Recovery Of Spinal Cord Injury Research Articles

Thermosensitive heparin-poloxamer hydrogel encapsulated bFGF and NGF to treat spinal cord injury.

The application of growth factors (GFs) for treating chronic spinal cord injury (SCI) has been shown to promote axonal regeneration and functional recovery. However, direct administration of GFs is limited by their rapid degradation and dilution at the injured sites. Moreover, SCI recovery is a multifactorial process that requires multiple GFs to participate in tissue regeneration. Based on these facts, controlled delivery of multiple growth factors (GFs) to lesion areas is becoming an attractive strategy for repairing SCI. Presently, we developed a GFs‐based delivery system (called GFs‐HP) that consisted of basic fibroblast growth factor (bFGF), nerve growth factor (NGF) and heparin‐poloxamer (HP) hydrogel through self‐assembly mode. This GFs‐HP was a kind of thermosensitive hydrogel that was suitable for orthotopic administration in vivo. Meanwhile, a 3D porous structure of this hydrogel is commonly used to load large amounts of GFs. After single injection of GFs‐HP into the lesioned spinal cord, the sustained release of NGF and bFGF from HP could significantly improve neuronal survival, axon regeneration, reactive astrogliosis suppression and locomotor recovery, when compared with the treatment of free GFs or HP. Moreover, we also revealed that these neuroprotective and neuroregenerative effects of GFs‐HP were likely through activating the phosphatidylinositol 3 kinase and protein kinase B (PI3K/Akt) and mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MAPK/ERK) signalling pathways. Overall, our work will provide an effective therapeutic strategy for SCI repair.

Inhibiting an inhibitor: a decoy to recover dexterity after spinal cord injury.

This scientific commentary refers to ‘Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury’, by Wang et al. (doi:10.1093/brain/awaa116).

GRP78-Mediated Signaling Contributes to Axonal Growth Resulting in Motor Function Recovery in Spinal Cord-Injured Mice.

Promoting axonal growth is essential for repairing damaged neuronal connections and motor function in spinal cord injury (SCI). Neuroleukin (NLK) exerts axonal growth activity in vitro and in vivo, but the mechanism remains unclear. This study reveals that the 78-kDa glucose-regulated protein (GRP78) is a NLK neuronal receptor that contributes to recovery from SCI. Binding and immunoprecipitation assays indicated that NLK binds to GRP78. Pretreatment to cultured neurons with a GRP78-neutralizing antibody suppressed NLK-induced axonal growth. Blocking cell surface GRP78 inhibited neuronal NLK-induced Akt activation. Treatment with an Akt inhibitor suppressed NLK-induced axonal growth. Continuous administration of NLK into the lateral ventricle of SCI mice increased axonal density in the injured region and restored motor function, which was not observed when NLK was simultaneously administered with a GRP78-neutralizing antibody. These results indicate that GRP78 regulates the NLK-induced axonal growth activity; NLK-GRP78 signaling promotes motor function recovery in SCI, presenting as a potential therapeutic target.

A Selective P2Y Purinergic Receptor Agonist 2-MesADP Enhances Locomotor Recovery after Acute Spinal Cord Injury

Introduction: Spinal cord injury (SCI) causes most severe motor and sensory dysfunctions. In Chinese traditional medicine, the agonist of a purinergic receptor is believed to have a positive effect on SCIs, and 2-Methylthio-adenosine-5′-diphosphate (2-MesADP) is a selective agonist of the P2Y purinergic receptor. Methods: To investigate its therapeutic function and molecular mechanism in SCI, transcriptome analysis associated with weighted gene co-expression network analysis (WGCNA) was carried out at various time points after T9 crush injury. Results: 2-MesADP demonstrated recovery of limb motor function at the 6 weeks after injury, accompanied by neuronal regeneration and axon remyelination at 2 and 6 weeks. Furthermore, gene profiling revealed alternated gene expression with the treatment of 2-MesADP. These genes were assigned to a total of 38 modules, followed by gene ontology analysis; of these, 18 represented neuronal apoptosis and regeneration, immune response, synaptic transmission, cell cycle, and angiogenesis. In the neuronal apoptosis and regeneration module, Nefh, NeuroD6, and Dcx in the 2-MesADP group were noticed due to their interesting expression pattern. The gene expression patterns of Mag, Mog, and Cnp, which played key roles in myelination, were significantly changed with the treatment of 2-MesADP. Wnt signal pathway was the most important pathway in 2-MesADP treatment for acute SCI. Conclusion: 2-MesADP enhanced locomotor recovery in mouse SCI by altering the expression of neuronal apoptosis and remyelination-related genes and Wnt signaling pathways.

