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International Journal of Molecular... Oct 2020Spinal cord injury (SCI) is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Its pathophysiology comprises... (Review)
Review
Spinal cord injury (SCI) is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Its pathophysiology comprises acute and chronic phases and incorporates a cascade of destructive events such as ischemia, oxidative stress, inflammatory events, apoptotic pathways and locomotor dysfunctions. Many therapeutic strategies have been proposed to overcome neurodegenerative events and reduce secondary neuronal damage. Efforts have also been devoted in developing neuroprotective and neuro-regenerative therapies that promote neuronal recovery and outcome. Although varying degrees of success have been achieved, curative accomplishment is still elusive probably due to the complex healing and protective mechanisms involved. Thus, current understanding in this area must be assessed to formulate appropriate treatment modalities to improve SCI recovery. This review aims to promote the understanding of SCI pathophysiology, interrelated or interlinked multimolecular interactions and various methods of neuronal recovery i.e., neuroprotective, immunomodulatory and neuro-regenerative pathways and relevant approaches.
Topics: Animals; Humans; Spinal Cord; Spinal Cord Injuries; Spinal Cord Regeneration
PubMed: 33066029
DOI: 10.3390/ijms21207533 -
Neurosurgery Mar 2017Traumatic spinal cord injuries (SCI) have devastating consequences for the physical, financial, and psychosocial well-being of patients and their caregivers. Expediently... (Review)
Review
BACKGROUND
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.
PATHOPHYSIOLOGY
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.
MANAGEMENT
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.
CONCLUSION
We conclude with our perspectives on the future of treatment and research in this rapidly evolving field.
Topics: Decompression, Surgical; Drainage; Humans; Hypothermia, Induced; Neuroprotective Agents; Recovery of Function; Spinal Cord Injuries; Spinal Cord Regeneration; Wound Healing
PubMed: 28350947
DOI: 10.1093/neuros/nyw080 -
Brain Research Sep 2015Spinal cord injury (SCI) is a traumatic event from which there is limited recovery of function, despite the best efforts of many investigators to devise realistic... (Review)
Review
Spinal cord injury (SCI) is a traumatic event from which there is limited recovery of function, despite the best efforts of many investigators to devise realistic therapeutic treatments. Partly this is due to the multifaceted nature of SCI, where there is considerable disarray and dysfunction secondary to the initial injury. Contributing to this secondary degeneration is neurotoxicity, vascular dysfunction, glial scarring, neuroinflammation, apoptosis and demyelination. It seems logical that addressing the need for neuroprotection, regeneration and rehabilitation will require different treatment strategies that may be applied at varied stages of the post-injury response. Here we focus on a single strategy, exercise/physical training, which appears to have multiple applications and benefits for an acute or chronic SCI. Exercise has been demonstrated to be advantageous at cellular and biochemical levels, as well as being of benefit for the whole animal or human subject. Data from our lab and others will be discussed to further elucidate the many positive aspects of implementing exercise following injury and to suggest that rehabilitation is not the sole target of a training regimen following SCI. This article is part of a Special Issue entitled SI: Spinal cord injury.
Topics: Animals; Exercise Therapy; Gray Matter; Humans; MicroRNAs; Motor Neurons; Neuronal Plasticity; Neuroprotection; Recovery of Function; Spinal Cord Injuries; Spinal Cord Regeneration
PubMed: 25866284
DOI: 10.1016/j.brainres.2015.03.052 -
International Journal of Molecular... May 2019Spinal cord injury (SCI) constitutes an inestimable public health issue. The most crucial phase in the pathophysiological process of SCI concerns the well-known... (Review)
Review
Spinal cord injury (SCI) constitutes an inestimable public health issue. The most crucial phase in the pathophysiological process of SCI concerns the well-known secondary injury, which is the uncontrolled and destructive cascade occurring later with aberrant molecular signaling, inflammation, vascular changes, and secondary cellular dysfunctions. The use of mesenchymal stem cells (MSCs) represents one of the most important and promising tested strategies. Their appeal, among the other sources and types of stem cells, increased because of their ease of isolation/preservation and their properties. Nevertheless, encouraging promise from preclinical studies was followed by weak and conflicting results in clinical trials. In this review, the therapeutic role of MSCs is discussed, together with their properties, application, limitations, and future perspectives.
