Extracellular Vesicles Mediate Neuroprotection and Functional Recovery after Traumatic Brain Injury.
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ABSTRACT:
SUBMITTER: Sun MK
PROVIDER: S-EPMC7249471 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite extensive preclinical research supporting the effectiveness of neuroprotective therapies for brain trauma, there have been no successful randomized controlled clinical trials to date. TBI results in delayed secondary tissue injury due to neurochemical, metabolic and cellular changes; modulating such effects has provided the basis for neuroprotective interventions. To establish more effective neuroprotective treatments for TBI it is essential to better understand the complex cellular and molecular events that contribute to secondary injury. Here we critically review relevant research related to causes and modulation of delayed tissue damage, with particular emphasis on cell death mechanisms and post-traumatic neuroinflammation. We discuss the concept of utilizing multipotential drugs that target multiple secondary injury pathways, rather than more specific "laser"-targeted strategies that have uniformly failed in clinical trials. Moreover, we assess data supporting use of neuroprotective drugs that are currently being evaluated in human clinical trials for TBI, as well as promising emerging experimental multipotential drug treatment strategies. Finally, we describe key challenges and provide suggestions to improve the likelihood of successful clinical translation.
| S-EPMC4808298 | biostudies-literature
Project description:Traumatic brain injury (TBI) elicits an inflammatory response in the central nervous system (CNS) that involves both resident and peripheral immune cells. Neuroinflammation can persist for years following a single TBI and may contribute to neurodegeneration. However, administration of anti-inflammatory drugs shortly after injury was not effective in the treatment of TBI patients. Some components of the neuroinflammatory response seem to play a beneficial role in the acute phase of TBI. Indeed, following CNS injury, early inflammation can set the stage for proper tissue regeneration and recovery, which can, perhaps, explain why general immunosuppression in TBI patients is disadvantageous. Here, we discuss some positive attributes of neuroinflammation and propose that inflammation be therapeutically guided in TBI patients rather than globally suppressed.
| S-EPMC5260471 | biostudies-literature
Project description:Local inflammation plays a pivotal role in the process of secondary damage after spinal cord injury. We recently reported that acute intravenous application of extracellular vesicles (EVs) secreted by human umbilical cord mesenchymal stromal cells dampens the induction of inflammatory processes following traumatic spinal cord injury. However, systemic application of EVs is associated with delayed delivery to the site of injury and the necessity for high doses to reach therapeutic levels locally. To resolve these two constraints, we injected EVs directly at the lesion site acutely after spinal cord injury. We report here that intralesional application of EVs resulted in a more robust improvement of motor recovery, assessed with the BBB score and sub-score, as compared to the intravenous delivery. Moreover, the intralesional application was more potent in reducing inflammation and scarring after spinal cord injury than intravenous administration. Hence, the development of EV-based therapy for spinal cord injury should aim at an early application of vesicles close to the lesion.
| S-EPMC8762366 | biostudies-literature
Project description:Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the post-traumatic activation of JNK in a rodent model of TBI. The recordings of field excitatory post-synaptic potentials in the hippocampal CA1 subfield demonstrate that TBI inhibits the expression of long-term potentiation (LTP) evoked by high-frequency stimulation of Schaffer collaterals, and that CN2097 attenuates this LTP impairment. Lastly, we demonstrate that CN2097 significantly improves the complex auditory processing deficits, which are impaired after injury. The multifunctionality of CN2097 strongly suggests that CN2097 could be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma.