Proanthocyanidin promotes functional recovery of spinal cord injury via inhibiting ferroptosis

Improving the microenvironment of lesioned spinal cord to minimize the secondary injury is one important strategy to treat spinal cord injury (SCI). The ensuing hemorrhage after SCI has tight connection with ferroptosis. This study investigated the effects of proanthocyanidins (PACs) on SCI repair and the underlying mechanisms. Adult female mice were divided into four groups, including sham, SCI, PACs5 and PACs10 (i.p. 5 and 10 mg/kg PACs after SCI respectively). The impacts of SCI and PACs treatment on redox parameters (iron contents, TBARS, GSH, and GPX activities) and ferroptosis essential factors such as ACSL4, LPCAT3, Alox15B, Nrf2, HO-1, GPX4 were investigated. The results demonstrated that PACs treatment significantly decreased the levels of iron, TBARS, ACSL4, and Alox15B, while increased the levels of GSH, GPX4, Nrf2, and HO-1 in traumatic spinal cords. Above all, PACs improved the locomotive function of SCI mice. These results suggest that PACs might be potential therapeutics for SCI repair by inhibiting ferroptosis in SCI.

The first 24 h: opioid administration in people with spinal cord injury and neurologic recovery.

Retrospective chart review. The objective of this study was to characterize opioid administration in people with acute SCI and examine the association between opioid dose and (1) changes in motor/functional scores from hospital to rehabilitation discharge, and (2) pain, depression, and quality of life (QOL) scores 1-year post injury. Spinal Cord Injury Model System (SCIMS) inpatient acute rehabilitation facility. Patients included in the SCIMS from 2008 to 2011 were linked to the National Trauma Registry and the electronic medical record. Three opioid dose groups (low, medium, and high) were defined based on the total morphine equivalence in milligrams at 24 h. The associations between opioid dose groups and functional/motor outcomes were assessed, as well as 1-year follow-up pain and QOL surveys. In all, 85/180 patients had complete medication records. By 24 h, all patients had received opioids. Patients receiving higher amounts of opioids had higher pain scores 1 year later compared with medium- and low-dose groups (pain levels 5.5 vs. 4 vs. 1, respectively, p = 0.018). There was also an 8× greater risk of depression 1 year later in the high-dose group compared with the low-dose group (OR: 8.1, 95% CI: 1.2-53.7). In analyses of motor scores, we did not find a significant interaction between opioid dose and duration of injury. These preliminary findings suggest that higher doses of opioids administered within 24 h of injury are associated with increased pain in the chronic phase of people with SCI.

Beta-band oscillations as a biomarker of gait recovery in spinal cord injury patients: A quantitative electroencephalography analysis

ObjectiveThe gait recovery in spinal cord injury (SCI) seems to be partially related to the reorganization of cerebral function; however, the neural mechanisms and the respective biomarkers are not well known. This study tested the hypothesis that enhanced beta-band oscillations may be a marker of compensatory neural plasticity during the recovery period in SCI. We tested this hypothesis at baseline in SCI subjects and also in response to cortical stimulation with transcranial direct current stimulation (tDCS) combined with robotic-assisted gait training (RAGT). MethodsIn this neurophysiological analysis of a randomized controlled trial, thirty-nine patients with incomplete SCI were included. They received 30 sessions of either active or sham anodal tDCS over the primary motor area for 20 min combined with RAGT. We analyzed the Electroencephalography (EEG) power spectrum and task-related power modulation of EEG oscillations, and their association with gait function indexed by Walk Index for Spinal Cord Injury (WISCI-II). Univariate and multivariate linear/logistic regression analyses were performed to identify the predictors of gait function and recovery. ResultsConsistent with our hypothesis, we found that in the sensorimotor area: (1) Anodal tDCS combined with RAGT can modulate high-beta EEG oscillations power and enhance gait recovery; (2) higher high-beta EEG oscillations power at baseline can predict baseline gait function; (3) high-beta EEG oscillations power at baseline can predict gait recovery – the higher power at baseline, the better gait recovery; (4) decreases in relative high-beta power and increases in beta power decrease during walking are associated with gait recovery. ConclusionsEnhanced EEG beta oscillations in the sensorimotor area in SCI subjects may be part of a compensatory mechanism to enhance local plasticity. Our results point to the direction that interventions enhancing local plasticity such as tDCS combined with robotic training also lead to an immediate increase in sensorimotor cortex activation, improvement in gait recovery, and subsequent decrease in high-beta power. These findings suggest that beta-band oscillations may be potential biomarkers of gait function and recovery in SCI. SignificanceThese findings are significant for rehabilitation in SCI patients, and as EEG is a portable, inexpensive, and easy-to-apply system, the clinical translation is feasible to follow better the recovery process and to help to individualize rehabilitation therapies of SCI patients.