Topics: Animals; Biocompatible Materials; Biomarkers; Cell- and Tissue-Based Therapy; Cord Blood Stem Cell Transplantation; Disease Models, Animal; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Nerve Growth Factors; Nerve Regeneration; Regenerative Medicine; Spinal Cord Injuries; Spinal Cord Regeneration; Tissue Scaffolds; Translational Research, Biomedical
PubMed: 31159345
DOI: 10.3390/ijms20112698 -
Arquivos de Neuro-psiquiatria Jun 2017Spinal cord injury (SCI) affects 1.3 million North Americans, with more than half occurring after trauma. In Brazil, few studies have evaluated the epidemiology of SCI... (Review)
Review
Spinal cord injury (SCI) affects 1.3 million North Americans, with more than half occurring after trauma. In Brazil, few studies have evaluated the epidemiology of SCI with an estimated incidence of 16 to 26 per million per year. The final extent of the spinal cord damage results from primary and secondary mechanisms that start at the moment of the injury and go on for days, and even weeks, after the event. There is convincing evidence that hypotension contributes to secondary injury after acute SCI. Surgical decompression aims at relieving mechanical pressure on the microvascular circulation, therefore reducing hypoxia and ischemia. The role of methylprednisolone as a therapeutic option is still a matter of debate, however most guidelines do not recommend its regular use. Neuroprotective therapies aiming to reduce further injury have been studied and many others are underway. Neuroregenerative therapies are being extensively investigated, with cell based therapy being very promising.
Topics: Decompression, Surgical; Humans; Methylprednisolone; Neuroprotective Agents; Spinal Cord Injuries; Trauma Severity Indices
PubMed: 28658409
DOI: 10.1590/0004-282X20170048 -
Frontiers in Immunology 2022Traumatic spinal cord injury (SCI) is a devastating condition that is often associated with significant loss of function and/or permanent disability. The pathophysiology... (Review)
Review
Traumatic spinal cord injury (SCI) is a devastating condition that is often associated with significant loss of function and/or permanent disability. The pathophysiology of SCI is complex and occurs in two phases. First, the mechanical damage from the trauma causes immediate acute cell dysfunction and cell death. Then, secondary mechanisms of injury further propagate the cell dysfunction and cell death over the course of days, weeks, or even months. Among the secondary injury mechanisms, inflammation has been shown to be a key determinant of the secondary injury severity and significantly worsens cell death and functional outcomes. Thus, in addition to surgical management of SCI, selectively targeting the immune response following SCI could substantially decrease the progression of secondary injury and improve patient outcomes. In order to develop such therapies, a detailed molecular understanding of the timing of the immune response following SCI is necessary. Recently, several studies have mapped the cytokine/chemokine and cell proliferation patterns following SCI. In this review, we examine the immune response underlying the pathophysiology of SCI and assess both current and future therapies including pharmaceutical therapies, stem cell therapy, and the exciting potential of extracellular vesicle therapy.
Topics: Humans; Spinal Cord Injuries; Cell Death; Inflammation; Immunity
PubMed: 36685598
DOI: 10.3389/fimmu.2022.1084101 -
Journal of Neurotrauma May 2021The predominant tool used to predict outcomes after traumatic spinal cord injury (SCI) is the International Standards for Neurological Classification of Spinal Cord... (Review)
Review
The predominant tool used to predict outcomes after traumatic spinal cord injury (SCI) is the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), in association with the American Spinal Injury Association (ASIA) Impairment Scale (AIS). These measures have evolved based on analyses of large amounts of longitudinal neurological recovery data published in numerous separate studies. This article reviews and synthesizes published data on neurological recovery from multiple sources, only utilizing data in which the sacral sparing definition was applied for determination of completeness. Conversion from a complete to incomplete injury is more common in tetraplegia than paraplegia. The majority of AIS conversion and motor recovery occurs within the first 6-9 months, with the most rapid rate of motor recovery occurring in the first three months after injury. Motor score changes, as well as recovery of motor levels, are described with the initial strength of muscles as well as the levels of the motor zone of partial preservation influencing the prognosis. Total motor recovery is greater for patients with initial AIS B than AIS A, and greater after initial AIS C than with motor complete injuries. Older age has a negative impact on neurological and functional recovery after SCI; however, the specific age (whether >50 or >65 years) and underlying reasons for this impact are unclear. Penetrating injury is more likely to lead to a classification of a neurological complete injury compared with blunt trauma and reduces the likelihood of AIS conversion at one year. There are insufficient data to support gender having a major effect on neurological recovery after SCI.
