Secondary Injury Cascade Research Articles

Circular Ribonucleic Acid Expression Profile in Mouse Cortex after Traumatic Brain Injury

Traumatic brain injury (TBI) causes high rates of worldwide death and morbidity because of the complex secondary injury cascade. Circular ribonucleic acid (RNA) (circRNA), a type of RNA that forms a covalently closed continuous loop, may be involved in the regulation of secondary injury because it is expressed widely in the brain and contributes to a large class of post-transcriptional regulators. Deep RNA sequencing (RNA-seq) and bioinformatic analysis were performed to investigate the expression profile and function of circRNAs in the mouse cortex after controlled cortical impact (CCI). A total of 19,794 circRNAs were identified, and 1315 were annotated in circBase. There were 191 filtered differentially expressed circRNAs (98 for up-regulated and 93 for down-regulated). The gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that inflammation, cell death, and repair of damage were the main biological processes and molecular mechanisms related to altered circRNAs. The pathway-circRNA interaction network revealed three core circRNAs and five corepathways related to TBI. The circRNA-messenger RNA (mRNA) interaction network and competitive endogenous RNA (ceRNA) analysis suggested potential microRNA (miRNA) sponges and target mRNAs. In addition to five optimal circRNA-miRNA-mRNA pairs were analyzed, circRNA_16895-miRNA myosin-10 (Myo 10) was predicted to regulate fragment crystallizable gamma receptors (FcγR)-mediated phagocytosis pathway. Four circRNAs were selected for quantitative real-time polymerase chain reaction analysis to validate the sequencing data. Our results provide promising functions of circRNAs aberrantly expressed in TBI to explore molecular mechanisms and potential therapeutic targets for its therapy.

Wednesday, September 26, 2018 10:35 AM – 12:00 PM Cervical Spine Trauma: 19. Efficacy and safety of riluzole in acute spinal cord injury (SCI): rationale and design of AOSpine phase III multicenter double blinded randomized controlled trial (RISCIS)

BACKGROUND CONTEXT There is convincing evidence from the preclinical realm that the pharmacologic agent riluzole attenuates certain aspects of the secondary injury cascade leading to diminished neurological tissue destruction in animal SCI models. The safety and pharmacokinetic profile of riluzole have been studied in a multicenter pilot study in 36 patients. Efficacy of riluzole in acute human SCI has not been established. PURPOSE This study aims to investigate efficacy of riluzole in acute SCI. STUDY DESIGN/SETTING This is an ongoing multicenter, international double-blinded phase III RCT. PATIENT SAMPLE A total of 351 patients with acute C4–C8 SCI and ASIA impairment grade A, B or C OUTCOME MEASURES Primary outcome is the change in ASIA motor score (AMS) between baseline and 180 days. Other outcomes include ASIA upper and lower extremity MS; ASIA sensory score; ASIA grade; SCIM); SF-36v2; EQ-5D and GRASSP. METHODS A total of 351 patients with acute C4–C8 SCI and ASIA impairment grade A, B or C randomized 1:1 to riluzole and placebo. Primary outcome is the change in ASIA motor score (AMS) between baseline and 180 days. Other outcomes include ASIA upper and lower extremity MS; ASIA sensory score; ASIA grade; SCIM); SF-36v2; EQ-5D and GRASSP. Two-stage sequential adaptive trial statistical design has 90% power to detect 9 points difference in the ASIA motor score at one-sidedalpha=.025. RESULTS A matched cohort analysis performed in the Phase I study showed that riluzole treated cervical SCI patients experienced an additional 15.5 points in AMS recovery at 90 days post injury. Although the phase I study was underpowered to investigate efficacy the current phase III study is poised to definitive address this question. To date, 112 subjects have been enrolled. Average age of the enrolled subjects is 48.0 (SD 16.4); 84% males. ASIA at arrival and preInjury status, ASIA grade A (48%), B (27%), C (25%). GRASSP 64.6 (SD 61.4), SF35v2 PCS 53.0(SD 9.0) SF36v2 MCS 54.3 (SD 11.5). CONCLUSIONS This is a Phase III study of riluzole in acute SCI. FDA DEVICE/DRUG STATUS Riluzole (Not approved for this indication).

Combination Therapy for Multi-Target Manipulation of Secondary Brain Injury Mechanisms.