Acupuncture combined with moxibustion promote the recovery of spinal cord injury in correlation with Shh/Gli-1 signaling pathway

Objective: Acupuncture combined with moxibustion (AM) therapy has been applied to treat spinal cord injury (SCI), but the underlying mechanism is unclear. The present study aimed to confirm the effect and mechanism of AM treatment on the recovery of SCI. Design: Male Sprague–Dawley rats were used to establish the SCI model by impact method. SCI rat models were subjected to AM treatment at Dazhui (GV14) and Jiaji points (T7-T12), Yaoyangguan (GV3), Zusanli (ST36) and Ciliao (BL32). Outcome measures: Motor function and cell apoptosis in rats after SCI. The mRNA and protein expression levels of Shh and Gli-1 were determined by real-time quantitative polymerase chain reaction, western blot and immunohistochemistry. Results: After AM treatment, the hindlimb motor function of SCI rats was significantly increased than the SCI group at 7, 9, 11, 14 days (P < 0.05). AM treatment 7 d and 14 d significantly preserved the nissl-stained positive neurons and significantly decreased number of apoptotic cells, compared to that of SCI 7 and 14 d groups (P < 0.05). AM treatment improved the mRNA protein levels of Shh and Gli-1 after 7 and 14 days treatment compared to the SCI group (P < 0.05). Conclusion: AM could improve the expression of Shh and Gli-1 in injured spinal cord of rats. That could be part of underlying mechanisms of AM treatment including recover motor function and preserve the neuron cells and alleviate the apoptosis of nerve cells in rats after SCI.

Improved Functional Recovery in Rat Spinal Cord Injury Induced by a Drug Combination Administered with an Implantable Polymeric Delivery System.

Spinal cord injury (SCI) is an incurable condition, in which a cascade of cellular and molecular events triggered by inflammation and excitotoxicity impairs endogenous regeneration, namely remyelination and axonal outgrowth. We designed a treatment solution based on an implantable biomaterial (electrospun poly (l-lactic acid) [PLLA]) loaded with ibuprofen and triiodothyronine (T3) to counteract inflammation, thus improving endogenous regeneration. In vivo efficacy was tested by implanting the drug-loaded PLLA in the rat model of T8 contusion SCI. We observed the expected recovery of locomotion beginning on day 7. In PLLA-implanted rats (i.e., controls), the recovery stabilized at 21 days post-lesion (DPL), after which no further improvement was observed. On the contrary, in PLLA + ibuprofen (Ibu) + T3 (PLLA-Ibu-T3) rats a further recovery and a significant treatment effect were observed, also confirmed by the gait analysis on 49 DPL. Glutamate release at 24 h and 8 DPL was reduced in PLLA-Ibu-T3- compared to PLLA-implanted rats, such as the estimated lesion volume at 60 DPL. The myelin- and 200-neurofilament-positive area fraction was higher in PLLA-Ibu-T3-implanted rats, where the percentage of astrocytes was significantly reduced. The implant of a PLLA electrospun scaffold loaded with Ibu and T3 significantly improves the endogenous regeneration, leading to an improvement of functional locomotion outcome in the SCI.

