Rodent Models Of Spinal Cord Injury Research Articles

Non-contrast ultrasound image analysis for spatial and temporal distribution of blood flow after spinal cord injury

Ultrasound technology can provide high-resolution imaging of blood flow following spinal cord injury (SCI). Blood flow imaging may improve critical care management of SCI, yet its duration is limited clinically by the amount of contrast agent injection required for high-resolution, continuous monitoring. In this study, we aim to establish non-contrast ultrasound as a clinically translatable imaging technique for spinal cord blood flow via comparison to contrast-based methods and by measuring the spatial distribution of blood flow after SCI. A rodent model of contusion SCI at the T12 spinal level was carried out using three different impact forces. We compared images of spinal cord blood flow taken using both non-contrast and contrast-enhanced ultrasound. Subsequently, we processed the images as a function of distance from injury, yielding the distribution of blood flow through space after SCI, and found the following. (1) Both non-contrast and contrast-enhanced imaging methods resulted in similar blood flow distributions (Spearman’s ρ = 0.55, p < 0.0001). (2) We found an area of decreased flow at the injury epicenter, or umbra (p < 0.0001). Unexpectedly, we found increased flow at the periphery, or penumbra (rostral, p < 0.05; caudal, p < 0.01), following SCI. However, distal flow remained unchanged, in what is presumably unaffected tissue. (3) Finally, tracking blood flow in the injury zones over time revealed interesting dynamic changes. After an initial decrease, blood flow in the penumbra increased during the first 10 min after injury, while blood flow in the umbra and distal tissue remained constant over time. These results demonstrate the viability of non-contrast ultrasound as a clinical monitoring tool. Furthermore, our surprising observations of increased flow in the injury periphery pose interesting new questions about how the spinal cord vasculature reacts to SCI, with potentially increased significance of the penumbra.

Electrical stimulation promotes functional recovery after spinal cord injury by activating endogenous spinal cord-derived neural stem/progenitor cell: an in vitro and in vivo study

Background contextElectrical stimulation is a noninvasive treatment method that has gained popularity in the treatment of spinal cord injury (SCI). Activation of spinal cord-derived neural stem/progenitor cell (SC-NSPC) proliferation and differentiation in the injured spinal cord may elicit considerable neural regenerative effects. PurposeThis study aimed to explore the effect of electrical stimulation on the neurogenesis of SC-NSPCs. Study designThis study analyzed the effects of electrical stimulation on neurogenesis in rodent SC-NSPCs in vitro and in vivo and evaluated functional recovery and neural circuitry improvements with electrical stimulation using a rodent SCI model. MethodsRats (20 rats/group) were assigned to sham (Group 1), SCI only (Group 2), SCI + electrode implant without stimulation (Group 3), and SCI + electrode with stimulation (Group 4) groups to count total SC-NSPCs and differentiated neurons and to evaluate morphological changes in differentiated neurons. Furthermore, the Basso, Beattie, and Bresnahan scores were analyzed, and the motor- and somatosensory-evoked potentials in all rats were monitored. ResultsBiphasic electrical currents enhanced SC-NSPC proliferation differentiation and caused qualitative morphological changes in differentiated neurons in vitro. Electrical stimulation promoted SC-NSPC proliferation and neuronal differentiation and improved functional outcomes and neural circuitry in SCI models. Increased Wnt3, Wnt7, and β-catenin protein levels were also observed after electrical stimulation. ConclusionsOur study proved the beneficial effects of electrical stimulation on SCI. The Wnt/β-catenin pathway activation may be associated with this relationship between electrical stimulation and neuronal regeneration after SCI. Clinical significanceThe study confirmed the benefits of electrical stimulation on SCI based on cellular, functional, electrophysiological, and histological evidence. Based on these findings, we expect electrical stimulation to make a positive and significant difference in SCI treatment strategies.

Human Spinal Oligodendrogenic Neural Progenitor Cells Enhance Pathophysiological Outcomes and Functional Recovery in a Clinically Relevant Cervical Spinal Cord Injury Rat Model.