| S-EPMC5591207 | biostudies-literature
Project description:IMPORTANCE:Traumatic brain injury (TBI) is a significant public health concern that affects individuals in all demographics. With increasing interest in the medical and public communities, understanding the inflammatory mechanisms that drive the pathologic and consequent cognitive outcomes can inform future research and clinical decisions for patients with TBI. OBJECTIVES:To review known inflammatory mechanisms in TBI and to highlight clinical trials and neuroprotective therapeutic manipulations of pathologic and inflammatory mechanisms of TBI. EVIDENCE REVIEW:We searched articles in PubMed published between 1960 and August 1, 2014, using the following keywords: traumatic brain injury, sterile injury, inflammation, astrocytes, microglia, monocytes, macrophages, neutrophils, T cells, reactive oxygen species, alarmins, danger-associated molecular patterns, purinergic receptors, neuroprotection, and clinical trials. Previous clinical trials or therapeutic studies that involved manipulation of the discussed mechanisms were considered for inclusion. The final list of selected studies was assembled based on novelty and direct relevance to the primary focus of this review. FINDINGS:Traumatic brain injury is a diverse group of sterile injuries induced by primary and secondary mechanisms that give rise to cell death, inflammation, and neurologic dysfunction in patients of all demographics. Pathogenesis is driven by complex, interacting mechanisms that include reactive oxygen species, ion channel and gap junction signaling, purinergic receptor signaling, excitotoxic neurotransmitter signaling, perturbations in calcium homeostasis, and damage-associated molecular pattern molecules, among others. Central nervous system resident and peripherally derived inflammatory cells respond to TBI and can provide neuroprotection or participate in maladaptive secondary injury reactions. The exact contribution of inflammatory cells to a TBI lesion is dictated by their anatomical positioning as well as the local cues to which they are exposed. CONCLUSIONS AND RELEVANCE:The mechanisms that drive TBI lesion development as well as those that promote repair are exceedingly complex and often superimposed. Because pathogenic mechanisms can diversify over time or even differ based on the injury type, it is important that neuroprotective therapeutics be developed and administered with these variables in mind. Due to its complexity, TBI has proven particularly challenging to treat; however, a number of promising therapeutic approaches are now under pre-clinical development, and recent clinical trials have even yielded a few successes. Given the worldwide impact of TBI on the human population, it is imperative that research remains active in this area and that we continue to develop therapeutics to improve outcome in afflicted patients.
| S-EPMC5001842 | biostudies-literature
Project description:Neuroprotection after traumatic brain injury (TBI) is an important goal pursued strenuously in the last 30 years. The acute cerebral injury triggers a cascade of biochemical events that may worsen the integrity, function, and connectivity of the brain cells and decrease the chance of functional recovery. A number of molecules acting against this deleterious cascade have been tested in the experimental setting, often with preliminary encouraging results. Unfortunately, clinical trials using those candidate neuroprotectants molecules have consistently produced disappointing results, highlighting the necessity of improving the research standards. Despite repeated failures in pharmacological neuroprotection, TBI treatment in neurointensive care units has achieved outcome improvement. It is likely that intensive treatment has contributed to this progress offering a different kind of neuroprotection, based on a careful prevention and limitations of intracranial and systemic threats. The natural course of acute brain damage, in fact, is often complicated by additional adverse events, like the development of intracranial hypertension, brain hypoxia, or hypoperfusion. All these events may lead to additional brain damage and worsen outcome. An approach designed for early identification and prompt correction of insults may, therefore, limit brain damage and improve results.
| S-EPMC5523726 | biostudies-other
Project description:Mild traumatic brain injury does not currently have a clear molecular diagnostic panel to either confirm the injury or to guide its treatment. Current biomarkers for traumatic brain injury rely mainly on detecting circulating proteins in blood that are associated with degenerating neurons, which are less common in mild traumatic brain injury, or with broad inflammatory cascades which are produced in multiple tissues and are thus not brain specific. To address this issue, we conducted an observational cohort study designed to measure a protein panel in two compartments-plasma and brain-derived extracellular vesicles-with the following hypotheses: (i) each compartment provides independent diagnostic information and (ii) algorithmically combining these compartments accurately classifies clinical mild traumatic brain injury. We evaluated this hypothesis using plasma samples from mild (Glasgow coma scale scores 13-15) traumatic brain injury patients (n = 47) and healthy and orthopaedic control subjects (n = 46) to evaluate biomarkers in brain-derived extracellular vesicles and plasma. We used our Track Etched Magnetic Nanopore technology to isolate brain-derived extracellular vesicles from plasma based on their expression of GluR2, combined with the ultrasensitive digital enzyme-linked immunosorbent assay technique, Single-Molecule Array. We quantified extracellular vesicle-packaged and plasma levels of biomarkers associated with two categories of traumatic brain injury pathology: neurodegeneration and neuronal/glial damage (ubiquitin C-terminal hydrolase L1, glial fibrillary acid protein, neurofilament light and Tau) and inflammation (interleukin-6, interleukin-10 and tumour necrosis factor alpha). We found that GluR2+ extracellular vesicles have distinct biomarker distributions than those present in the plasma. As a proof of concept, we showed that using a panel of biomarkers comprised of both plasma and GluR2+ extracellular vesicles, injured patients could be accurately classified versus non-injured patients.