Topics: Age Factors; Disability Evaluation; Emergency Medical Services; Humans; Muscle Strength; Prognosis; Recovery of Function; Spinal Cord Injuries; Trauma Severity Indices
PubMed: 33339474
DOI: 10.1089/neu.2020.7473 -
Signal Transduction and Targeted Therapy Mar 2022Spinal cord injury (SCI) involves diverse injury responses in different cell types in a temporally and spatially specific manner. Here, using single-cell transcriptomic...
Spinal cord injury (SCI) involves diverse injury responses in different cell types in a temporally and spatially specific manner. Here, using single-cell transcriptomic analyses combined with classic anatomical, behavioral, electrophysiological analyses, we report, with single-cell resolution, temporal molecular and cellular changes in crush-injured adult mouse spinal cord. Data revealed pathological changes of 12 different major cell types, three of which infiltrated into the spinal cord at distinct times post-injury. We discovered novel microglia and astrocyte subtypes in the uninjured spinal cord, and their dynamic conversions into additional stage-specific subtypes/states. Most dynamic changes occur at 3-days post-injury and by day-14 the second wave of microglial activation emerged, accompanied with changes in various cell types including neurons, indicative of the second round of attacks. By day-38, major cell types are still substantially deviated from uninjured states, demonstrating prolonged alterations. This study provides a comprehensive mapping of cellular/molecular pathological changes along the temporal axis after SCI, which may facilitate the development of novel therapeutic strategies, including those targeting microglia.
Topics: Animals; Astrocytes; Mice; Microglia; Neurons; Spinal Cord Injuries
PubMed: 35232960
DOI: 10.1038/s41392-022-00885-4 -
Cell Transplantation Jun 2018Spinal cord injury (SCI), for which there currently is no cure, is a heavy burden on patient physiology and psychology. The microenvironment of the injured spinal cord... (Review)
Review
Spinal cord injury (SCI), for which there currently is no cure, is a heavy burden on patient physiology and psychology. The microenvironment of the injured spinal cord is complicated. According to our previous work and the advancements in SCI research, 'microenvironment imbalance' is the main cause of the poor regeneration and recovery of SCI. Microenvironment imbalance is defined as an increase in inhibitory factors and decrease in promoting factors for tissues, cells and molecules at different times and spaces. There are imbalance of hemorrhage and ischemia, glial scar formation, demyelination and re-myelination at the tissue's level. The cellular level imbalance involves an imbalance in the differentiation of endogenous stem cells and the transformation phenotypes of microglia and macrophages. The molecular level includes an imbalance of neurotrophic factors and their pro-peptides, cytokines, and chemokines. The imbalanced microenvironment of the spinal cord impairs regeneration and functional recovery. This review will aid in the understanding of the pathological processes involved in and the development of comprehensive treatments for SCI.
Topics: Animals; Cytokines; Hemorrhage; Humans; Microglia; Nerve Growth Factors; Nerve Regeneration; Neural Stem Cells; Neurons; Spinal Cord; Spinal Cord Injuries
PubMed: 29871522
DOI: 10.1177/0963689718755778 -
Brain Research Sep 2015The injured spinal cord does not heal properly. In contrast, tissue repair and functional recovery occur after skin or muscle injuries. The reason for this dichotomy in... (Review)
Review
The injured spinal cord does not heal properly. In contrast, tissue repair and functional recovery occur after skin or muscle injuries. The reason for this dichotomy in wound repair is unclear but inflammation, and specifically macrophage activation, likely plays a key role. Macrophages have the ability to promote the repair of injured tissue by regulating transitions through different phase of the healing response. In the current review we compare and contrast the healing and inflammatory responses between spinal cord injuries and tissues that undergo complete wound resolution. Through this comparison, we identify key macrophage phenotypes that are inaptly triggered or absent after spinal cord injury and discuss spinal cord stimuli that contribute to this maladaptive response. Sequential activation of classic, pro-inflammatory, M1 macrophages and alternatively activated, M2a, M2b, and M2c macrophages occurs during normal healing and facilitates transitions through the inflammatory, proliferative, and remodeling phases of repair. In contrast, in the injured spinal cord, pro-inflammatory macrophages potentiate a prolonged inflammatory phase and remodeling is not properly initiated. The desynchronized macrophage activation after spinal cord injury is reminiscent of the inflammation present in chronic, non-healing wounds. By refining the role macrophages play in spinal cord injury repair we bring to light important areas for future neuroinflammation and neurotrauma research. This article is part of a Special Issue entitled SI: Spinal cord injury.
Topics: Animals; Humans; Macrophage Activation; Macrophages; Myelitis; Spinal Cord Injuries; Spinal Cord Regeneration
PubMed: 25578260
DOI: 10.1016/j.brainres.2014.12.045