Traumatic spinal cord injury (SCI) results in the loss of neurons, oligodendrocytes, and astrocytes. Present interventions for SCI include decompressive surgery, anti-inflammatory therapies, and rehabilitation programs. Nonetheless, these approaches do not offer regenerative solutions to replace the lost cells, fiber tracts, and circuits. Neural stem/progenitor cell (NPC) transplantation is a promising strategy that aims to encourage regeneration. However, NPC differentiation remains inconsistent, thus, contributing to suboptimal functional recovery. As such, we have previously engineered oligodendrogenically biased NPCs (oNPCs) and demonstrated their efficacy in a thoracic model of SCI. Since the majority of patients with SCI experience cervical injuries, our objective in the current study was to generate human induced pluripotent stem cell-derived oNPCs (hiPSC-oNPCs) and to characterize these cells in vitro and in vivo, utilizing a clinically relevant rodent model of cervical SCI. Following transplantation, the oNPCs engrafted, migrated to the rostral and caudal regions of the lesion, and demonstrated preferential differentiation toward oligodendrocytes. Histopathological evaluations revealed that oNPC transplantation facilitated tissue preservation while diminishing astrogliosis. Moreover, oNPC transplantation fostered remyelination of the spared tissue. Functional analyses indicated improved forelimb grip strength, gait, and locomotor function in the oNPC-transplanted rats. Importantly, oNPC transplantation did not exacerbate neuropathic pain or induce tumor formation. In conclusion, these findings underscore the therapeutic potential of oNPCs in promoting functional recovery and histopathological improvements in cervical SCI. This evidence warrants further investigation to optimize and advance this promising cell-based therapeutic approach.

Understanding the Role of the Glial Scar through the Depletion of Glial Cells after Spinal Cord Injury.

Spinal cord injury (SCI) is a condition that affects between 8.8 and 246 people in a million and, unlike many other neurological disorders, it affects mostly young people, causing deficits in sensory, motor, and autonomic functions. Promoting the regrowth of axons is one of the most important goals for the neurological recovery of patients after SCI, but it is also one of the most challenging goals. A key event after SCI is the formation of a glial scar around the lesion core, mainly comprised of astrocytes, NG2+-glia, and microglia. Traditionally, the glial scar has been regarded as detrimental to recovery because it may act as a physical barrier to axon regrowth and release various inhibitory factors. However, more and more evidence now suggests that the glial scar is beneficial for the surrounding spared tissue after SCI. Here, we review experimental studies that used genetic and pharmacological approaches to ablate specific populations of glial cells in rodent models of SCI in order to understand their functional role. The studies showed that ablation of either astrocytes, NG2+-glia, or microglia might result in disorganization of the glial scar, increased inflammation, extended tissue degeneration, and impaired recovery after SCI. Hence, glial cells and glial scars appear as important beneficial players after SCI.

Effects of a neurokinin-1 receptor antagonist in the acute phase after thoracic spinal cord injury in a rat model.

Disruption of the blood-spinal cord barrier (BSCB) with subsequent edema formation and further neuroinflammation contributes to aggravation of spinal cord injury (SCI). We aimed to observe the effect of antagonizing the binding of the neuropeptide Substance-P (SP) to its neurokinin-1 (NK1) receptor in a rodent SCI model. Female Wistar rats were subjected to a T9 laminectomy with or without (Sham) a T9 clip-contusion/compression SCI, followed by the implantation of an osmotic pump for the continuous, seven-day-long infusion of a NK1 receptor antagonist (NRA) or saline (vehicle) into the intrathecal space. The animals were assessed via MRI, and behavioral tests were performed during the experiment. 7 days after SCI, wet & dry weight and immunohistological analyses were conducted. Substance-P inhibition via NRA showed limited effects on reducing edema. However, the invasion of T-lymphocytes and the number of apoptotic cells were significantly reduced with the NRA treatment. Moreover, a trend of reduced fibrinogen leakage, endothelial and microglial activation, CS-GAG deposition, and astrogliosis was found. Nevertheless, only insignificant general locomotion recovery could be observed in the BBB open field score and the Gridwalk test. In contrast, the CatWalk gait analysis showed an early onset of recovery in several parameters. Intrathecal administration of NRA might reinforce the integrity of the BSCB in the acute phase after SCI, potentially attenuating aspects of neurogenic inflammation, reducing edema formation, and improving functional recovery.

