Research

19 pages, 8240 KiB

Open AccessArticle

Mouse Spinal Cord Vascular Transcriptome Analysis Identifies CD9 and MYLIP as Injury-Induced Players

by Isaura Martins, Dalila Neves-Silva, Mariana Ascensão-Ferreira, Ana Filipa Dias, Daniel Ribeiro, Ana Filipa Isidro, Raquel Quitéria, Diogo Paramos-de-Carvalho, Nuno L. Barbosa-Morais and Leonor Saúde

Int. J. Mol. Sci. 2023, 24(7), 6433; https://doi.org/10.3390/ijms24076433 - 29 Mar 2023

Cited by 1 | Viewed by 2699

Abstract

Traumatic spinal cord injury (SCI) initiates a cascade of cellular events, culminating in irreversible tissue loss and neuroinflammation. After the trauma, the blood vessels are destroyed. The blood-spinal cord barrier (BSCB), a physical barrier between the blood and spinal cord parenchyma, is disrupted, [...] Read more.

Traumatic spinal cord injury (SCI) initiates a cascade of cellular events, culminating in irreversible tissue loss and neuroinflammation. After the trauma, the blood vessels are destroyed. The blood-spinal cord barrier (BSCB), a physical barrier between the blood and spinal cord parenchyma, is disrupted, facilitating the infiltration of immune cells, and contributing to a toxic spinal microenvironment, affecting axonal regeneration. Understanding how the vascular constituents of the BSCB respond to injury is crucial to prevent BSCB impairment and to improve spinal cord repair. Here, we focus our attention on the vascular transcriptome at 3- and 7-days post-injury (dpi), during which BSCB is abnormally leaky, to identify potential molecular players that are injury-specific. Using the mouse contusion model, we identified Cd9 and Mylip genes as differentially expressed at 3 and 7 dpi. CD9 and MYLIP expression were injury-induced on vascular cells, endothelial cells and pericytes, at the injury epicentre at 7 dpi, with a spatial expression predominantly at the caudal region of the lesion. These results establish CD9 and MYLIP as two new potential players after SCI, and future studies targeting their expression might bring promising results for spinal cord repair. Full article

(This article belongs to the Special Issue Spinal Cord Injury: From Mechanisms to Therapeutic Approaches)

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21 pages, 8275 KiB

Open AccessArticle

Neurovascular Unit Compensation from Adjacent Level May Contribute to Spontaneous Functional Recovery in Experimental Cervical Spondylotic Myelopathy

by Guang-Sheng Li, Guang-Hua Chen, Kang-Heng Wang, Xu-Xiang Wang, Xiao-Song Hu, Bo Wei and Yong Hu

Int. J. Mol. Sci. 2023, 24(4), 3408; https://doi.org/10.3390/ijms24043408 - 08 Feb 2023

Cited by 3 | Viewed by 1672

Abstract

The progression and remission of cervical spondylotic myelopathy (CSM) are quite unpredictable due to the ambiguous pathomechanisms. Spontaneous functional recovery (SFR) has been commonly implicated in the natural course of incomplete acute spinal cord injury (SCI), while the evidence and underlying pathomechanisms of [...] Read more.

The progression and remission of cervical spondylotic myelopathy (CSM) are quite unpredictable due to the ambiguous pathomechanisms. Spontaneous functional recovery (SFR) has been commonly implicated in the natural course of incomplete acute spinal cord injury (SCI), while the evidence and underlying pathomechanisms of neurovascular unit (NVU) compensation involved in SFR remains poorly understood in CSM. In this study, we investigate whether compensatory change of NVU, in particular in the adjacent level of the compressive epicenter, is involved in the natural course of SFR, using an established experimental CSM model. Chronic compression was created by an expandable water-absorbing polyurethane polymer at C5 level. Neurological function was dynamically assessed by BBB scoring and somatosensory evoked potential (SEP) up to 2 months. (Ultra)pathological features of NVUs were presented by histopathological and TEM examination. Quantitative analysis of regional vascular profile area/number (RVPA/RVPN) and neuroglial cells numbers were based on the specific EBA immunoreactivity and neuroglial biomarkers, respectively. Functional integrity of blood spinal cord barrier (BSCB) was detected by Evan blue extravasation test. Although destruction of the NVU, including disruption of the BSCB, neuronal degeneration and axon demyelination, as well as dramatic neuroglia reaction, were found in the compressive epicenter and spontaneous locomotor and sensory function recovery were verified in the modeling rats. In particular, restoration of BSCB permeability and an evident increase in RVPA with wrapping proliferated astrocytic endfeet in gray matter and neuron survival and synaptic plasticity were confirmed in the adjacent level. TEM findings also proved ultrastructural restoration of the NVU. Thus, NVU compensation changes in the adjacent level may be one of the essential pathomechanisms of SFR in CSM, which could be a promising endogenous target for neurorestoration. Full article

