individualized risk-benefit assessment.
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
2026-03-30 | 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.
2024-09-19 | Parsimonious immune-response endotypes and global outcome in patients with traumatic brain injury.
The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.
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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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Exenatide | peptides | EMA | 2023-06-20 | — | Boyd Consultants Limited |
Progesterone [BHR-100] | small molecules | EMA | 2013-02-08 | — | [INACTIVE] Bhr Pharma Belgium |
Apomorphine hydrochloride | small molecules | EMA | 2011-05-13 | — | Dr Elkan Raphael Gamzu |
cyclosporine; ciclosporin | small molecules | FDA | 2010-11-23 | — | Owl Therapeutics |
Ciclosporin | small molecules | EMA | 2010-10-01 | — | ICON Clinical Research Limited |
progesterone | small molecules | FDA | 2009-09-03 | — | BHR Pharma, LLC |
(-)-(2R)-3-(2-hydroxymethylindanyl-4-oxy)-phenyl-4,4,4-trifluorobutane-1-sulfonate | small molecules | EMA | 2008-09-05 | — | KeyNeurotek Pharmaceuticals AG |
4-amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride | small molecules | EMA | 2006-08-28 | — | veriNOS operations GmbH |
Apomorphine hydrochloride | small molecules | FDA | 2006-05-23 | — | NeuroHealing Pharmaceuticals, Inc. |
dimethyl sulfoxide | small molecules | EMA | 2005-03-03 | — | Aop Orphan Pharmaceuticals GmbH |
dexanabinol | small molecules | FDA | 2004-08-11 | — | 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 | 2004-02-23 | — | Xytis Pharmaceuticals Limited |
Sodium dichloroacetate | small molecules | FDA | 1999-06-14 | — | Questcor Pharmaceuticals, Inc. |
Enadoline hydrochloride | small molecules | FDA | 1997-01-28 | — | Warner-Lambert Company |
Dimethyl sulfoxide | small molecules | FDA | 1994-11-22 | — | Abela Pharmaceuticals, Inc. |
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