Teriparatide: an innovative and promising strategy for protecting the blood-spinal cord barrier following spinal cord injury

The blood-spinal cord barrier (BSCB) is disrupted within minutes of spinal cord injury, leading to increased permeability and secondary spinal cord injury, resulting in more severe neurological damage. The preservation of blood-spinal cord barrier following spinal cord injury plays a crucial role in determining the prognosis. Teriparatide, widely used in clinical treatment for osteoporosis and promoting fracture healing, has been found in our previous study to have the effect of inhibiting the expression of MMP9 and alleviating blood-brain barrier disruption after ischemic stroke, thereby improving neurological damage symptoms. However, there are limited research on whether it has the potential to improve the prognosis of spinal cord injury. This article summarizes the main pathological mechanisms of blood-spinal cord barrier disruption after spinal cord injury and its relationship with Teriparatide, and explores the therapeutic potential of Teriparatide in improving the prognosis of spinal cord injury by reducing blood-spinal cord barrier disruption

Safety Review of Therapeutic Ultrasound for Spinal Cord Neuromodulation and Blood-Spinal Cord Barrier Opening

New focused ultrasound spinal cord applications have emerged, particularly those improving therapeutic agent delivery to the spinal cord via blood-spinal cord barrier opening and the neuromodulation of spinal cord tracts. One hurdle in the development of these applications is safety. It may be possible to use safety trends from seminal and subsequent works in focused ultrasound to guide the development of safety guidelines for spinal cord applications. We collated data from decades of pre-clinical studies and illustrate a clear relationship between damage, time-averaged spatial peak intensity and exposure duration. This relationship suggests a thermal mechanism underlies ultrasound-induced spinal cord damage. We developed minimum and mean thresholds for damage from these pre-clinical studies. When these thresholds were plotted against the parameters used in recent pre-clinical ultrasonic spinal cord neuromodulation studies, the majority of the neuromodulation studies were near or above the minimum threshold. This suggests that a thermal neuromodulatory effect may exist for ultrasonic spinal cord neuromodulation, and that the thermal dose must be carefully controlled to avoid damage to the spinal cord. By contrast, the intensity-exposure duration threshold had no predictive value when applied to blood-spinal cord barrier opening studies that employed injected contrast agents. Most blood-spinal cord barrier opening studies observed slight to severe damage, except for small animal studies that employed an active feedback control method to limit pressures based on measured bubble oscillation behavior. The development of new focused ultrasound spinal cord applications perhaps reflects the recent success in the development of focused ultrasound brain applications, and recent work has begun on the translation of these technologies from brain to spinal cord. However, a great deal of work remains to be done, particularly with respect to developing and accepting safety standards for these applications

A NOVEL PERFUSED CONTUSION SPINAL CORD INJURY MODEL TO ASSESS RAPID MECHANICAL PROPERTIES CHANGES AFTER BLOOD SPINAL CORD BARRIER BREAKDOWN

Blood-spinal cord barrier (BSCB) disruption exacerbates the tissue damage caused by spinal cord injury (SCI), but the mechanisms and dynamics of how the barrier breakdown affects the mechanical properties of the tissue remain unclear. The perfused bovine ex vivo indentation injury model described here represents a new platform to investigate the short-term effects of altered blood flow and vascular permeability following traumatic spinal cord injury. Our results indicate that injured cords exhibit changes to bulk perfusion, as evidenced by laser speckle contrast imaging, in addition to decreased barrier function shortly after injury. Indentation tests that simultaneously simulate a crush injury and provide force-indentation data reveal that tissue softening initiates as early as 30 minutes when perfused with whole blood. Perfusing with resuspended RBC (rRBC) instead of whole blood mitigates the decreased stiffness, highlighting the importance of white blood cells and plasma proteins in mediating the extracellular matrix mechanical response after SCI. Immunohistochemical staining indicates increased levels of extravasated Evans blue, ED-1, and vimentin in injured sections, suggesting mechanisms underlying the rapid response in mechanical properties following injury. This research provides novel insights into the immediate mechanical and vascular changes following spinal cord injury

Evidence of Compromised Blood-Spinal Cord Barrier in Early and Late Symptomatic SOD1 Mice Modeling ALS