Acute Intermittent Hypoxia and Respiratory Strength Training to Improve Respiratory Function in Individuals with Chronic Spinal Cord Injury: Preliminary Outcomes

Spinal cord injury (SCI) disrupts neural pathways to respiratory motor neurons, causing paralysis and breathing impairment, a major cause of illness and death in SCI. Acute intermittent hypoxia (AIH) is a promising therapeutic modality that elicits spinal synaptic plasticity, improving breathing in rodent models of SCI. AIH also elicits plasticity in limb motor systems in both rodent models and humans with chronic SCI, where functional gains are greatest when paired with task-specific training. The impact of similar combinatorial treatments on breathing ability is unknown. Here, we report preliminary breathing outcomes in seventeen adults with chronic SCI who received AIH and task-specific training (respiratory strength training; RST). Seventeen males with chronic SCI (33.7 ± 15 yrs of age; 1-28 yrs post-SCI; 12 cervical, 5 thoracic injuries; C1-T6 AIS A-D). Respiratory function was 52% ± 19% of the age-predicted normative function for expiratory pressure generation and 123% ± 32% of normative values for inspiratory function. Participants completed four random ordered 5-day protocols of AIH, Sham, RST, and AIH+RST, &gt;3 weeks apart. AIH consisted of 15, 1-minute episodes of breathing a hypoxic gas mixture (9% oxygen), interspersed with 1.5-minute episodes of breathing room air (21% oxygen). Thirty minutes after AIH, RST involved both inspiratory and expiratory training; 4 sets of 6-12 breaths with the pressure threshold device set to 80% of each individual’s maximum. Sham treatments replicated AIH but used room air. A linear mixed model was used to test for differences in maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and forced vital capacity (FVC) prior to and 1 day post-intervention. MIP increased 10±15.6% (pre 120±34cmH20, post 129±36 cmH20) 1 day after RST (p=0.001) and 6±10.5% (pre 123±34cmH20; post 131±34cmH20) 1 day after AIH+RST (p=0.04), but did not change after AIH or Sham. MIP increased by &gt;10% in 5/17 participants following AIH+RST and 9/17 participants following RST. Neither MEP nor FVC changed following any block. Although there were no significant differences between AIH+RST and RST intervention blocks, there was a medium effect size (0.44). Since RST and AIH+RST preliminary outcomes suggest functional respiratory benefit, future steps will determine if the combinatorial treatment elicits greater gains. Examination of biomarkers associated with outcomes will provide insight into outcome variability. Department of Defense CDMRP W81XWH1810718 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Composite Fibrin and Carbon Microfibre Implant to Modulate Postraumatic Inflammation after Spinal Cord Injury.

Poor functional recovery after spinal cord injury (SCI) drives the development of novel strategies to manage this devastating condition. We recently showed promising immunomodulatory and pro-regenerative actions of bio-functionalized carbon microfibres (MFs) implanted in a rodent model of SCI. In order to maximize tissue repair while easing MF implantation, we produced a composite implant based on the embedding of several MFs within a fibrin hydrogel. We used intravital imaging of fluorescent reporter mice at the early stages and spinal sections of the same animals 3 months later to characterize the neuroinflammatory response to the implant and its impact on axonal regeneration. Whereas fibrin alone was inert in the first week, its enzymatic degradation drove the chronic activation of microglial cells and axonal degeneration within 3 months. However, the presence of MFs inside the fibrin hydrogel slowed down fibrin degradation and boosted the early recruitment of immune cells. Noteworthy, there was an enhanced contribution of monocyte-derived dendritic cells (moDCs), preceding a faster transition toward an anti-inflammatory environment with increased axonal regeneration over 3 months. The inclusion of MF here ensured the long-term biocompatibility of fibrin hydrogels, which would otherwise preclude successful spinal cord regeneration.