The Impact of Urgent (

The relationship between urgent decompression and neurologic recovery for traumatic spinal cord injury (TSCI) remains controversial. This meta-analysis was conducted to determine the beneficial effects of surgery within 8 hours for patients with TSCI. A systematic search in EMBASE, MEDLINE, Cochrane Library, and PubMed for relevant studies was conducted from the earliest records until December 2019. Studies that compared outcomes of early (<8 hours) surgery versus late (≥8 hours) surgery for patients with TSCI were selected for analysis. Nine cohort studies involving 716 participants met the eligibility criteria. Early (<8 hours) surgery for patients showed a more significant improvement in American Spinal Injury Association scores (standardized mean difference, 0.75, 95% confidence interval [CI], 0.51-0.99; P <0.05). Especially for patients with initial complete TSCI, neurologic improvement rate significantly increased in theearly surgery group (relative ratio [RR], 3.96; 95% CI, 2.02-7.76; P < 0.05), whereas in patients with initial incomplete TSCI, no significant differences were found between the 2 groups in neurologic improvement rate (RR, 1.41; 95% CI, 0.95-2.10; P > 0.05). There were no significant differences between the 2 groups in length of hospital stay (standardized mean difference, 0.34; 95% CI, -0.24 to 0.92; P >0.05) and complications (RR, 0.92; 95% CI, 0.70-1.22; P>0.05). This meta-analysis provides evidence of benefits from urgent (<8 hours) decompression for patients with TSCI in terms of neurologic recovery. The improvement effect is more definite in patients with initial complete TSCI.

Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury.

After CNS trauma such as spinal cord injury, the ability of surviving neural elements to sprout axons, reorganize neural networks and support recovery of function is severely restricted, contributing to chronic neurological deficits. Among limitations on neural recovery are myelin-associated inhibitors functioning as ligands for neuronal Nogo receptor 1 (NgR1). A soluble decoy (NgR1-Fc, AXER-204) blocks these ligands and provides a means to promote recovery of function in multiple preclinical rodent models of spinal cord injury. However, the safety and efficacy of this reagent in non-human primate spinal cord injury and its toxicological profile have not been described. Here, we provide evidence that chronic intrathecal and intravenous administration of NgR1-Fc to cynomolgus monkey and to rat are without evident toxicity at doses of 20 mg and greater every other day (≥2.0 mg/kg/day), and far greater than the projected human dose. Adult female African green monkeys underwent right C5/6 lateral hemisection with evidence of persistent disuse of the right forelimb during feeding and right hindlimb during locomotion. At 1 month post-injury, the animals were randomized to treatment with vehicle (n = 6) or 0.10-0.17 mg/kg/day of NgR1-Fc (n = 8) delivered via intrathecal lumbar catheter and osmotic minipump for 4 months. One animal was removed from the study because of surgical complications of the catheter, but no treatment-related adverse events were noted in either group. Animal behaviour was evaluated at 6-7 months post-injury, i.e. 1-2 months after treatment cessation. The use of the impaired forelimb during spontaneous feeding and the impaired hindlimb during locomotion were both significantly greater in the treatment group. Tissue collected at 7-12 months post-injury showed no significant differences in lesion size, fibrotic scar, gliosis or neuroinflammation between groups. Serotoninergic raphespinal fibres below the lesion showed no deficit, with equal density on the lesioned and intact side below the level of the injury in both groups. Corticospinal axons traced from biotin-dextran-amine injections in the left motor cortex were equally labelled across groups and reduced caudal to the injury. The NgR1-Fc group tissue exhibited a significant 2-3-fold increased corticospinal axon density in the cervical cord below the level of the injury relative to the vehicle group. The data show that NgR1-Fc does not have preclinical toxicological issues in healthy animals or safety concerns in spinal cord injury animals. Thus, it presents as a potential therapeutic for spinal cord injury with evidence for behavioural improvement and growth of injured pathways in non-human primate spinal cord injury.

Directional axonal regrowth induced by an aligned fibrin nanofiber hydrogel contributes to improved motor function recovery in canine L2 spinal cord injury.

