Efficacy In Traumatic Brain Injury Research Articles

Engineered exosomes enriched with select microRNAs amplify their therapeutic efficacy for traumatic brain injury and stroke.

Traumatic brain injury (TBI) and stroke stand as prominent causes of global disability and mortality. Treatment strategies for stroke and TBI are shifting from targeting neuroprotection toward cell-based neurorestorative strategy, aiming to augment endogenous brain remodeling, which holds considerable promise for the treatment of TBI and stroke. Compelling evidence underscores that the therapeutic effects of cell-based therapy are mediated by the active generation and release of exosomes from administered cells. Exosomes, endosomal derived and nano-sized extracellular vesicles, play a pivotal role in intercellular communication. Thus, we may independently employ exosomes to treat stroke and TBI. Systemic administration of mesenchymal stem cell (MSC) derived exosomes promotes neuroplasticity and neurological functional recovery in preclinical animal models of TBI and stroke. In this mini review, we describe the properties of exosomes and recent exosome-based therapies of TBI and stroke. It is noteworthy that the microRNA cargo within exosomes contributes to their therapeutic effects. Thus, we provide a brief introduction to microRNAs and insight into their key roles in mediating therapeutic effects. With the increasing knowledge of exosomes, researchers have "engineered" exosome microRNA content to amplify their therapeutic benefits. We therefore focus our discussion on the therapeutic benefits of recently employed microRNA-enriched engineered exosomes. We also discuss the current opportunities and challenges in translating exosome-based therapy to clinical applications.

Role of hydrogen in traumatic brain injury: a narrative review.

Traumatic brain injury (TBI) is a serious global public health problem. Survivors of TBI often suffer from long-term disability, which puts a heavy burden on society and families. Unfortunately, up to now, there is no efficacious treatment for TBI patients in clinical practice. As a reducing gas, hydrogen has been shown to be neuroprotective in multiple cerebral disease models; however, its efficacy in TBI remains controversial. In this review, we will focus on the results of hydrogen in experimental TBI, elaborate the potential mechanisms, and put forward for future researches based on our current understanding and views.

Steroids for delayed cerebral edema after traumatic brain injury.

Background: Brain edema is a common phenomenon after traumatic brain injury (TBI) resulting in increased intracranial pressure and subsequent neurological deterioration. Experimental studies have proven that brain edema is biphasic (cytotoxic followed by vasogenic). Till date, all studies, including the corticosteroid randomization after significant head injury (HI) trial, have used high-dose steroids in the acute period during which the edema is essentially cytotoxic in nature. No clinical data exist pertaining to delayed cerebral edema (vasogenic) and steroids.Methods: Patients who had received steroids for delayed cerebral edema after TBI were retrospectively analyzed over a 2-year period. Steroid dose, timing of steroid prescription, time to improvement of symptoms, and complications were noted.Results: There were six males and three females. Mean age was 41.1 years. There were no severe HI cases. All subjects had cerebral contusions on imaging. Dexamethasone was the preferred steroid starting with 12 mg/day and tapered in 5–7 days. The mean interval to steroid administration after trauma was 7 days. The mean duration of steroid prescription was 6.3 days. All patients had complete symptomatic improvement. The mean time to symptom resolution was 3.8 days. No patients experienced any complications pertinent to steroid usage.Conclusion: This is the first study to document efficacy of steroids for delayed cerebral edema after TBI, at least in mild/moderate head injuries. The timing of steroid usage and dose of steroids is key aspects that might determine its efficacy in TBI which was the drawbacks of the previous studies. Future prospective trials with the above factors in consideration may confirm/refute above findings.

Use of Medical Cannabis to Treat Traumatic Brain Injury.

There is not a single pharmacological agent with demonstrated therapeutic efficacy for traumatic brain injury (TBI). With recent legalization efforts and the growing popularity of medical cannabis, patients with TBI will inevitably consider medical cannabis as a treatment option. Pre-clinical TBI research suggests that cannabinoids have neuroprotective and psychotherapeutic properties. In contrast, recreational cannabis use has consistently shown to have detrimental effects. Our review identified a paucity of high-quality studies examining the beneficial and adverse effects of medical cannabis on TBI, with only a single phase III randomized control trial. However, observational studies demonstrate that TBI patients are using medical and recreational cannabis to treat their symptoms, highlighting inconsistencies between public policy, perception of potential efficacy, and the dearth of empirical evidence. We conclude that randomized controlled trials and prospective studies with appropriate control groups are necessary to fully understand the efficacy and potential adverse effects of medical cannabis for TBI.