| S-EPMC8491985 | biostudies-literature
Project description:To provide an overview of the preclinical literature on progesterone for neuroprotection after traumatic brain injury and to describe unique features of developmental brain injury that should be considered when evaluating the therapeutic potential for progesterone treatment after pediatric traumatic brain injury.National Library of Medicine PubMed literature review.The mechanisms of neuroprotection by progesterone are reviewed, and the preclinical literature using progesterone treatment in adult animal models of traumatic brain injury is summarized. Unique features of the developing brain that could either enhance or limit the efficacy of neuroprotection by progesterone are discussed, and the limited preclinical literature using progesterone after acute injury to the developing brain is described. Finally, the current status of clinical trials of progesterone for adult traumatic brain injury is reviewed.Progesterone is a pleiotropic agent with beneficial effects on secondary injury cascades that occur after traumatic brain injury, including cerebral edema, neuroinflammation, oxidative stress, and excitotoxicity. More than 40 studies have used progesterone for treatment after traumatic brain injury in adult animal models, with results summarized in tabular form. However, very few studies have evaluated progesterone in pediatric animal models of brain injury. To date, two human phase II trials of progesterone for adult traumatic brain injury have been published, and two multicenter phase III trials are underway.The unique features of the developing brain from that of a mature adult brain make it necessary to independently study progesterone in clinically relevant, immature animal models of traumatic brain injury. Additional preclinical studies could lead to the development of a novel neuroprotective therapy that could reduce the long-term disability in head-injured children and could potentially provide benefit in other forms of pediatric brain injury (global ischemia, stroke, and statue epilepticus).
| S-EPMC4806367 | biostudies-literature
Project description:The accurate diagnosis and clinical management of traumatic brain injury (TBI) is currently limited by the lack of accessible molecular biomarkers that reflect the pathophysiology of this heterogeneous disease. To address this challenge, we developed a microchip diagnostic that can characterize TBI more comprehensively using the RNA found in brain-derived extracellular vesicles (EVs). Our approach measures a panel of EV miRNAs, processed with machine learning algorithms to capture the state of the injured and recovering brain. Our diagnostic combines surface marker-specific nanomagnetic isolation of brain-derived EVs, biomarker discovery using RNA sequencing, and machine learning processing of the EV miRNA cargo to minimally invasively measure the state of TBI. We achieved an accuracy of 99% identifying the signature of injured vs. sham control mice using an independent blinded test set (N = 77), where the injured group consists of heterogeneous populations (injury intensity, elapsed time since injury) to model the variability present in clinical samples. Moreover, we successfully predicted the intensity of the injury, the elapsed time since injury, and the presence of a prior injury using independent blinded test sets (N = 82). We demonstrated the translatability in a blinded test set by identifying TBI patients from healthy controls (AUC = 0.9, N = 60). This approach, which can detect signatures of injury that persist across a variety of injury types and individual responses to injury, more accurately reflects the heterogeneity of human TBI injury and recovery than conventional diagnostics, opening new opportunities to improve treatment of traumatic brain injuries.
| S-EPMC6334845 | biostudies-literature
Project description:Traumatic brain injury (TBI) is a common cause of death and acquired disability in adults and children. Identifying biomarkers for mild TBI (mTBI) that can predict functional impairments on neuropsychiatric and neurocognitive testing after head trauma is yet to be firmly established. Extracellular vesicles (EVs) are known to traffic from the brain to the oral cavity and can be detected in saliva. We hypothesize the genetic profile of salivary EVs in patients who have suffered head trauma will differ from normal healthy controls, thus constituting a unique expression signature for mTBI. We enrolled a total of 54 subjects including for saliva sampling, 23 controls with no history of head traumas, 16 patients enrolled from an outpatient concussion clinic, and 15 patients from the emergency department who had sustained a head trauma within 24 hr. We performed real-time PCR of the salivary EVs of the 54 subjects profiling 96 genes from the TaqMan Human Alzheimer's disease array. Real-time PCR analysis revealed 57 (15 genes, p < 0.05) upregulated genes in emergency department patients and 56 (14 genes, p < 0.05) upregulated genes in concussion clinic patients when compared with controls. Three genes were upregulated in both the emergency department patients and concussion clinic patients: CDC2, CSNK1A1, and CTSD ( p < 0.05). Our results demonstrate that salivary EVs gene expression can serve as a viable source of biomarkers for mTBI. This study shows multiple Alzheimer's disease genes present after an mTBI.
| S-EPMC6478516 | biostudies-literature