Spinal cord injuries (SCI) normally disrupt the long axonal tracts of the spinal cord and cause permanent neurological deficits, for which there is currently a lack of effective therapeutic methods. Biomaterial-based regenerative medicine is a pivotal strategy to induce axonal regeneration through delivery of biophysical and/or biochemical regulatory cues by biomaterials. We previously fabricated a hierarchically aligned fibrin hydrogel (AFG) that could promote neurogenic differentiation of stem cells in vitro and has been successfully applied for peripheral nerve and spinal cord regeneration in rats. In this study, AFG was used to repair a canine lumbar segment 2 hemisection spinal cord injury, and the consistency of histological, imageological and behavioral results was compared. AFG was used to construct an aligned fiber bridge that supported cell adhesion in vitro and rapidly facilitated tissue invasion along the long axis of fibers in vivo, Moreover, in vivo results demonstrated regrowth of axons in an oriented pattern connecting the rostral and caudal stumps. Consistent results were confirmed by diffusion tensor imaging, which allowed successful tracing of reconnected nerve fibers across the defect. As a result, directional axonal regrowth contributed to significantly improved recovery of motor functional behavior of SCI canines with AFG implantation. Our results suggest that AFG has great promise for rapidly directing axonal regrowth for nerve regeneration.

Prospective evaluation of relationship between MRI findings and ASIA score to predict neurological recovery in acute traumatic spinal cord injury

The role of MRI in evaluating the acutely injured spine is well established and contributes to assessment of ligamentous disruption, associated disc protrusions as well as exact site of maximal canal stenosis and nature of cord injury; and neurological assessment as per ASIA score is an internationally accepted method.

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

Recovery from spinal cord injury (SCI) remains an unsolved problem. As a major component of the SCI lesion, the glial scar is primarily composed of scar-forming astrocytes and plays a crucial role in spinal cord regeneration. In recent years, it has become increasingly accepted that the glial scar plays a dual role in SCI recovery. However, the underlying mechanisms of this dual role are complex and need further clarification. This dual role also makes it difficult to manipulate the glial scar for therapeutic purposes. Here, we briefly discuss glial scar formation and some representative components associated with scar-forming astrocytes. Then, we analyze the dual role of the glial scar in a dynamic perspective with special attention to scar-forming astrocytes to explore the underlying mechanisms of this dual role. Finally, taking the dual role of the glial scar into account, we provide several pieces of advice on novel therapeutic strategies targeting the glial scar and scar-forming astrocytes.

Curcumin Promotes Recovery of Motor Function After Spinal Cord Injury in Rats Through Mammalian Target of Rapamycin (mTOR)-Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway

Objective: Curcumin possesses extensive therapeutic effects on several diseases and tumor cells, which has inhibitory effects on mammalian target of rapamycin (mTOR)-STAT3 signaling. Our study aims to explore the influences of curcumin on promoting the recovery of motor function after spinal cord injury (SCI) in rats through the mTOR-STAT3 signaling pathway. Methods : SCI rats were treated with rapamycin and curcumin followed by establishing rat models of SCI. The influences of rapamycin and curcumin on the protein expressions of PTEN, Akt, phosphorylated S6 and chondroitin sulphate proteoglycans (CSPGs) were measured by western blot. Means of Basso, Beattie and Bresnahan (BBB) locomotor rating scale was used to assess motor function. Results: After SCI, curcumin promoted the expression of PTEN, reduced the proliferation of neuroglia cells, affected the expressions of CSPGs and improved the motor function. Conclusion: Curcumin can promote motor function recovery after SCI which is possibly by up-regulating the PTEN expression via the mTOR-STAT3 signaling pathway.

Relationship (?) Between Histological and Functional Measures in Moderate Contusion SCI in Adult Rat