Slacklining Improves Functional Independence, Fatigue and Balance 2 Years Post Severe Traumatic Brain Injury: A Single Case Study

Objective: Individuals with traumatic brain injury (TBI) recover functional independence to varying degrees due to numerous factors. However, plateaued recovery often initiates between 6-12 months. We investigated whether introducing slacklining, a whole-body interactive balance approach, would provide further improvement in a chronic severe-TBI patient. Methods: A retrospective pragmatic single case-report on a 40-year-old woman two-years post severe-TBI working part-time. Global-functional status had plateaued with ongoing affected balance, left-sided weakness, and fatigue. Slacklining was added to an existing daily multi-disciplinary, self-managed rehabilitation program initially ‘ad-hoc’ and self-managed over nine weeks (Phase-1); then formalized therapist-directed over four weeks (Phase-2). The primary outcome was global-functional status; secondary was the 4-stage 20-step slackline graded-progression, and fatigue; tertiary was balance. All outcomes were reported at slacklining initiation (baseline) and Phase-1 and Phase-2 completion. Findings/ Results: Improvements were found from baseline till Phase-1 completion, and subsequently Phase-2 completion. Global-functional status increased 15% in Phase-1 (baseline=22% to completion=37%); and 18% in Phase-2 (completion=55%); slackline ability from baseline=step-1 to Phase-1 completion=step-6 then Phase-2 completion=step-10; balance duration increased 1.5-fold in Phase-1 and 3-6-fold in Phase-2; and fatigue reduced 22% overall baseline=63% to Phase-2=41% (no Phase-1 measure). Balance, confidence, and function were all self-reported as improved from baseline to program completion. Conclusions: The findings provide evidence for using slacklining to overcome plateaued recovery during rehabilitation of a severe-TBI patient; and imply that supervised programs have greater impact than un-supervised. Further research is required to determine slacklining’s efficacy for TBI, and potentially concussion, through dose, frequency, and intensity.

Hydrogen sulfide protects against cell damage through modulation of PI3K/Akt/Nrf2 signaling.

Hydrogen sulfide as the third endogenous gaseous mediator had protective effects against traumatic brain injury-induced neuronal damage in mice. However, the exact pathophysiological mechanism underlying traumatic brain injury is complicated and the protective role of H2S is not yet fully known. Therefore, we combined the mechanical injury (scratch) with secondary injury including metabolic impairment (no glucose) together to investigate the underlying cellular mechanism of hydrogen sulfide in vitro models of traumatic brain injury. In the present study, we found that H2S could prevent the scratch-induced decrease in the expression of cystathionine-β-synthetase, a key enzyme involved in the source of hydrogen sulfide, and endogenous hydrogen sulfide generation in PC12 cells. We also found that hydrogen sulfide could prevent scratch-induced cellular injury, alteration of mitochondrial membrane potential, intracellular accumulation of reactive oxygen species and cell death (autophagic cell death and apoptosis) in PC12 cells. It was also found that blocking PI3K/AKT pathway by LY294002, abolished the protection of H2S against scratch-induced cellular reactive oxygen species level and NRF2 accumulation and function in the nucleus. These results suggest that hydrogen sulfide protects against cell damage induced by scratch injury through modulation of the PI3K/Akt/Nrf2 pathway. This study raises the possibility that hydrogen sulfide may have therapeutic efficacy in traumatic brain injury.