Traumatic brain injury (TBI) is a major healthcare problem that affects millions of people worldwide. Despite advances in understanding and developing preventative and treatment strategies using preclinical animal models, clinical trials to date have failed, and a 'magic bullet’ for effectively treating TBI-induced damage does not exist. Thus, novel pharmacological strategies to effectively manipulate the complex and heterogeneous pathophysiology of secondary injury mechanisms are needed. Given that goal, this paper discusses the relevance and advantages of combination therapies (COMTs) for ‘multi-target manipulation’ of the secondary injury cascade by administering multiple drugs to achieve an optimal therapeutic window of opportunity (e.g., temporally broad window) and compares these regimens to monotherapies that manipulate a single target with a single drug at a given time. Furthermore, we posit that integrated mechanistic multiscale models that combine primary injury biomechanics, secondary injury mechanobiology/neurobiology, physiology, pharmacology and mathematical programming techniques could account for vast differences in the biological space and time scales and help to accelerate drug development, to optimize pharmacological COMT protocols and to improve treatment outcomes.

Continuous Infusion of Phenelzine, Cyclosporine A, or Their Combination: Evaluation of Mitochondrial Bioenergetics, Oxidative Damage, and Cytoskeletal Degradation following Severe Controlled Cortical Impact Traumatic Brain Injury in Rats.

To date, all monotherapy clinical traumatic brain injury (TBI) trials have failed, and there are currently no Food and Drug Administration (FDA)-approved pharmacotherapies for the acute treatment of severe TBI. Due to the complex secondary injury cascade following injury, there is a need to develop multi-mechanistic combinational neuroprotective approaches for the treatment of acute TBI. As central mediators of the TBI secondary injury cascade, both mitochondria and lipid peroxidation-derived aldehydes make promising therapeutic targets. Cyclosporine A (CsA), an FDA-approved immunosuppressant capable of inhibiting the mitochondrial permeability transition pore, and phenelzine (PZ), an FDA-approved monoamine oxidase inhibitor capable of scavenging neurotoxic lipid peroxidation-derived aldehydes, have both been shown to be partially neuroprotective following experimental TBI. Therefore, it follows that the combination of PZ and CsA may enhance neuroprotection over either agent alone through the combining of distinct but complementary mechanisms of action. Additionally, as the first 72 h represents a critical time period following injury, it follows that continuous drug infusion over the first 72 h following injury may also lead to optimal neuroprotective effects. This is the first study to examine the effects of a 72 h subcutaneous continuous infusion of PZ, CsA, and the combination of these two agents on mitochondrial respiration, mitochondrial bound 4-hydroxynonenal (4-HNE), and acrolein, and α-spectrin degradation 72 h following a severe controlled cortical impact injury in rats. Our results indicate that individually, both CsA and PZ are able to attenuate mitochondrial 4-HNE and acrolein, PZ is able to maintain mitochondrial respiratory control ratio and cytoskeletal integrity but together, PZ and CsA are unable to maintain neuroprotective effects.

An In Vivo Duo-color Method for Imaging Vascular Dynamics Following Contusive Spinal Cord Injury.

Spinal cord injury (SCI) causes significant vascular disruption at the site of injury. Vascular pathology occurs immediately after SCI and continues throughout the acute injury phase. In fact, endothelial cells appear to be the first to die after a contusive SCI. The early vascular events, including increased permeability of the blood-spinal cord barrier (BSCB), induce vasogenic edema and contribute to detrimental secondary injury events caused by complex injury mechanisms. Targeting the vascular disruption, therefore, could be a key strategy to reduce secondary injury cascades that contribute to histological and functional impairments after SCI. Previous studies were mostly performed on postmortem samples and were unable to capture the dynamic changes of the vascular network. In this study, we have developed an in vivo duo-color two-photon imaging method to monitor acute vascular dynamic changes following contusive SCI. This approach allows detecting blood flow, vessel diameter, and other vascular pathologies at various sites of the same rat pre- and post-injury. Overall, this method provides an excellent venue for investigating vascular dynamics.