(This article belongs to the Special Issue Spinal Cord Injury: From Mechanisms to Therapeutic Approaches)

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13 pages, 2292 KiB

Open AccessArticle

Improved Locomotor Recovery in a Rat Model of Spinal Cord Injury by BioLuminescent-OptoGenetic (BL-OG) Stimulation with an Enhanced Luminopsin

by Ebenezer C. Ikefuama, Griffin E. Kendziorski, Kevin Anderson, Lateef Shafau, Mansi Prakash, Ute Hochgeschwender and Eric D. Petersen

Int. J. Mol. Sci. 2022, 23(21), 12994; https://doi.org/10.3390/ijms232112994 - 27 Oct 2022

Cited by 7 | Viewed by 2542

Abstract

Irrespective of the many strategies focused on dealing with spinal cord injury (SCI), there is still no way to restore motor function efficiently or an adequate regenerative therapy. One promising method that could potentially prove highly beneficial for rehabilitation in patients is to [...] Read more.

Irrespective of the many strategies focused on dealing with spinal cord injury (SCI), there is still no way to restore motor function efficiently or an adequate regenerative therapy. One promising method that could potentially prove highly beneficial for rehabilitation in patients is to re-engage specific neuronal populations of the spinal cord following SCI. Targeted activation may maintain and strengthen existing neuronal connections and/or facilitate the reorganization and development of new connections. BioLuminescent-OptoGenetics (BL-OG) presents an avenue to non-invasively and specifically stimulate neurons; genetically targeted neurons express luminopsins (LMOs), light-emitting luciferases tethered to light-sensitive channelrhodopsins that are activated by adding the luciferase substrate coelenterazine (CTZ). This approach employs ion channels for current conduction while activating the channels through treatment with the small molecule CTZ, thus allowing non-invasive stimulation of all targeted neurons. We previously showed the efficacy of this approach for improving locomotor recovery following severe spinal cord contusion injury in rats expressing the excitatory luminopsin 3 (LMO3) under control of a pan-neuronal and motor-neuron-specific promoter with CTZ applied through a lateral ventricle cannula. The goal of the present study was to test a new generation of LMOs based on opsins with higher light sensitivity which will allow for peripheral delivery of the CTZ. In this construct, the slow-burn Gaussia luciferase variant (sbGLuc) is fused to the opsin CheRiff, creating LMO3.2. Taking advantage of the high light sensitivity of this opsin, we stimulated transduced lumbar neurons after thoracic SCI by intraperitoneal application of CTZ, allowing for a less invasive treatment. The efficacy of this non-invasive BioLuminescent-OptoGenetic approach was confirmed by improved locomotor function. This study demonstrates that peripheral delivery of the luciferin CTZ can be used to activate LMOs expressed in spinal cord neurons that employ an opsin with increased light sensitivity. Full article

(This article belongs to the Special Issue Spinal Cord Injury: From Mechanisms to Therapeutic Approaches)

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17 pages, 4011 KiB

Open AccessArticle

Motor Neuroplastic Effects of a Novel Paired Stimulation Technology in an Incomplete Spinal Cord Injury Animal Model

by Muhammad Adeel, Bor-Shing Lin, Hung-Chou Chen, Chien-Hung Lai, Jian-Chiun Liou, Chun-Wei Wu, Wing P. Chan and Chih-Wei Peng

Int. J. Mol. Sci. 2022, 23(16), 9447; https://doi.org/10.3390/ijms23169447 - 21 Aug 2022

Cited by 3 | Viewed by 1781

Abstract

Paired stimulation of the brain and spinal cord can remodel the central nervous tissue circuitry in an animal model to induce motor neuroplasticity. The effects of simultaneous stimulation vary according to the extent and severity of spinal cord injury. Therefore, our study aimed [...] Read more.