Cognitive Training Reorganizes Network Modularity in Traumatic Brain Injury

Background. Graph-theoretic approaches are increasingly popular for identifying the patterns of disrupted neural systems after traumatic brain injury (TBI). However, the patterns of neuroplasticity in brain organization after cognitive training in TBI are less well understood. Objective. We identified the patterns of training-induced neuroplasticity of the whole-brain network in TBI, using resting-state functional connectivity and graph theory. Methods. A total of 64 civilians and veterans with TBI were randomized into either a strategy-based cognitive training group (n = 33) or a knowledge-based training group (active control group; n = 31) for 8 weeks. The participants experienced mild to severe TBI without focal damage and persistent cognitive dysfunctions. A subset of participants complained of subclinical but residual psychiatric symptoms. We acquired their resting-state functional magnetic resonance imaging before training, immediately posttraining, and 3 months posttraining. From participants’ resting-state networks, we obtained the modularity, participation coefficient, within-module connectivity, global efficiency, and local efficiency over multiple network densities. We next performed longitudinal analyses on those measures corrected for multiple comparisons across network densities using false discovery rate (FDR). Results. Relative to the knowledge-based training group, the strategy-based cognitive training group had reduced modularity and increased participation coefficient, global efficiency, and local efficiency over time (Pnodal < .05; qFDR < 0.05). Brain behavior analysis revealed that the participation coefficient and global efficiency within the strategy-based cognitive training group correlated with trail-making scores in the context of training (Pnodal < .05; qFDR < 0.05). Conclusions. Cognitive training reorganized modular networks in TBI over the whole brain. Graph-theoretic approaches may be useful in identifying a potential brain-based marker of training efficacy in TBI.

Abstract 701: Mesenchymal Stem Cells Overexpressing FGF21 Improve Functional Recovery After Traumatic Brain Injury

Traumatic Brain Injury (TBI) is a progressive and complex brain injury that results in many adverse and long term neurological consequences. Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that has emerged as a therapeutic agent for the treatment of neurodegenerative diseases and brain injuries, as it has been shown to exhibit neuroprotective effects, promote remyelination, enhances angiogenesis, and to stimulate the neurite growth of glia-like cells. In this study, MSCs were genetically engineered to overexpress fibroblast growth factor 21 (FGF21) in order to improve their efficacy in TBI. MSCs overexpressing FGF21 (MSC-FGF21) were transplanted to mouse brain by intracerebroventricular (ICV) injection 24 hours after TBI. Spatial learning and memory tests were performed to examine the effects of MSC-FGF21 at 24 hours following controlled cortical impact (CCI) insult in TBI mice model. We found the FGF21 levels were reduced in the hippocampus of vehicle- treated group mice and that MSC-FGF21 treatment restored the FGF21 level significantly. MSC-FGF21 treatment significantly reduced spatial learning/memory decline at 21 days post injury as measured in the Morris water maze test. Both MSC-mCherry (vehicle control) and MSC-FGF21 treatments induced a significant improvement in short term memory formation as determined by the novel object recognition test (NOR) after 14 days of injury. In addition, MSC-FGF21treatment significantly increased the impaired neurogenesis and restored the dendritic process and morphology of immature neurons in the hippocampal dentate gyrus (DG). Taken together, these data provide compelling evidence that MSC-FGF21 treatment promotes neurogenesis and hippocampal neuroplasticity following TBI insult.

Tachykinin NK1 receptor antagonist L-733,060 and substance P deletion exert neuroprotection through inhibiting oxidative stress and cell death after traumatic brain injury in mice.

Substance P (SP) is believed to play a role in traumatic brain injury (TBI), and the inhibition of binding of SP to the tachykinin neurokinin-1 receptor (NK1R) using NK1R antagonists had made favorable effects on TBI. Our current study addresses the functional roles and underlying mechanisms of SP and NK1R antagonist L-733,060 following TBI. Adult male wild type C57BL/6 J and SP knock out (SPKO) mice received a controlled cortical impact and outcome parameters were assessed. The results showed that TBI-induced motor and spatial memory deficits, lesion volume, brain water content and blood-brain barrier disruption were alleviated both in L-733,060-treated C57BL/6 J mice and vehicle-treated SPKO mice. L-733,060 treatment and SP deletion inhibited TBI-induced the release of cytochrome c from mitochondria to cytoplasm, activation of caspase-3, oxidative stress and neuroinflammation. Higher SP levels in serum and cortex were observed in wild type mice undergoing TBI relative to wild type sham group, but very little expression of cortical SP was detected in the SP-/- mice either TBI or not. Upregulation of NK1R expression after TBI was observed, and there was no significant difference between wild type and SPKO groups. in vitro, L-733,060 and SP deletion inhibited scratch injury-induced cell death, loss of mitochondrial membrane potential and reactive oxygen species (ROS) production following TBI. Together, the results of this study implicate a functional role for NK1-R antagonist L-733,060 and deletion of SP in TBI-induced neurological outcome, oxidative damage, neuroinflammation and cell death. Upregulation of NK1R maybe a consequence of TBI, independent of the levels of substance P. This study raises the possibility that targeting SP through its receptor NK1R or genetic deletion may have therapeutic efficacy in TBI.