Validation of Spinal Cord Injury Sensory Deficit Model with Head-Fixed Rat

Background/Objective: Numerous studies have reported restoring motor function through spinal cord stimulation in a rodent spinal cord injury model; however, replicating sensory information through spinal cord stimulation has not been thoroughly tested.We have previously trained rats to detect artificial sensations which lead to the question if this can be generated in a spinal cord injured rat. Our study begins to address this question by first validating a spinal cord injury model to test. Our hypothesis is if a decrease in the percent correct response compared to pre-procedure is observed, then this will verify sensory loss in this dorsal column lesion model of spinal cord injury.&#x0D; Methods: We use sensory detection in a head-fixed rat to verify a spinal cord injury sensory deficit model. We begin by placing a water-deprived rat into a custom-made head-fix set up where two water spouts are placed in front of the rat. Vibration stimuli is applied to the hind paw via a vibration motor set at 200 hz ± 50 hz. The rat is trained to associate stimulus with left spout and no stimulus with right spout. Correct percent response is recorded and once rat demonstrates detection, the rat undergoes a dorsal column hemi-section procedure. Post procedure, the rat will be placed back in the head-fix set up to repeat the behavioral experiment.&#x0D; Results: Thus far, only habituation training has been completed with the rat. The following steps include detection training, dorsal column hemi section, and re doing the detection training to measure a difference in correct response rate.&#x0D; Conclusion and Potential Impact:This is a crucial step for spinal cord injury research as this confirms sensory loss and will allow further testing to restore sensation. After validation, we can begin testing to restore sensation using stimulation of the spinal cord.

Rehabilitative Training Enhances Therapeutic Effect of Human-iPSC-Derived Neural Stem/Progenitor Cells Transplantation in Chronic Spinal Cord Injury.

Cell transplantation therapy using human-induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) is a new therapeutic strategy for spinal cord injury (SCI). Preclinical studies have demonstrated the efficacy of hiPSC-NS/PCs transplantation in the subacute phase of SCI. However, locomotor recovery secondary to hiPSC-NS/PCs transplantation is limited in the chronic phase, suggesting that additional treatment, including rehabilitative training, is required to ensure recovery. The therapeutic potential of hiPSC-NS/PCs that qualify for clinical application is yet to be fully delineated. Therefore, in this study, we investigated the therapeutic effect of the combined therapy of clinical-grade hiPSC-NS/PCs transplantation and rehabilitative training that could produce synergistic effects in a rodent model of chronic SCI. Our findings indicated that rehabilitative training promoted the survival rate and neuronal differentiation of transplanted hiPSC-NS/PCs. The combination therapy was able to enhance the expressions of the BDNF and NT-3 proteins in the spinal cord tissue. Moreover, rehabilitation promoted neuronal activity and increased 5-HT-positive fibers at the lumbar enlargement. Consequently, the combination therapy significantly improved motor functions. The findings of this study suggest that the combined therapy of hiPSC-NS/PCs transplantation and rehabilitative training has the potential to promote functional recovery even when initiated during chronic SCI.

Is TGR5 a therapeutic target for the treatment of spinal cordinjury?

Bile acids, which are synthesized in liver and colon, facilitate the digestion of dietary lipids. In addition to this metabolic function, they also act as molecular signals with activities in the nervous system. These are mediated primarily by a G-protein-coupled bile acid receptor (known as TGR5). Preceded by a long tradition in Chinese medicine, bile acids are now being investigated as therapeutic options in several neuropathologies. Specifically, one bile acid, tauroursodeoxycholic acid (TUDCA), which passes the blood-brain barrier and shows anti-inflammatory and anti-apoptotic effects, has been tested in animal models of spinal cord injury (SCI). In this review, we discuss the evidence for a therapeutic benefit in these preclinical experiments. At the time of writing, 12 studies with TGR5 agonists have been published that report functional outcomes with rodent models of SCI. Most investigations found cytoprotective effects and benefits regarding the recovery of sensorimotor function in the subacute phase. When TUDCA was applied in a hydrogel into the lesion site, a significant improvement was obtained at 2 weeks after SCI. However, no lasting improvements with TUDCA treatment were found, when animals were assessed in later, chronic stages. A combination of TUDCA with stem cell injection failed to improve the effect of the cellular treatment. We conclude that the evidence does not support the use of TUDCA as a treatment of SCI. Nevertheless, cytoprotective effects suggest that different modes of application or combinatorial therapies might still be explored.

Early Detrusor Application of Botulinum Toxin A Results in Reduced Bladder Hypertrophy and Fibrosis after Spinal Cord Injury in a Rodent Model.