<em>An In Vivo</em> Duo-color Method for Imaging Vascular Dynamics Following Contusive Spinal Cord Injury

Spinal cord injury (SCI) causes significant vascular disruption at the site of injury. Vascular pathology occurs immediately after SCI and continues throughout the acute injury phase. In fact, endothelial cells appear to be the first to die after a contusive SCI. The early vascular events, including increased permeability of the blood-spinal cord barrier (BSCB), induce vasogenic edema and contribute to detrimental secondary injury events caused by complex injury mechanisms. Targeting the vascular disruption, therefore, could be a key strategy to reduce secondary injury cascades that contribute to histological and functional impairments after SCI. Previous studies were mostly performed on postmortem samples and were unable to capture the dynamic changes of the vascular network. In this study, we have developed an in vivo duo-color two-photon imaging method to monitor acute vascular dynamic changes following contusive SCI. This approach allows detecting blood flow, vessel diameter, and other vascular pathologies at various sites of the same rat pre- and post-injury. Overall, this method provides an excellent venue for investigating vascular dynamics.

Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration.

Translational Advances in the Management of Acute Spinal Cord Injury

Translational Advances in the Management of Acute Spinal Cord Injury

The Role of Neurogenic Inflammation in Blood-Brain Barrier Disruption and Development of Cerebral Oedema Following Acute Central Nervous System (CNS) Injury.

Acute central nervous system (CNS) injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide, largely attributable to the development of cerebral oedema and elevated intracranial pressure (ICP). Despite this, clinical treatments are limited and new therapies are urgently required to improve patient outcomes and survival. Originally characterised in peripheral tissues, such as the skin and lungs as a neurally-elicited inflammatory process that contributes to increased microvascular permeability and tissue swelling, neurogenic inflammation has now been described in acute injury to the brain where it may play a key role in the secondary injury cascades that evolve following both TBI and stroke. In particular, release of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) appear to be critically involved. In particular, increased SP expression is observed in perivascular tissue following acute CNS injury, with the magnitude of SP release being related to both the frequency and degree of the insult. SP release is associated with profound blood-brain barrier disruption and the subsequent development of vasogenic oedema, as well as neuronal injury and poor functional outcomes. Inhibition of SP through use of a neurokinin 1 (NK1) antagonist is highly beneficial following both TBI and ischaemic stroke in pre-clinical models. The role of CGRP is more unclear, especially with respect to TBI, with both elevations and reductions in CGRP levels reported following trauma. However, a beneficial role has been delineated in stroke, given its potent vasodilatory effects. Thus, modulating neuropeptides represents a novel therapeutic target in the treatment of cerebral oedema following acute CNS injury.

Functional Medicine Approach to Traumatic Brain Injury.

Background: The U.S. military has seen dramatic increases in traumatic brain injuries (TBIs) among military personnel due to the nature of modern-day conflicts. Conventional TBI treatment for secondary brain injuries has suboptimal success rates, and patients, families, and healthcare professionals are increasingly turning to alternative medicine treatments. Objective: Effective treatments for the secondary injury cascades that occur after an initial brain trauma are unclear at this time. The goal of successful treatment options for secondary TBI injuries is to reduce oxidative stress, excitotoxicity, and inflammation while supporting mitochondrial functions and repair of membranes, synapses, and axons. Intervention: A new paradigm of medical care, known as functional medicine, is increasing in popularity and acceptance. Functional medicine combines conventional treatment methods with complementary, genetic, holistic, and nutritional therapies. The approach is to assess the patient as a whole person, taking into account the interconnectedness of the body and its unique reaction to disease, injury, and illness while working to restore balance and optimal health. Functional medicine treatment recommendations often include the use of acupuncture, Ayurveda, chiropractic manipulation, detoxification programs, herbal and homeopathic supplements, specialized diets, massage, meditation and mindfulness practices, neurobiofeedback, nutritional supplements, t'ai chi, and yoga. At present, some of these alternative treatments appear to be beneficial, but more research is needed to validate reported outcomes. Conclusions: Few clinical studies validate the effectiveness of alternative therapies for TBIs. However, further clinical trials and empirical studies warrant further investigation based on some reported positive results from research studies, case histories, anecdotal evidence, and widespread popularity of some approaches. To date, only nutritional therapies and hyperbaric oxygen therapy have shown the most promise and potential for improved outcomes for the treatment of secondary TBI injuries.

Huperzine A alleviates neuroinflammation, oxidative stress and improves cognitive function after repetitive traumatic brain injury.