Deletion of NADPH oxidase 4 reduces severity of traumatic brain injury.

Traumatic brain injury (TBI) contributes to over 30% of injury-related deaths and is a major cause of disability without effective clinical therapies. Oxidative stress contributes to neurodegeneration, neuroinflammation, and neuronal death to amplify the primary injury after TBI. NADPH oxidase (NOX) is a major source of reactive oxygen species following brain injury. Our current study addresses the functional role of the NOX4 isoform in the damaged cortex following TBI. Adult male C57BL/6 J and NOX4-/- mice received a controlled cortical impact and lesion size, NOX4 expression, oxidative stress, neurodegeneration, and cell death were assessed in the injured cerebral cortex. The results revealed that NOX4 mRNA and protein expression were significantly upregulated at 1-7 days post-TBI in the injured cerebral cortex. Expression of the oxidative stress markers, 8-OHdG, 4-HNE, and nitrotyrosine was upregulated at 2 and 4 days post-TBI in the WT injured cerebral cortex, and nitrotyrosine primarily colocalized with neurons. In the NOX4-/- mice, expression of these oxidative stress markers, 8-OHdG, 4-HNE, and nitrotyrosine were significantly attenuated at both timepoints. In addition, examination of NOX4-/- mice revealed a reduced number of apoptotic (TUNEL+) and degenerating (FJB+) cells in the perilesional cortex after TBI, as well as a smaller lesion size compared with the WT group. The results of this study implicate a functional role for NOX4 in TBI induced oxidative damage and neurodegeneration and raise the possibility that targeting NOX4 may have therapeutic efficacy in TBI.

Animal modelling of traumatic brain injury in preclinical drug development: where do we go from here?

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults. Survivors of TBI frequently suffer from long-term personality changes and deficits in cognitive and motor performance, urgently calling for novel pharmacological treatment options. To date, all clinical trials evaluating neuroprotective compounds have failed in demonstrating clinical efficacy in cohorts of severely injured TBI patients. The purpose of the present review is to describe the utility of animal models of TBI for preclinical evaluation of pharmacological compounds. No single animal model can adequately mimic all aspects of human TBI owing to the heterogeneity of clinical TBI. To successfully develop compounds for clinical TBI, a thorough evaluation in several TBI models and injury severities is crucial. Additionally, brain pharmacokinetics and the time window must be carefully evaluated. Although the search for a single-compound, 'silver bullet' therapy is ongoing, a combination of drugs targeting various aspects of neuroprotection, neuroinflammation and regeneration may be needed. In summary, finding drugs and prove clinical efficacy in TBI is a major challenge ahead for the research community and the drug industry. For a successful translation of basic science knowledge to the clinic to occur we believe that a further refinement of animal models and functional outcome methods is important. In the clinical setting, improved patient classification, more homogenous patient cohorts in clinical trials, standardized treatment strategies, improved central nervous system drug delivery systems and monitoring of target drug levels and drug effects is warranted.

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

Traumatic brain injury (TBI) remains a serious health concern, and TBI is one of the leading causes of death and disability, especially among young adults. Although preventive education, increased usage of safety devices, and TBI management have dramatically increased the potential for surviving a brain injury, there is still a need to develop reliable methods to diagnose TBI, the secondary pathologies associated with TBI, and predicting the outcomes of TBI. Biomarkers (changes of amount or activity in a biomolecule that reflect injury or disease) have shown promise in the diagnosis of several conditions, including cancer, heart failure, infection, and genetic disorders. A variety of proteins, small molecules, and lipid products have been proposed as potential biomarkers of brain damage from TBI. Although some of these changes have been reported to correlate with mortality and outcome, further research is required to identify prognostic biomarkers. This need is punctuated in mild injuries that cannot be readily detected using current techniques, as well as in defining patient risk for developing TBI-associated secondary injuries.