Following spinal cord injury (SCI), pathological reflexes develop that result in altered bladder function and sphincter dis-coordination, with accompanying changes in the detrusor. Bladder chemodenervation is known to ablate the pathological reflexes, but the resultant effects on the bladder tissue are poorly defined. In a rodent model of contusion SCI, we examined the effect of early bladder chemodenervation with botulinum toxin A (BoNT-A) on bladder histopathology and collagen deposition. Adult female Long Evans rats were given a severe contusion SCI at spinal level T9. The SCI rats immediately underwent open laparotomy and received detrusor injections of either BoNT-A (10 U/animal) or saline. At eight weeks post injury, the bladders were collected, weighed, and examined histologically. BoNT-A injected bladders of SCI rats (SCI + BoNT-A) weighed significantly less than saline injected bladders of SCI rats (SCI + saline) (241 ± 25 mg vs. 183 ± 42 mg; p < 0.05). Histological analyses showed that SCI resulted in significantly thicker bladder walls due to detrusor hypertrophy and fibrosis compared to bladders from uninjured animals (339 ± 89.0 μm vs. 193 ± 47.9 μm; p < 0.0001). SCI + BoNT-A animals had significantly thinner bladder walls compared to SCI + saline animals (202 ± 55.4 μm vs. 339 ± 89.0 μm; p < 0.0001). SCI + BoNT-A animals had collagen organization in the bladder walls similar to that of uninjured animals. Detrusor chemodenervation soon after SCI appears to preserve bladder tissue integrity by reducing the development of detrusor fibrosis and hypertrophy associated with SCI.

Blood Flow Changes Associated with Spinal Cord Injury Assessed by Non-linear Doppler Contrast-Enhanced Ultrasound.

Contrast-enhanced ultrasound (CEUS) is clinically used to image the microcirculation at lower imaging frequencies (<2 MHz). Recently, plane-wave acquisitions and Doppler processing have revealed improved microbubble sensitivity, enabling CEUS use at higher frequencies (15 MHz) and the ability to image simultaneously blood flow in the micro- and macrocirculations. We used this approach to assess acute and chronic blood flow changes within contused spinal cord in a rodent spinal cord injury model. Immediately after spinal cord injury, we found significant differences in perfusion deficit between moderate and severe injuries (1.73 ± 0.1 mm2 vs. 3.2 ± 0.3 mm2, respectively), as well as a delay in microbubble arrival time in tissue adjacent to the injury site (0.97 ± 0.1 s vs. 1.54 ± 0.1 s, respectively). Acutely, morphological changes to central sulcal arteries were observed where vessels rostral to the contusion were displaced 4.8 ± 2.2° and 8.2 ± 3.1° anteriorly, and vessels caudal to the contusion 17.8 ± 3.9° and 24.2 ± 4.1° posteriorly, respectively, for moderate and severe injuries. Significant correlation of the acute perfusion deficit and arrival time were found with the chronic assessment of locomotive function and histological estimate of spared spinal cord tissue.

Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury

Chondroitin sulfate proteoglycans (CSPGs) act as potent inhibitors of axonal growth and neuroplasticity after spinal cord injury (SCI). Here we reveal that CSPGs also play a critical role in preventing inflammation resolution by blocking the conversion of pro-inflammatory immune cells to a pro-repair phenotype in rodent models of SCI. We demonstrate that enzymatic digestion of CSPG glycosaminoglycans enhances immune cell clearance and reduces pro-inflammatory protein and gene expression profiles at key resolution time points. Analysis of phenotypically distinct immune cell clusters revealed CSPG-mediated modulation of macrophage and microglial subtypes which, together with T lymphocyte infiltration and composition changes, suggests a role for CSPGs in modulating both innate and adaptive immune responses after SCI. Mechanistically, CSPG activation of a pro-inflammatory phenotype in pro-repair immune cells was found to be TLR4-dependent, identifying TLR4 signalling as a key driver of CSPG-mediated immune modulation. These findings establish CSPGs as critical mediators of inflammation resolution failure after SCI in rodents, which leads to prolonged inflammatory pathology and irreversible tissue destruction.