Background: The blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), and blood-cerebrospinal fluid barrier (BCSFB) control cerebral/spinal cord homeostasis by selective transport of molecules and cells from the systemic compartment. In the spinal cord and brain of both ALS patients and animal models, infiltration of T-cell lymphocytes, monocyte-derived macrophages and dendritic cells, and IgG deposits have been observed that may have a critical role in motor neuron damage. Additionally, increased levels of albumin and IgG have been found in the cerebrospinal fluid in ALS patients. These findings suggest altered barrier permeability in ALS. Recently, we showed disruption of the BBB and BSCB in areas of motor neuron degeneration in the brain and spinal cord in G93A SOD1 mice modeling ALS at both early and late stages of disease using electron microscopy. Examination of capillary ultrastructure revealed endothelial cell degeneration, which, along with astrocyte alteration, compromised the BBB and BSCB. However, the effect of these alterations upon barrier function in ALS is still unclear. The aim of this study was to determine the functional competence of the BSCB in G93A mice at different stages of disease. Methodology/Principal Findings: Evans Blue (EB) dye was intravenously injected into ALS mice at early or late stage disease. Vascular leakage and the condition of basement membranes, endothelial cells, and astrocytes were investigated in cervical and lumbar spinal cords using immunohistochemistry. Results showed EB leakage in spinal cord microvessels from all G93A mice, indicating dysfunction in endothelia and basement membranes and confirming our previous ultrastructural findings on BSCB disruption. Additionally, downregulation of Glut-1 and CD146 expressions in the endothelial cells of the BSCB were found which may relate to vascular leakage. Conclusions/Significance: Results suggest that the BSCB is compromised in areas of motor neuron degeneration in ALS mice at both early and late stages of the disease

Molecular mechanisms involved in T cell migration across the blood-brain barrier

In the healthy individuum lymphocyte traffic into the central nervous system (CNS) is very low and tightly controlled by the highly specialized blood-brain barrier (BBB). In contrast, under inflammatory conditions of the CNS such as in multiple sclerosis or in its animal model experimental autoimmune encephalomyelitis (EAE) circulating lymphocytes and monocytes/macrophages readily cross the BBB and gain access to the CNS leading to edema, inflammation and demyelination. Interaction of circulating leukocytes with the endothelium of the blood-spinal cord and blood-brain barrier therefore is a critical step in the pathogenesis of inflammatory diseases of the CNS. Leukocyte/endothelial interactions are mediated by adhesion molecules and chemokines and their respective chemokine receptors. We have developed a novel spinal cord window preparation, which enables us to directly visualize CNS white matter microcirculation by intravital fluorescence videomicroscopy. Applying this technique of intravital fluorescence videomicroscopy we could provide direct in vivo evidence that encephalitogenic T cell blasts interact with the spinal cord white matter microvasculature without rolling and that alpha4-integrin mediates the G-protein independent capture and subsequently the G-protein dependent adhesion strengthening of T cell blasts to microvascular VCAM-1. LFA-1 was found to neither mediate the G-protein independent capture nor the G- protein dependent initial adhesion strengthening of encephalitogenic T cell blasts within spinal cord microvessel, but was rather involved in T cell extravasation across the vascular wall into the spinal cord parenchyme. Our observation that G-protein mediated signalling is required to promote adhesion strengthening of encephalitogenic T cells on BBB endothelium in vivo suggested the involvement of chemokines in this process. We found functional expression of the lymphoid chemokines CCL19/ELC and CCL21/SLC in CNS venules surrounded by inflammatory cells in brain and spinal cord sections of mice afflicted with EAE suggesting that the lymphoid chemokines CCL19 and CCL21 besides regulating lymphocyte homing to secondary lymphoid tissue might be involved in T lymphocyte migration into the immuneprivileged CNS during immunosurveillance and chronic inflammation. Here, I summarize our current knowledge on the sequence of traffic signals involved in T lymphocyte recruitment across the healthy and inflamed blood-brain and blood-spinal cord barrier based on our in vitro and in vivo investigations

The consequence of endothelial remodelling on the blood spinal cord barrier and nociception

