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Different Approaches to Modulation of Microglia Phenotypes After Spinal Cord Injury.

ABSTRACT: Microglial cells, which are highly plastic, immediately respond to any change in the microenvironment by becoming activated and shifting the phenotype toward neurotoxicity or neuroprotection. The polarization of microglia/macrophages after spinal cord injury (SCI) seems to be a dynamic process and can change depending on the microenvironment, stage, course, and severity of the posttraumatic process. Effective methods to modulate microglia toward a neuroprotective phenotype in order to stimulate neuroregeneration are actively sought for. In this context, available approaches that can selectively impact the polarization of microglia/macrophages regulate synthesis of trophic factors and cytokines/chemokines in them, and their phagocytic function and effects on the course and outcome of SCI are discussed in this review.

SUBMITTER: Akhmetzyanova E

PROVIDER: S-EPMC6718713 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Different Approaches to Modulation of Microglia Phenotypes After Spinal Cord Injury.

Akhmetzyanova Elvira E Kletenkov Konstantin K Mukhamedshina Yana Y Rizvanov Albert A

Frontiers in systems neuroscience 20190827

Microglial cells, which are highly plastic, immediately respond to any change in the microenvironment by becoming activated and shifting the phenotype toward neurotoxicity or neuroprotection. The polarization of microglia/macrophages after spinal cord injury (SCI) seems to be a dynamic process and can change depending on the microenvironment, stage, course, and severity of the posttraumatic process. Effective methods to modulate microglia toward a neuroprotective phenotype in order to stimulate ...[more]

PMID: 31507384

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Molecular approaches for spinal cord injury treatment.

Project description:Injuries to the spinal cord result in permanent disabilities that limit daily life activities. The main reasons for these poor outcomes are the limited regenerative capacity of central neurons and the inhibitory milieu that is established upon traumatic injuries. Despite decades of research, there is still no efficient treatment for spinal cord injury. Many strategies are tested in preclinical studies that focus on ameliorating the functional outcomes after spinal cord injury. Among these, molecular compounds are currently being used for neurological recovery, with promising results. These molecules target the axon collapsed growth cone, the inhibitory microenvironment, the survival of neurons and glial cells, and the re-establishment of lost connections. In this review we focused on molecules that are being used, either in preclinical or clinical studies, to treat spinal cord injuries, such as drugs, growth and neurotrophic factors, enzymes, and purines. The mechanisms of action of these molecules are discussed, considering traumatic spinal cord injury in rodents and humans.

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Severity- and Time-Dependent Activation of Microglia in Spinal Cord Injury.

Project description:A spinal cord injury (SCI) initiates a number of cascades of biochemical reactions and intercellular interactions, the outcome of which determines the regenerative potential of the nervous tissue and opens up capacities for preserving its functions. The key elements of the above-mentioned processes are microglia. Many assumptions have been put forward, and the first evidence has been obtained, suggesting that, depending on the severity of SCI and the post-traumatic period, microglia behave differently. In this regard, we conducted a study to assess the microglia behavior in the model of mild, moderate and severe SCI in vitro for various post-traumatic periods. We reported for the first time that microglia make a significant contribution to both anti- and pro-inflammatory patterns for a prolonged period after severe SCI (60 dpi), while reduced severities of SCI do not lead to prolonged activation of microglia. The study also revealed the following trend: the greater the severity of the SCI, the lower the proliferative and phagocytic activity of microglia, which is true for all post-traumatic periods of SCI.

| S-EPMC10179339 | biostudies-literature

Brain-controlled modulation of spinal circuits improves recovery from spinal cord injury.

Project description:The delivery of brain-controlled neuromodulation therapies during motor rehabilitation may augment recovery from neurological disorders. To test this hypothesis, we conceived a brain-controlled neuromodulation therapy that combines the technical and practical features necessary to be deployed daily during gait rehabilitation. Rats received a severe spinal cord contusion that led to leg paralysis. We engineered a proportional brain-spine interface whereby cortical ensemble activity constantly determines the amplitude of spinal cord stimulation protocols promoting leg flexion during swing. After minimal calibration time and without prior training, this neural bypass enables paralyzed rats to walk overground and adjust foot clearance in order to climb a staircase. Compared to continuous spinal cord stimulation, brain-controlled stimulation accelerates and enhances the long-term recovery of locomotion. These results demonstrate the relevance of brain-controlled neuromodulation therapies to augment recovery from motor disorders, establishing important proofs-of-concept that warrant clinical studies.

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Resident immune responses to spinal cord injury: role of astrocytes and microglia.

Project description:Spinal cord injury can be traumatic or non-traumatic in origin, with the latter rising in incidence and prevalence with the aging demographics of our society. Moreover, as the global population ages, individuals with co-existent degenerative spinal pathology comprise a growing number of traumatic spinal cord injury cases, especially involving the cervical spinal cord. This makes recovery and treatment approaches particularly challenging as age and comorbidities may limit regenerative capacity. For these reasons, it is critical to better understand the complex milieu of spinal cord injury lesion pathobiology and the ensuing inflammatory response. This review discusses microglia-specific purinergic and cytokine signaling pathways, as well as microglial modulation of synaptic stability and plasticity after injury. Further, we evaluate the role of astrocytes in neurotransmission and calcium signaling, as well as their border-forming response to neural lesions. Both the inflammatory and reparative roles of these cells have eluded our complete understanding and remain key therapeutic targets due to their extensive structural and functional roles in the nervous system. Recent advances have shed light on the roles of glia in neurotransmission and reparative injury responses that will change how interventions are directed. Understanding key processes and existing knowledge gaps will allow future research to effectively target these cells and harness their regenerative potential.