Acute Intermittent Hypoxia Improves Orthostatic Tolerance in Chronic but not Acute Spinal Cord Injured Rats

Spinal cord injury (SCI) causes hypotension and orthostatic intolerance due to disrupted sympathetic input to the heart and vasculature following injury1. A neuro‐therapeutic strategy shown to increase somatic motor function below the injury is acute intermittent hypoxia (AIH). While AIH is known to improve control over respiratory and non‐respiratory motor systems with incomplete cervical SCI2,3, cardio‐autonomic responses to AIH after SCI are unknown. In able‐bodied individuals, AIH increases blood pressure (BP), improves orthostatic tolerance (OT), and heightens sympathetic activity4. In incomplete SCI, intact neural pathways regulating sympathetic nerve activity suggest the potential for AIH to increase sub‐lesional sympathetic activity, thus improving cardiovascular function. Previous work has demonstrated that the response to AIH is greatest in rats at least 4 weeks post‐injury due to reestablishment of serotonergic pathways2, therefore the purpose of this project is to investigate whether AIH improves OT in rats following acute (2 weeks) and/or chronic (4 weeks) high‐thoracic SCI. We believe AIH will improve OT more in chronically versus acutely injured rats.12 Wistar rats underwent T3 300 kdyn SCI. At 14 (n=6) or 28 (n=6) days post‐SCI rats were tracheotomized, ventilated and arterial catheterization was performed to assess BP. Rats were subjected to lower body negative pressure (LBNP; recorded with manometer) to decrease mean arterial pressure (MAP) by 5 and 10 mmHg for 1 min. Rats were exposed to isocapnic AIH (10 x 1‐min FIO2=0.10 separated by 2 min of FIO2=1.00; targeting a PaCO2 of 40 mmHg). LBNP was repeated 90 minutes post‐AIH, the expected peak response. Blood gases were measured pre‐ and post‐AIH. A mixed‐design ANOVA was performed to examine effects of time post‐SCI (group) and AIH (treatment) on change in box pressure required to decrease MAP by ‐5 and ‐10 mmHg.There was a significant group*treatment interaction for the ‐5 mmHg (p=0.011) and ‐10 mmHg LBNP stage (p=0.017). Post hoc comparisons demonstrate that in chronic SCI the box pressure required to drop MAP by ‐5 and ‐10mmHg was increased by 41±16% (p=0.009) and 46±22% (p=0.079) versus pre‐AIH, respectively, implying improved OT (Fig 1).We demonstrate that AIH has the capacity to improve OT in a rodent model of SCI in a chronic, but not acute setting.

184 Placental Mesenchymal Stromal Cells Seeded on an Extracellular Matrix Scaffold Improve Motor Function Recovery After Acute Spinal Cord Injury

INTRODUCTION: Spinal cord injury (SCI) is a devasting disease associated with severe disability and no effective cure. SCI involves a primary traumatic injury followed by a secondary injury characterized by inflammation, ischemia, and formation of a glial scar. Cellular therapies aim to minimize the secondary injury by protecting the remaining cells and promoting neuronal and glial regeneration. We have shown placental mesenchymal stromal cells (PMSCs) applied in utero improve ambulatory function and preserve motor neurons in an ovine model of spina bifida and have begun a first-in-human clinical trial for fetal spina bifida. METHODS: Female Sprague Dawley rats were given a right C5 hemi-contusion injury using an RWD Precise Impactor and 8 rats served as sham surgery controls. Immediately following injury, rats were treated with an ECM only (n = 9) or an ECM seeded with 3 x 105 PMSCs (PMSC-ECM, n = 11). Weekly motor function testing included Irvine, Beatties, and Bresnahan (IBB) Forelimb Recovery Scale testing by blinded reviewers. After 8 weeks, rats were euthanized, and tissue collected for histology. RESULTS: Four second trimester PMSC cell lines were evaluated with our established anti-apoptotic neuroprotection assay and a single cell line was chosen based on increased neurite outgrowths. Within the PMSC-ECM group, rats had statistically significant improvement in their IBB scores between week 1 and week 8 (p = 0.002) compared to ECM only group, where rats did not show improvement (p = 0.063). When comparing IBB scores between groups at week 8, PMSC-ECM rats had a significantly higher IBB score compared to ECM only rats (p = 0.015). CONCLUSION: PMSCs improved motor function recovery in a rodent model of SCI. Further studies include immunohistochemical analysis and delivering PMSC derived exosomes as a cell-free treatment.

Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function.