Nociception is a fundamental acute protective mechanism that prevents harm to an organism. Understanding the integral processes that control nociceptive processing are fundamental to our appreciation of which cellular and molecular features underlie this process. There is an extensive understanding of how sensory neurons interpret differing sensory modalities and intensities. However, it is widely appreciated that the sensory neurons do not act alone. These work in harmony with inflammatory and vascular systems to modulate pain perception. The spinal cord has an extensive interaction with the capillary network in the form of a blood spinal cord barrier to ensure homeostatic control of the spinal cord neuron milieu. However, there is an extensive appreciation that disturbances in the blood spinal cord barrier contribute to the onset of chronic pain. Enhanced vascular permeability and impaired blood perfusion have both been highlighted as contributors to chronic pain manifestation. Here, we discuss the evidence that demonstrates alterations in the blood spinal cord barrier influences nociceptive processing and perception of pain

Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema

Swelling of the brain or spinal cord (CNS edema) affects millions of people every year. All potential pharmacological interventions have failed in clinical trials, meaning that symptom management is the only treatment option. The water channel protein aquaporin-4 (AQP4) is expressed in astrocytes and mediates water flux across the blood-brain and blood-spinal cord barriers. Here we show that AQP4 cell-surface abundance increases in response to hypoxia-induced cell swelling in a calmodulin-dependent manner. Calmodulin directly binds the AQP4 carboxyl terminus, causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licensed drug trifluoperazine inhibited AQP4 localization to the blood-spinal cord barrier, ablated CNS edema, and led to accelerated functional recovery compared with untreated animals. We propose that targeting the mechanism of calmodulin-mediated cell-surface localization of AQP4 is a viable strategy for development of CNS edema therapies

Imatinib Enhances Functional Outcome after Spinal Cord Injury

We investigated whether imatinib (Gleevec®, Novartis), a tyrosine kinase inhibitor, could improve functional outcome in experimental spinal cord injury. Rats subjected to contusion spinal cord injury were treated orally with imatinib for 5 days beginning 30 minutes after injury. We found that imatinib significantly enhanced blood-spinal cord-barrier integrity, hindlimb locomotor function, sensorimotor integration, and bladder function, as well as attenuated astrogliosis and deposition of chondroitin sulfate proteoglycans, and increased tissue preservation. These improvements were associated with enhanced vascular integrity and reduced inflammation. Our results show that imatinib improves recovery in spinal cord injury by preserving axons and other spinal cord tissue components. The rapid time course of these beneficial effects suggests that the effects of imatinib are neuroprotective rather than neurorestorative. The positive effects on experimental spinal cord injury, obtained by oral delivery of a clinically used drug, makes imatinib an interesting candidate drug for clinical trials in spinal cord injury

Uncovering the role of blood vessels during spinal cord regeneration in zebrafish

The spinal cord is the region of the central nervous system responsible for the bidirectional relay of information between the brain and the rest of the body. For this reason, damages to the spinal cord can result in devastating consequences. Spinal cord injury (SCI) occurs due to a physical trauma and causes loss of motor and sensitive function. Additionally, the initial trauma provokes the disruption of the blood-spinal cord barrier (BSCB). This results in the leakage of blood to the tissue, further damaging the spinal cord. In mammals, like humans and mice (Mus musculus), endogenous attempts to repair the resulting damage occur, however, these attempts are mostly unsuccessful due to the present of growthinhibitory molecules and structures. As such, no significant recovery is accomplished. By contrast, zebrafish (Danio rerio) are able to regenerate their spinal cord and previous work from our lab showed that, during regeneration, the injured tissue revascularizes and that blood flow is observed in these vessels. In this work, we followed the recovery of the BSCB during spinal cord regeneration in zebrafish at different timepoints after injury. Our results showed that the reestablishment of the BSCB occurred between 3 dpi and 7 dpi, indicating that the new blood vessels rapidly become functional in zebrafish. In addition, in order to study the importance of revascularization after SCI, we attempted to inhibit the angiogenic process that occurs during spinal cord regeneration. Our preliminary results suggest that the inhibition of angiogenesis results in impaired motor function. However, the cellular and molecular mechanisms involved are not yet understood. These results allow a better understanding of the regenerative process in zebrafish and may provide clues regarding the fundamental differences that exist between this animal model and mammals