To create a spinal cord injury (SCI), most laboratories implement a standardized method; however, considerable variability in injury size and associated functional deficits can occur across subjects. The present study was initiated to explore relationships between the histological features of spinal cord (SC) lesion and the associated functional deficits in locomotor, respiratory, and lower urinary tract (LUT) function in a widely used rat contusion SCI model that is generated using an Infinite Horizon impactor. To this end, adult female rats (n=8) received a moderate mid‐thoracic contusion SCI (200 kdyn, T8), and the impact displacement and force were recorded. Indices of functional recovery included: (1) BBB open field locomotor scoring at 1‐week post SCI, (2) total volume of expressed urine during the first 2‐weeks post SCI, and (3) diaphragm EMG activity and reflex micturition behavior and residual urine volume recorded during an acute cystometry experiment at 4‐weeks post SCI, after which the bladder was removed and weighed. Following fixation (4% PFA) and cryoprotection of the SC, 20 μm thick horizonal sections were obtained and counterstained with cresyl violet and Cyanine R / FeCl3 to visualize cell bodies and myelin, respectively, and the section at the level of the central canal was used as the site for preliminary analysis of the extent of lesion damage and degree of white matter sparing. The lesion area ranged from 27–49% and was measured by outlining the perimeter of the lesion site using a threshold tool and then normalized (%) to the area of a standardized 7 mm rostral‐caudal length region of SC that included the injury site. Myelin thickness was measured at 3 sites at the level of the injury and at the rostral and caudal ends of the tissue (uninjured) on each side of the SC, and the injury site measurements were normalized to the average myelin thickness of the corresponding uninjured side. A spared myelin index (%) using the larger minimum myelin thickness from the right or left side of the SC was then determined and ranged from 19–91%. For generation of the SCI, impactor displacement varied from 1287 to 1728 μm, with larger displacements being associated with larger injury sites and less myelin sparing. The lesion area, however, was not a strong predictor of myelin sparing, particularly in cases with asymmetrical lesions (n=2). Both lesion area and spared myelin index were reasonable predictors of post SCI recovery of locomotor (BBB scores) and LUT (expressed urine volume) function but not in predicting the degree of dysfunction in reflex micturition (increased residual volume) and bladder hypertrophy or inspiratory burst measures and their variability. These preliminary results suggest that factors in addition to the histological characteristics of the lesion site contribute to the degree of functional deficits/recovery following SCI.Support or Funding InformationDOD CDMRP W81XWH‐17‐1‐0260; NIH NS096514; NYS DOH SCIRB C32088GG

MiR-384-5p promotes spinal cord injury recovery in rats through suppressing of autophagy and endoplasmic reticulum stress

BackgroundSpinal cord injury (SCI) is one of the most serious neurological disorders and is characterized by high morbidity and disability. Unfortunately, there is a lack of effective treatment. Recently, the micro RNA, miR-384-5p, was reported to play a significant role in cell survival in response to different insults. MethodsIn vitro model of traumatic neuronal injury was induced by application of a sharp sterile blade to generate cuts in PC12 cells, and in vivo SCI was produced by applying vascular clips (force of 15 g) to the dura via T9–T10 laminectomy, and then, the role of miR-384-5p in the development of SCI was investigated. ResultsDual-luciferase reporter assays confirmed that miR-384-5p regulates the gene expression of Beclin-1, an important promoter of autophagy. Quantitative polymerase chain reaction and western blot analyses revealed that treatment with miR-384-5p decreased mRNA and protein expression of Beclin-1 in the mechanically injured PC12 cells. In rats with spinal cord compression injuries, miR-384-5p expression was significantly decreased. Treatment with miR-384-5p increased spinal cord neuron survival and promoted locomotor function recovery in rats. Further study revealed that miR-384-5p administration decreased immunofluorescent labeling of Beclin-1 in spinal cord tissues and reduced autophagosome formation in neurons, as shown by transmission electron microscopy. These results indicated that miR-384-5p promotes recovery of rats with SCI by suppressing autophagy via direct targeting of Beclin-1. Moreover, miR-384-5p also inhibited the activation of endoplasmic reticulum (ER) stress by decreasing GRP78 expression in both in vitro and in vivo models. ConclusionsThis study for the first time demonstrates that the protective role of miR-384-5p in the process of SCI is associated with simultaneous suppression of autophagy and ER stress and miR-384-5p could be a promising candidate for SCI therapeutics.

Exosomes derived from GIT1-overexpressing bone marrow mesenchymal stem cells promote traumatic spinal cord injury recovery in a rat model