In cell transplantation therapy for spinal cord injury (SCI), grafted human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) mainly differentiate into neurons, forming synapses in a process similar to neurodevelopment. In the developing nervous system, the activity of immature neurons has an important role in constructing and maintaining new synapses. Thus, we investigate how enhancing the activity of transplanted hiPSC-NS/PCs affects both the transplanted cells themselves and the host tissue. We find that chemogenetic stimulation of hiPSC-derived neural cells enhances cell activity and neuron-to-neuron interactions invitro. In a rodent model of SCI, consecutive and selective chemogenetic stimulation of transplanted hiPSC-NS/PCs also enhances the expression of synapse-related genes and proteins in surrounding host tissues and prevents atrophy of the injured spinal cord, thereby improving locomotor function. These findings provide a strategy for enhancing activity within the graft to improve the efficacy of cell transplantation therapy for SCI.

Markers of susceptibility to cardiac arrhythmia in experimental spinal cord injury and the impact of sympathetic stimulation and exercise training.

Injury to descending autonomic (sympathetic) pathways is common after high-level spinal cord injury (SCI) and associated with abnormal blood pressure and heart rate regulation. In individuals with high-level SCI, abnormal sympathovagal balance (such as during autonomic dysreflexia; paroxysmal hypertension provoked by sensory stimuli below the injury) is proarrhythmogenic. Exercise training is a key component of SCI rehabilitation and management of cardiovascular disease risk, but it is unclear whether exercise training influences susceptibility to cardiac arrhythmia. We aimed to evaluate: (i) whether susceptibility to arrhythmia increases in a rodent-model of SCI; (ii) the impact of the sympathomimetic drug dobutamine (DOB) on arrhythmia risk; (iii) whether exercise training ameliorates arrhythmia risk. Twenty-one Wistar rats were divided into 3 subgroups: T2-contusive SCI (T2, n = 7), T2-contusive SCI completing passive hindlimb cycling training (PHLC, n = 7), and T10-contusive SCI (T10, n = 7). Known electrocardiographic arrhythmia markers and heart rate variability parameters were evaluated before (PRE), 1-week (POST) and 5-weeks post-SCI (TERM) at baseline and during DOB infusion (30 μg/kg/min). Baseline markers of arrhythmia risk were increased in both T2 and T10 animals. DOB decreased R-R interval (p < 0.001), and increased markers of risk for ventricular arrhythmia, particularly in high-level (T2) animals (p < 0.05). Exercise training blunted the exacerbation of markers of arrhythmia risk in the presence of DOB. Markers of risk for cardiac arrhythmia are increased in experimental SCI, and DOB further increases arrhythmia risk in high-level SCI. Exercise training did not improve markers of arrhythmia risk at rest, but did ameliorate markers of arrhythmia risk during sympathetic stimulation.

Comparative analysis of functional assessment for contusion and transection models of spinal cord injury.

Descriptive secondary analysis of two spinal cord injury (SCI) animal models. To compare the somatosensory evoked potential (SSEP) and motor behavioral (BBB) assessments of the two most used rodent SCI models (contusion and transection), to elucidate their functional similarity and differences over the acute phase of 3 weeks. Neuro-electrophysiology SSEP and motor behavioral BBB assessments are used to provide a comparative analysis of the functional changes among various severities of contusion and transection SCI. Adult male and female rats randomly grouped (n = 5) as following: mild (6.25 mm), moderate (12.5 mm), severe (25 mm), and very severe (50 mm) contusion as well as right T10 hemi-transection (RxI), left T8 and right T10 double hemi-transection (DxI), and T8 complete transection (CxI) injuries, plus the control group (laminectomy with no injury). Animal weight, body temperature, anesthesia, surgical procedures, electrophysiological SSEP monitoring, locomotion BBB scoring, and statistical analysis were identical among all animal groups. Statistical analysis of the SSEP and BBB data from both contusion and transection injury models indicate significant differences (P < 0.05). The results also show remarkable similarity for the severe and very severe contusion injuries to the complete transection, the moderate contusion injury to the double hemi-transection, and the mild contusion injury to the T10 hemi-transection injury. Although contusion and transection spinal cord injuries have two completely different pathophysiologies, their injury progress during acute phase follow a similar trend.