Traumatic brain injury (TBI) may trigger secondary injury cascades including endoplasmic reticulum stress, oxidative stress, and neuroinflammation. Unfortunately, there are no effective treatments targeting either primary or secondary injuries that result in long-term detrimental consequences. Huperzine A (HupA) is a potent acetylcholinesterase inhibitor (AChEI) that has been used treatment of Alzheimer's disease (AD). This study aimed to explore the neuroprotective effects of HupA in TBI and its possible mechanisms. Repetitive mild closed head injury (CHI) model was used to mimic concussive TBI. Mice were randomly assigned into three groups including sham, vehicle-treated and HupA-treated injured mice. The HupA was given at dose of 1.0mg/kg/day and was initiated 30min after the first injury, then administered daily for a total of 30days. The neuronal functions including motor functions, emotion-like behaviors, learning and memory were tested. Axonal injury, reactive oxygen species (ROS), and neuroinflammation were examined as well. The results showed that injured mice treated with HupA had significant improvement in Morris water maze performance compared with vehicle-treated injured mice. HupA treatment significantly attenuated markers of neuroinflammation and oxidative stress in the injured mice. Taken together, HupA was effective in reducing neuroinflammation, oxidative stress and behavioral recovery after TBI. HupA is a promising candidate for treatment of TBI.

Post-injury administration of a combination of memantine and 17β-estradiol is protective in a rat model of traumatic brain injury

Traumatic brain injury (TBI) often leads to substantial adverse cognitive and health outcomes, including permanent disability and death. Preventing these outcomes requires attenuation of the secondary biochemical damage that follows the initial biomechanical insult, but a clinically proven pharmacotherapeutic capable of such has not been identified. In fact, the heterogeneous nature of TBI and the complexity of secondary injury cascades suggest a polytherapeutic approach that targets multiple pathways might be necessary. We and others have reported that 17β-estradiol (E2) is neuroprotective in models of central nervous system injury. Although E2 is neuroprotective and favorably modulates several key components of secondary injury, it does not effectively block the destructive excitotoxic cascade. Thus, administering E2 in combination with a second drug that targets excitotoxicity, such as the FDA-approved uncompetitive NMDA receptor antagonist memantine hydrochloride, may provide additional benefits. Here, we assessed the neuroprotective potential of an acutely administered intravenous bolus dose of a combination of memantine and E2 after induction of experimental TBI in the clinically relevant lateral fluid percussion model. Our results indicate that the combination of these drugs conferred neuroprotection by increasing neuronal survival and decreasing neuronal degeneration in the hippocampus and cortex ipsilateral to injury. Furthermore, administration of this combination improved vestibulomotor deficits and modestly reduced anxiety. We conclude that further investigation of the neuroprotective potential of memantine administered with E2 is warranted.

A mouse Model of Focal Vascular Injury Induces Astrocyte Reactivity, Tau Oligomers, and Aberrant Behavior.

Neuropsychiatric symptom development has become more prevalent with 270,000 blast exposures occurring in the past 10 years in the United States. How blast injury leads to neuropsychiatric symptomology is currently unknown. Preclinical models of blast-induced traumatic brain injury have been used to demonstrate blood-brain barrier disruption, degenerative pathophysiology, and behavioral deficits. Vascular injury is a primary effect of neurotrauma that can trigger secondary injury cascades and neurodegeneration. Here we present data from a novel scaled and clinically relevant mouse blast model that was specifically developed to assess the outcome of vascular injury. We look at the biochemical effects and behavioral changes associated with blast injury in young-adult male BALB/c mice. We report that blast exposure causes focal vascular injury in the Somatosensory Barrel Field cortex, which leads to perivascular astrocyte reactivity, as well as acute aberrant behavior. Biochemical analysis revealed that mild blast exposure also invokes tauopathy, neuroinflammation, and oxidative stress. Overall, we propose our model to be used to evaluate focal blood-brain barrier disruption and to discover novel therapies for human neuropsychiatric symptoms.

Traumatic spinal cord injury.