Paired stimulation of the brain and spinal cord can remodel the central nervous tissue circuitry in an animal model to induce motor neuroplasticity. The effects of simultaneous stimulation vary according to the extent and severity of spinal cord injury. Therefore, our study aimed to determine the significant effects on an incomplete SCI rat brain and spinal cord through 3 min and 20 min stimulations after 4 weeks of intervention. Thirty-three Sprague Dawley rats were classified into six groups: (1) normal, (2) sham, (3) iTBS/tsDCS, (4) iTBS/ts-iTBS, (5) rTMS/tsDCS, and (6) rTMS/ts-iTBS. Paired stimulation of the brain cortex and spinal cord thoracic (T10) level was applied simultaneously for 3–20 min. The motor evoked potential (MEP) and Basso, Beattie, and Bresnahan (BBB) scores were recorded after every week of intervention for four weeks along with wheel training for 20 min. Three-minute stimulation with the iTBS/tsDCS intervention induced a significant (p < 0.050 *) increase in MEP after week 2 and week 4 treatments, while 3 min iTBS/ts-iTBS significantly improved MEP (p < 0.050 *) only after the week 3 intervention. The 20 min rTMS/ts-iTBS intervention showed a significant change only in post_5 min after week 4. The BBB score also changed significantly in all groups except for the 20 min rTMS/tsDCS intervention. iTBS/tsDCS and rTMS/ts-iTBS interventions induce neuroplasticity in an incomplete SCI animal model by significantly changing electrophysiological (MEP) and locomotion (BBB) outcomes. Full article

(This article belongs to the Special Issue Spinal Cord Injury: From Mechanisms to Therapeutic Approaches)

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22 pages, 3401 KiB

Open AccessArticle

Development of Neurogenic Detrusor Overactivity after Thoracic Spinal Cord Injury Is Accompanied by Time-Dependent Changes in Lumbosacral Expression of Axonal Growth Regulators

by Sílvia Sousa Chambel, Ana Ferreira, Raquel Oliveira, Rafael Miranda, Luís Vale, Carlos Reguenga, Martin E. Schwab and Célia Duarte Cruz

Int. J. Mol. Sci. 2022, 23(15), 8667; https://doi.org/10.3390/ijms23158667 - 04 Aug 2022

Cited by 3 | Viewed by 2079

Abstract

Thoracic spinal cord injury (SCI) results in urinary dysfunction, which majorly affects the quality of life of SCI patients. Abnormal sprouting of lumbosacral bladder afferents plays a crucial role in this condition. Underlying mechanisms may include changes in expression of regulators of axonal [...] Read more.

Thoracic spinal cord injury (SCI) results in urinary dysfunction, which majorly affects the quality of life of SCI patients. Abnormal sprouting of lumbosacral bladder afferents plays a crucial role in this condition. Underlying mechanisms may include changes in expression of regulators of axonal growth, including chondroitin sulphate proteoglycans (CSPGs), myelin-associated inhibitors (MAIs) and repulsive guidance molecules, known to be upregulated at the injury site post SCI. Here, we confirmed lumbosacral upregulation of the growth-associated protein GAP43 in SCI animals with bladder dysfunction, indicating the occurrence of axonal sprouting. Neurocan and Phosphacan (CSPGs), as well as Nogo-A (MAI), at the same spinal segments were upregulated 7 days post injury (dpi) but returned to baseline values 28 dpi. In turn, qPCR analysis of the mRNA levels for receptors of those repulsive molecules in dorsal root ganglia (DRG) neurons showed a time-dependent decrease in receptor expression. In vitro assays with DRG neurons from SCI rats demonstrated that exposure to high levels of NGF downregulated the expression of some, but not all, receptors for those regulators of axonal growth. The present results, therefore, show significant molecular changes at the lumbosacral cord and DRGs after thoracic lesion, likely critically involved in neuroplastic events leading to urinary impairment. Full article

(This article belongs to the Special Issue Spinal Cord Injury: From Mechanisms to Therapeutic Approaches)

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Review

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13 pages, 841 KiB

Open AccessReview

Spinal Cord Injury and Complications Related to Neuraxial Anaesthesia Procedures: A Systematic Review

by Daniel H. Pozza, Isaura Tavares, Célia Duarte Cruz and Sara Fonseca

Int. J. Mol. Sci. 2023, 24(5), 4665; https://doi.org/10.3390/ijms24054665 - 28 Feb 2023

Cited by 2 | Viewed by 3315

Abstract

The use of neuraxial procedures, such as spinal and epidural anaesthesia, has been linked to some possible complications. In addition, spinal cord injuries due to anaesthetic practice (Anaes-SCI) are rare events but remain a significant concern for many patients undergoing surgery. This systematic [...] Read more.