Objective This study aims to explore the effects of exosomes derived from G protein-coupled receptor kinase 2 interacting protein 1 (GIT1)-overexpressing bone marrow mesenchymal stem cell (GIT1-BMSC-Exos) on the treatment of traumatic spinal cord injury (SCI) in a rat model. Methods All the rats underwent a T10 laminectomy. A weight-drop impact was performed using a 10-g rod from a height of 12.5 mm except the sham group. Rats with SCI were distributed into three groups randomly and then treated with tail vein injection of GIT1-BMSCs-Exos, BMSCs-Exos and PBS, respectively. The effects of GIT1-Exos on glutamate (GLU)-induced apoptosis in vitro were also evaluated by TUNEL staining. Results The results showed that rats treated with GIT1-BMSCs-Exos had better functional behavioral recovery than those treated with PBS or BMSCs-Exos only. The overexpression of GIT1 in BMSCs-Exos not only restrained glial scar formation and neuroinflammation after SCI, but also attenuated apoptosis and promoted axonal regeneration in the injured lesion area. Neuronal cell death induced by GLU was controlled remarkably in vitro as well. Conclusion In conclusion, our study suggested that the application of GIT1-BMSCs-Exos may provide a novel avenue for traumatic SCI treatment.

Transsynaptic tracing and its emerging use to assess graft-reconstructed neural circuits.

Fetal neural progenitor grafts have been evaluated in preclinical animal models of spinal cord injury and Parkinson's disease for decades, but the initial reliance on primary tissue as a cell source limited the scale of their clinical translatability. With the development of robust methods to differentiate human pluripotent stem cells to specific neural subtypes, cell replacement therapy holds renewed promise to treat a variety of neurodegenerative diseases and injuries at scale. As these cell sources are evaluated in preclinical models, new transsynaptic tracing methods are making it possible to study the connectivity between host and graft neurons with greater speed and detail than was previously possible. To date, these studies have revealed that widespread, long-lasting, and anatomically appropriate synaptic contacts are established between host and graft neurons, as well as new aspects of host-graft connectivity which may be relevant to clinical cell replacement therapy. It is not yet clear, however, whether the synaptic connectivity between graft and host neurons is as cell-type specific as it is in the endogenous nervous system, or whether that connectivity is responsible for the functional efficacy of cell replacement therapy. Here, we review evidence suggesting that the new contacts established between host and graft neurons may indeed be cell-type specific, and how transsynaptic tracing can be used in the future to further elucidate the mechanisms of graft-mediated functional recovery in spinal cord injury and Parkinson's disease.

DBcAMP Rescues the Neurons From Degeneration in Kainic Acid-Injured Hippocampus, Enhances Neurogenesis, Learning, and Memory.

Dibutyryl cyclic adenosine monophosphate (dBcAMP) is a cell-permeable synthetic analog of cyclic adenosine monophosphate (cAMP). Although the elevation of cAMP levels was reported to promote the functional recovery in spinal cord injury, its role in neurogenesis or functional recovery after hippocampal injury is unknown. The objective of the study was to investigate the effects of dBcAMP on learning, memory, and hippocampal neurogenesis in the excitotoxically lesioned hippocampus. An excitotoxic lesion was induced in the hippocampi of 4-month-old male BALB/c mice by injecting 0.25 μg/μl into the lateral ventricles of both sides. The lesioned mice (L) were divided into L+dBcAMP and L+phosphate-buffered saline (PBS) groups. Sham surgery (S) was done by the injection of 1 μl of sterile saline into the lateral ventricles. The sham surgery mice were divided into S+dBcAMP and S+PBS groups. Mice in the L+dBcAMP and S+dBcAMP groups were treated with dBcAMP for 1 week (i.p., 50 mg/kg), whereas mice in the L+PBS and S+PBS groups were treated with PBS. The mice in all groups were subjected to water maze and passive avoidance tests at the end of the 4th week. Cresyl violet staining and NeuN and doublecortin immunostaining were done to analyze the morphology and neurogenesis. The water maze learning sessions did not show a significant difference in escape latency between the groups, suggesting an unimpaired learning ability of mice in all groups. The L+dBcAMP mice had significantly short entry latency and higher target quadrant time/distance traveled compared to the L+PBS group, suggesting better memory retention. The L+dBcAMP group had a significantly improved memory retention compared to the L+PBS mice during the passive avoidance test. Morphological studies showed significantly greater adult neurons and increased hippocampal neurogenesis in the hippocampus of mice in the L+dBcAMP group compared to those in the L+PBS group. There was no significant difference between the S+dBcAMP and S+PBS groups in the water maze/passive avoidance tests and the number of neurons. In conclusion, dBcAMP protects the hippocampal neuron from degeneration and enhances hippocampal neurogenesis, learning, and memory.