PD27-03 EARLY DETRUSOR CHEMODENERVATION AFTER SPINAL CORD INJURY CAN REDUCE BLADDER HYPERTROPHY AND FIBROSIS

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology (PD27)1 Sep 2021PD27-03 EARLY DETRUSOR CHEMODENERVATION AFTER SPINAL CORD INJURY CAN REDUCE BLADDER HYPERTROPHY AND FIBROSIS Zin Khiang, Juliana Bushnell, Jeffrey Hyde, and Claire Yang Zin KhiangZin Khiang More articles by this author , Juliana BushnellJuliana Bushnell More articles by this author , Jeffrey HydeJeffrey Hyde More articles by this author , and Claire YangClaire Yang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002020.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Following spinal cord injury (SCI), pathological reflexes develop, altering bladder and sphincter function, and resulting in detrusor changes within weeks after injury. Detrusor chemodenervation is known to ablate the pathological reflexes, but its effects on the development of detrusor changes is unknown. In a rodent model of SCI, we examine the effect of early detrusor chemodenervation. METHODS: Adult female Sprague Dawley rats (250–300g) were given a severe contusion SCI with 200-kDyne force with zero dwell time using an Infinite Horizon device following laminectomy, at spinal level T9 (N=8). A group of control rats did not undergo spinal injury (N=3) but underwent laminectomy only. The SCI rats immediately underwent laparotomy, and either saline (N=4) or botulinum toxin A (BoNT-A) 10U (N=4) was injected into the detrusor in 8 equal aliquots of 3 microliters per injection. The animals were sacrificed at 8 weeks post injury (wpi), and the bladders harvested and weighed. Tissue was stained using hematoxylin and eosin and Masson’s trichrome. RESULTS: SCI without bladder chemodenervation (SCI-saline injected) resulted in significantly heavier bladders compared to the bladders of control (spinal-intact) animals (241±25 mg vs. 137±30 mg; p<0.01). BoNT-A injected bladders of SCI rats (SCI-BoNT-A) were significantly lighter compared to saline injected bladders of SCI rats (183±42 mg vs. 241±25 mg; p<0.05). SCI-saline rats had thicker bladder walls due to detrusor hypertrophy and fibrosis compared to bladders from control animals (339±89 mm vs. 193±48 mm; p<0.0002). Bladder wall thickness in the SCI-BoNT-A rats was significantly less compared to SCI-saline rats (202±55 mm vs. 339±89 mm; p<0.0001) (Figure). CONCLUSIONS: Chemodenervation immediately following SCI significantly mitigates the development of pathologic detrusor histology by reducing the development of fibrosis and hypertrophy. Source of Funding: William E. Bradley Family Foundation © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e444-e444 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zin Khiang More articles by this author Juliana Bushnell More articles by this author Jeffrey Hyde More articles by this author Claire Yang More articles by this author Expand All Advertisement Loading ...

Alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss

Synucleinopathies are neurodegenerative diseases in which α-synuclein protein accumulates in neurons and glia. In these diseases, α-synuclein forms dense intracellular aggregates that are disease hallmarks and actively contribute to tissue pathology. Interestingly, many pathological mechanisms, including iron accumulation and lipid peroxidation, are shared between classical synucleinopathies such as Alzheimer’s disease, Parkinson’s disease and traumatic spinal cord injury (SCI). However, to date, no studies have determined if α-synuclein accumulation occurs after human SCI. To examine this, cross-sections from injured and non-injured human spinal cords were immunolabeled for α-synuclein. This showed robust α-synuclein accumulation in profiles resembling axons and astrocytes in tissue surrounding the injury, revealing that α-synuclein markedly aggregates in traumatically injured human spinal cords. We also detected significant iron deposition in the injury site, a known catalyst for α-synuclein aggregation. Next a rodent SCI model mimicking the histological features of human SCI revealed aggregates and structurally altered monomers of α-synuclein are present after SCI. To determine if α-synuclein exacerbates SCI pathology, α-synuclein knockout mice were tested. Compared to wild type mice, α-synuclein knockout mice had significantly more spared axons and neurons and lower pro-inflammatory mediators, macrophage accumulation, and iron deposition in the injured spinal cord. Interestingly, locomotor analysis revealed that α-synuclein may be essential for dopamine-mediated hindlimb function after SCI. Collectively, the marked upregulation and long-lasting accumulation of α-synuclein and iron suggests that SCI may fit within the family of synucleinopathies and offer new therapeutic targets for promoting neuron preservation and improving function after spinal trauma.