The use of neuraxial procedures, such as spinal and epidural anaesthesia, has been linked to some possible complications. In addition, spinal cord injuries due to anaesthetic practice (Anaes-SCI) are rare events but remain a significant concern for many patients undergoing surgery. This systematic review aimed to identify high-risk patients summarise the causes, consequences, and management/recommendations of SCI due to neuraxial techniques in anaesthesia. A comprehensive search of the literature was conducted in accordance with Cochrane recommendations, and inclusion criteria were applied to identify relevant studies. From the 384 studies initially screened, 31 were critically appraised, and the data were extracted and analysed. The results of this review suggest that the main risk factors reported were extremes of age, obesity, and diabetes. Anaes-SCI was reported as a consequence of hematoma, trauma, abscess, ischemia, and infarction, among others. As a result, mainly motor deficits, sensory loss, and pain were reported. Many authors reported delayed treatments to resolve Anaes-SCI. Despite the potential complications, neuraxial techniques are still one of the best options for opioid-sparing pain prevention and management, reducing patients’ morbidity, improving outcomes, reducing the length of hospital stay, and pain chronification, with a consequent economic benefit. The main findings of this review highlight the importance of careful patient management and close monitoring during neuraxial anaesthesia procedures to minimise the risk of spinal cord injury and complications. Full article

(This article belongs to the Special Issue Spinal Cord Injury: From Mechanisms to Therapeutic Approaches)

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32 pages, 1481 KiB

Open AccessReview

Pathophysiology and Therapeutic Approaches for Spinal Cord Injury

by Rui Lima, Andreia Monteiro, António J. Salgado, Susana Monteiro and Nuno A. Silva

Int. J. Mol. Sci. 2022, 23(22), 13833; https://doi.org/10.3390/ijms232213833 - 10 Nov 2022

Cited by 12 | Viewed by 6181

Abstract

Spinal cord injury (SCI) is a disabling condition that disrupts motor, sensory, and autonomic functions. Despite extensive research in the last decades, SCI continues to be a global health priority affecting thousands of individuals every year. The lack of effective therapeutic strategies for [...] Read more.

Spinal cord injury (SCI) is a disabling condition that disrupts motor, sensory, and autonomic functions. Despite extensive research in the last decades, SCI continues to be a global health priority affecting thousands of individuals every year. The lack of effective therapeutic strategies for patients with SCI reflects its complex pathophysiology that leads to the point of no return in its function repair and regeneration capacity. Recently, however, several studies started to uncover the intricate network of mechanisms involved in SCI leading to the development of new therapeutic approaches. In this work, we present a detailed description of the physiology and anatomy of the spinal cord and the pathophysiology of SCI. Additionally, we provide an overview of different molecular strategies that demonstrate promising potential in the modulation of the secondary injury events that promote neuroprotection or neuroregeneration. We also briefly discuss other emerging therapies, including cell-based therapies, biomaterials, and epidural electric stimulation. A successful therapy might target different pathologic events to control the progression of secondary damage of SCI and promote regeneration leading to functional recovery. Full article

(This article belongs to the Special Issue Spinal Cord Injury: From Mechanisms to Therapeutic Approaches)

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Other

Jump to: Research, Review

11 pages, 1788 KiB

Open AccessBrief Report

Acute Systemic White Blood Cell Changes following Degenerative Cervical Myelopathy (DCM) in a Mouse Model

by Antigona Ulndreaj, Ariel Ávila, James Hong, Cindy Zhou, Michael G. Fehlings and Pia M. Vidal

Int. J. Mol. Sci. 2022, 23(19), 11496; https://doi.org/10.3390/ijms231911496 - 29 Sep 2022

Cited by 3 | Viewed by 1726

Abstract

Degenerative cervical myelopathy (DCM) is caused by age-related degeneration of the cervical spine, causing chronic spinal cord compression and inflammation. The aim of this study was to assess whether the natural progression of DCM is accompanied by hematological changes in the white blood [...] Read more.

Degenerative cervical myelopathy (DCM) is caused by age-related degeneration of the cervical spine, causing chronic spinal cord compression and inflammation. The aim of this study was to assess whether the natural progression of DCM is accompanied by hematological changes in the white blood cell composition. If so, these changes can be used for diagnosis complementing established imaging approaches and for the development of treatment strategies, since peripheral immunity affects the progression of DCM. Gradual compression of the spinal cord was induced in C57B/L mice at the C5-6 level. The composition of circulating white blood cells was analyzed longitudinally at four time points after induction of DCM using flow cytometry. At 12 weeks, serum cytokine levels were measured using a Luminex x-MAP assay. Neurological impairment in the mouse model was also assessed using the ladder walk test and CatWalk. Stepping function (* p < 0.05) and overground locomotion (*** p < 0.001) were impaired in the DCM group. Importantly, circulating monocytes and T cells were affected primarily at 3 weeks following DCM. T cells were two-fold lower in the DCM group (*** p < 0.0006), whereas monocytes were four-fold increased (*** p < 0.0006) in the DCM compared with the sham group. Our data suggest that changes in white blood cell populations are modest, which is unique to other spinal cord pathologies, and precede the development of neurobehavioral symptoms. Full article

(This article belongs to the Special Issue Spinal Cord Injury: From Mechanisms to Therapeutic Approaches)

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