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Gramine promotes functional recovery after spinal cord injury via ameliorating microglia activation.

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Phenotypes of Motor Deficit and Pain after Experimental Spinal Cord Injury.

Project description:Motor disability is a common outcome of spinal cord injury (SCI). The recovery of motor function after injury depends on the severity of neurotrauma; motor deficit can be reversible, at least partially, due to the innate tissue capability to recover, which, however, deteriorates with age. Pain is often a comorbidity of injury, although its prediction remains poor. It is largely unknown whether pain can attend motor dysfunction. Here, we implemented SCI for modelling severe and moderate neurotrauma and monitored SCI rats for up to 5 months post-injury to determine the profiles of both motor deficit and nociceptive sensitivity. Our data showed that motor dysfunction remained persistent after a moderate SCI in older animals (5-month-old); however, there were two populations among young SCI rats (1 month-old) whose motor deficit either declined or exacerbated even more over 4-5 weeks after identical injury. All young SCI rats displayed changed nociceptive sensitivity in thermal and mechanical modalities. The regression analysis of the changes revealed a population trend with respect to hyper- or hyposensitivity/motor deficit. Together, our data describe the phenotypes of motor deficit and pain, the two severe complications of neurotrauma. Our findings also suggest the predictability of motor dysfunction and pain syndromes following SCI that can be a hallmark for long-term rehabilitation and recovery after injury.

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Depletion of microglia exacerbates injury and impairs function recovery after spinal cord injury in mice.

Project description:The role of microglia in spinal cord injury (SCI) remains ambiguous, partially due to the paucity of efficient methods to discriminate these resident microglia with blood-derived monocytes/macrophages. Here, we used pharmacological treatments to specifically eliminate microglia and subsequently to investigate the response of microglia after SCI in mice. We showed that treatment with colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 eliminated ~90% microglia and did not affect other cell types in mouse spinal cord. PLX3397 treatment also induced a strong decrease in microglial proliferation induced by SCI. Depletion of microglia after SCI disrupted glial scar formation, enhanced immune cell infiltrates, reduced neuronal survival, delayed astrocyte repopulation, exacerbated axonal dieback, and impaired locomotor recovery. Therefore, our findings suggest microglia may play a protective role after SCI in mice.

| S-EPMC7359318 | biostudies-literature

Population-based approaches to treatment and readmission after spinal cord injury.

Project description:BackgroundRecent studies in surgical and non-surgical specialties have suggested that patients admitted on the weekend may have worse outcomes. In particular, patients with stroke and acute cardiovascular events have shown worse outcomes with weekend treatment. It is unclear whether this extends to patients with spinal cord injury (SCI). This study was designed to evaluate factors for readmission after index hospitalization for spinal cord injury.MethodsThis cohort was constructed from the State Inpatient Databases of California, New York, and Florida. For this study 14,396 patients with SCI were identified. The primary outcome measure evaluated was 30-day readmission. Secondary measures include in-hospital complications. Univariate and multivariate analysis were utilized to evaluate covariates. c2, Fisher's exact, and linear, logistic, and modified Poisson regression methods were utilized for statistical analysis. Propensity score methods were used with matched pairs analysis performed by the McNemar's Test.ResultsWeekend admission was not associated with increased 30- day readmission rates in multivariate analysis. Race and discharge to a facility (RR 1.60 [1.43-1.79]) or home with home care (RR 1.23 [1.07-1.42]), were statistically significant risk factors for readmission. Payor status did not affect rates of readmission. In propensity score matched pairs analysis, weekend admission was not associated with increased odds of 30-day readmission (OR 1.04 [0.89-1.21]). Patients admitted to high volume centers had significantly lower risk of readmission when compared with patients admitted to low volume centers.ConclusionsOur results suggest that the weekend effect, described previously in other patient populations, may not play as important a role in patients with SCI.

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Spinal cord injury

Project description:Spinal cord injury

| PRJNA532533 | ENA

Emerging approaches to the surgical management of acute traumatic spinal cord injury.

Project description:Traumatic, spinal cord injury (SCI) is a potentially catastrophic event causing major impact at both a personal and societal level. To date, virtually all therapies that have shown promise at the preclinical stage of study have failed to translate into clinically effective treatments. Surgery is performed in the setting of SCI, with the goals of decompressing the spinal cord and restoring spinal stability. Although a consensus regarding the optimal timing of surgical decompression for SCI has not been reached, much of the preclinical and clinical evidence, as well as a recent international survey of spine surgeons, support performing early surgery (<24 hours). Results of the multicenter, Surgical Trial in Acute Spinal Cord Injury Study (STASCIS), expected later this year, should further clarify this important management issue. The overall goal of this review is to provide an update regarding the current status of surgical therapy for traumatic SCI by reviewing relevant pathophysiology, laboratory, and clinical evidence, as well as to introduce radiologic and clinical tools that aid in the surgical decision-making process.

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