Traumatic spinal cord injury (SCI) has devastating consequences for the physical, social and vocational well-being of patients. The demographic of SCIs is shifting such that an increasing proportion of older individuals are being affected. Pathophysiologically, the initial mechanical trauma (the primary injury) permeabilizes neurons and glia and initiates a secondary injury cascade that leads to progressive cell death and spinal cord damage over the subsequent weeks. Over time, the lesion remodels and is composed of cystic cavitations and a glial scar, both of which potently inhibit regeneration. Several animal models and complementary behavioural tests of SCI have been developed to mimic this pathological process and form the basis for the development of preclinical and translational neuroprotective and neuroregenerative strategies. Diagnosis requires a thorough patient history, standardized neurological physical examination and radiographic imaging of the spinal cord. Following diagnosis, several interventions need to be rapidly applied, including haemodynamic monitoring in the intensive care unit, early surgical decompression, blood pressure augmentation and, potentially, the administration of methylprednisolone. Managing the complications of SCI, such as bowel and bladder dysfunction, the formation of pressure sores and infections, is key to address all facets of the patient's injury experience.

Neuroprotective effects of astaxanthin in a rat model of spinal cord injury

Spinal cord injury (SCI) often leads to constant neurological deficits and long-term unalterable disability. Apoptosis plays an important role in the initiation of the secondary injury cascades leading to progressive tissue damage and severely functional deficits after SCI. Although the primary mechanical destructive events cannot be reversed, a therapeutic intervention could be carried out in order to moderate the secondary injury damage several hours to weeks after injury. Astaxanthin (AST) is a strong antioxidant and anti-inflammatory agents with the potential to render anti-apoptotic and neuroprotective effects. In the current study, we examined the therapeutic potential of AST on adult rats after severe SCI contusion. Results of BBB scores showed that AST improved motor function after SCI compared to control groups. Western blot analysis showed reduced expression of Bax and Cleaved-caspase-3 proteins and increased expression of the Bcl-2 protein in response to AST treatment (p<0.05). The histology results also showed that AST considerably preserved myelinated white matter and the number of motor neurons. This study is the first to report that AST reduces neuronal apoptosis, diminishes pathological tissue damage and improves functional recovery after SCI. The observed prominent neuroprotective effects, introduces AST as a promising therapy for SCI.

Targeting mitochondrial dysfunction in CNS injury using Methylene Blue; still a magic bullet?

Complex, multi-factorial secondary injury cascades are initiated following traumatic brain injury, which makes this a difficult disease to treat. The secondary injury cascades following the primary mechanical tissue damage, are likely where effective therapeutic interventions may be targeted. One promising therapeutic target following brain injury are mitochondria. Mitochondria are complex organelles found within the cell, which act as powerhouses within all cells by supplying ATP. These organelles are also necessary for calcium cycling, redox signaling and play a major role in the initiation of cell death pathways. When mitochondria become dysfunctional, there is a tendency for the cell to loose cellular homeostasis and can lead to eventual cell death. Targeting of mitochondrial dysfunction in various diseases has proven a successful approach, lending support to mitochondria as a pivotal player in TBI cell death and loss of behavioral function.Within this mixed mini review/research article there will be a general discussion of mitochondrial bioenergetics, followed by a brief discussion of traumatic brain injury and how mitochondria play an integral role in the neuropathological sequelae following an injury. We will also give an overview of one relatively new TBI therapeutic approach, Methylene Blue, currently being studied to ameliorate mitochondrial dysfunction following brain injury. We will also present novel experimental findings, that for the first time, characterize the ex vivo effect of Methylene Blue on mitochondrial function in synaptic and non-synaptic populations of mitochondria.

Alteration in Long Non-Coding RNA Expression after Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) causes a primary insult and initiates a secondary injury cascade. The mechanisms underlying the secondary injury are multifactorial and may include the aberrant expression of long non-coding RNA (lncRNA) post-TBI. Here, lncRNA microarray analysis was performed to profile the altered lncRNAs in the rat hippocampus after TBI. A total of 271 lncRNA probe sets and 1046 messenger RNA (mRNA) probe sets were differentially expressed after TBI. Gene ontology analysis showed that the main components of the most significantly changed categories were inflammation, DNA transcription, apoptosis, and necroptosis. Additionally, the pathway analysis and the pathway relation network revealed correlated pathways mainly involving inflammation, cell cycle, and apoptosis. A co-expression network of these aberrantly expressed lncRNAs and mRNAs was further constructed to predict the potential function of individual lncRNAs. Sub-co-expression networks were formed for the top three lncRNAs: NR_002704, ENSRNOT00000062543, and Zfas1. Thus, our study demonstrated differential expression of a series of lncRNAs in the rat hippocampus after TBI, which may be correlated with post-TBI physiological and pathological processes. The findings also may provide novel targets for further investigation of both the molecular mechanisms underlying TBI and potential therapeutic interventions.

Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study.

Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF) that may influence secondary injury cascades associated with traumatic brain injury (TBI) and predict outcome. We investigated concurrent CSF BDNF and cortisol relationships in 117 patients sampled days 0–6 after severe TBI while accounting for BDNF genetics and age. We also determined associations between CSF BDNF and cortisol with 6-month mortality. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to previously published hypothesized risk for mortality in “younger patients” (<48 years) and hypothesized BDNF production/secretion capacity with these variants. Group based trajectory analysis (TRAJ) was used to create two cortisol groups (high and low trajectories). A Bayesian estimation approach informed the mediation models. Results show CSF BDNF predicted patient cortisol TRAJ group (P = 0.001). Also, GRS moderated BDNF associations with cortisol TRAJ group. Additionally, cortisol TRAJ predicted 6-month mortality (P = 0.001). In a mediation analysis, BDNF predicted mortality, with cortisol acting as the mediator (P = 0.011), yielding a mediation percentage of 29.92%. Mediation effects increased to 45.45% among younger patients. A BDNF*GRS interaction predicted mortality in younger patients (P = 0.004). Thus, we conclude 6-month mortality after severe TBI can be predicted through a mediation model with CSF cortisol and BDNF, suggesting a regulatory role for cortisol with BDNF's contribution to TBI pathophysiology and mortality, particularly among younger individuals with severe TBI. Based on the literature, cortisol modulated BDNF effects on mortality after TBI may be related to known hormone and neurotrophin relationships to neurological injury severity and autonomic nervous system imbalance.

Traumatic Spinal Cord Injury-Repair and Regeneration.

Traumatic spinal cord injuries (SCI) have devastating consequences for the physical, financial, and psychosocial well-being of patients and their caregivers. Expediently delivering interventions during the early postinjury period can have a tremendous impact on long-term functional recovery. This is largely due to the unique pathophysiology of SCI where the initial traumatic insult (primary injury) is followed by a progressive secondary injury cascade characterized by ischemia, proapoptotic signaling, and peripheral inflammatory cell infiltration. Over the subsequent hours, release of proinflammatory cytokines and cytotoxic debris (DNA, ATP, reactive oxygen species) cyclically adds to the harsh postinjury microenvironment. As the lesions mature into the chronic phase, regeneration is severely impeded by the development of an astroglial-fibrous scar surrounding coalesced cystic cavities. Addressing these challenges forms the basis of current and upcoming treatments for SCI. This paper discusses the evidence-based management of a patient with SCI while emphasizing the importance of early definitive care. Key neuroprotective therapies are summarized including surgical decompression, methylprednisolone, and blood pressure augmentation. We then review exciting neuroprotective interventions on the cusp of translation such as Riluzole, Minocycline, magnesium, therapeutic hypothermia, and CSF drainage. We also explore the most promising neuroregenerative strategies in trial today including Cethrin™, anti-NOGO antibody, cell-based approaches, and bioengineered biomaterials. Each section provides a working knowledge of the key preclinical and patient trials relevant to clinicians while highlighting the pathophysiologic rationale for the therapies. We conclude with our perspectives on the future of treatment and research in this rapidly evolving field.

Mesenchymal Stem Cells in the Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. The primary insult to the brain initiates secondary injury cascades consisting of multiple complex biochemical responses of the brain that significantly influence the overall severity of the brain damage and clinical sequelae. The use of mesenchymal stem cells (MSCs) offers huge potential for application in the treatment of TBI. MSCs have immunosuppressive properties that reduce inflammation in injured tissue. As such, they could be used to modulate the secondary mechanisms of injury and halt the progression of the secondary insult in the brain after injury. Particularly, MSCs are capable of secreting growth factors that facilitate the regrowth of neurons in the brain. The relative abundance of harvest sources of MSCs also makes them particularly appealing. Recently, numerous studies have investigated the effects of infusion of MSCs into animal models of TBI. The results have shown significant improvement in the motor function of the damaged brain tissues. In this review, we summarize the recent advances in the application of MSCs in the treatment of TBI. The review starts with a brief introduction of the pathophysiology of TBI, followed by the biology of MSCs, and the application of MSCs in TBI treatment. The challenges associated with the application of MSCs in the treatment of TBI and strategies to address those challenges in the future have also been discussed.