Spinal Cord Transection Research Articles

Developmental Changes in Locomotion and Sensorimotor Reflexes Following Spinal Cord Transection.

The developmental trajectory of weight-bearing locomotion and sensorimotor reflexes following a spinal cord injury, as well as the mechanisms for plasticity, remain unclear. In rats, the second postnatal week is a critical period for the development and recovery of spinal sensorimotor function. The purpose of the present study was to characterize developmental changes during this time frame to provide a basis for potential interventions and future research. Rats underwent a complete low-thoracic (T8-T10) spinal cord transection surgery, or sham procedure, on postnatal day (P)1. Spontaneous locomotion and sensorimotor reflexes (surface righting, hindlimb placing, and crossed-extensor reflex) were tested on P7, P14, or P21. Results show that spinal-transected and sham rats exhibited the same amount of spontaneous locomotion, but the degree of relative weight bearing on the hindlimbs was different between groups and changed over time. Reflex findings showed that throughout the neonatal period, the isolated lumbar spinal cord can respond to sensory input and execute coordinated motor output following spinal cord transection. These insights contribute to understanding the developmental trajectory of spinal cord function after injury and provide a foundation for interventions to enhance recovery outcomes.

Muscle-restricted knockout of connexin 43 and connexin 45 accelerates and improves locomotor recovery after contusion spinal cord injury.

Traumatic spinal cord injury (SCI) results in the disruption of physiological systems below the level of the spinal lesion. Connexin hemichannels (CxHCs) are membrane-bound, non-selective pore proteins that are lost in mature myofibers but reappear de novo on the sarcolemma after peripheral denervation, chronic SCI, diabetes, and severe systemic stress such as sepsis. Cx43 and Cx45 have been implicated as the major CxHCs present in diseased muscle, and muscle-restricted knockout of these genes reduces muscle atrophy after denervation, likely by reducing excess calcium influx with resultant inflammasome activation. A muscle-restricted Cx43/45 conditional knockout (mKO) mouse model was developed and tested to check whether it would improve outcomes following either a complete spinal cord transection at the level of thoracic vertebrae-9 (T9) or a motor-incomplete T9 impact-contusion SCI. mKO had no effect on the body mass after complete T9 transection. There was reduced atrophy of the plantaris 15 days post-SCI that was not associated with molecular markers of inflammation, hypertrophic/atrophic protein signaling, or protein and mRNA expression related to mitochondrial integrity and function. mKO mice had faster and greater locomotor recovery across 28 days after a motor-incomplete contusion SCI with no differences in spared white matter; male mKO mice generally had greater muscle mass than genotype controls post-injury, but muscle sparing was not observed in female mKO mice post-injury. The data establish a new paradigm where muscle Cx43/45 may contribute to the tissue crosstalk that determines the neuromuscular function of sub-lesional musculature after motor-incomplete SCI in a sex-dependent manner. Our novel findings should promote investigation to develop innovative treatment strategies to improve the function and quality of life for persons with SCI.

A biodegradable piezoelectric scaffold promotes spinal cord injury nerve regeneration

Neural repair and regeneration remain one of the greatest challenges in regenerative medicine. The incorporation of intelligent scaffolds with noninvasive in vivo electrical stimulation illustrates considerable potential for tissue repair and regeneration. Nevertheless, the development of biomaterials that possess both biodegradable tissue scaffolds and electrical stimulation capabilities at a high level remains a significant obstacle. In this study, we effectively integrated the organic piezoelectric material poly-L-lactic acid (PLLA) with inorganic piezoelectric nanowires (potassium sodium niobate coated with polydopamine, KNN@PDA) to fabricate PLLA/KNN@PDA piezoelectric composite fibers. These fibers exhibit in-situ electrical stimulation capabilities, rendering them suitable for direct application in living tissues. The PLLA/KNN@PDA piezoelectric composite fibers not only function as biodegradable scaffolds for regenerative tissue engineering and platforms for in-situ electrical stimulation to enhance dorsal root ganglion axon growth, proliferation, and neuronal differentiation but also serve as versatile scaffolds for broader tissue engineering applications. In the complete spinal cord transection rat model, the piezoelectric scaffold enabled the recovery of rat motor function, indicating its significant ability to promote tissue formation and regeneration. Therefore, combining biodegradable piezoelectric tissue scaffolds with in situ electrical stimulation has significant therapeutic advantages for spinal cord injury repair and may be extended to other damaged tissues regeneration.

Case Report: Aspirated Airway Foreign Body Mimicking Endobronchial Mass: A Diagnostic Challenge

Abstract Introduction/Objective Despite advancements in imaging modalities, identifying retained foreign bodies within the lung remains arduous. Detecting small foreign bodies is crucial as they can serve as a focal point for subsequent infections. Initial assessments may mimic malignancy. Herein, we present a case of a retained foreign body masquerading as an endobronchial mass, accompanied by unilateral pleural effusion and persistent hypoxia. Subsequent bronchoscopy showed a pearly white endobronchial mass partially obstructing the segmental bronchus at the posterior basal segment of the right lower lobe of lung with accompanying right pleural effusion and atelectasis. Methods/Case Report This is a 58-year-old male with history of hypertension, deep vein thrombosis, transient ischemic attack, and a recent motor vehicle accident with blunt chest trauma. He had a thoracic spinal cord transection with grade III blunt thoracic aortic injury, developed anasarca, hypoxia, right pleural fluid requiring multiple thoracentesis, and right sided hemothorax requiring massive transfusion protocol. Subsequent evaluations, including bronchoscopic transbronchial forceps biopsies and bronchial wash and pleural fluid cytologic examinations showed no malignant cells. Repeat bronchoscopy was concerning for enlarging mass and obstruction. Bronchoscopy almost 2 months after MVA revealed an endobronchial foreign body (tooth) lodged in the left lower lobe of lung posterior segment. Results (if a Case Study enter NA) N/A Conclusion While aspiration of foreign bodies into the tracheobronchial tree is not uncommon especially in children, foreign bodies, particularly teeth, are rare in adults. Bronchial foreign body aspiration may occur in trauma, with diagnosis typically relying on history and physical examination. Detection remains challenging despite imaging advancements, with implications including infection nidus formation. In our case, delayed diagnosis highlights the importance of considering unusual etiologies in persistent pulmonary pathology. Retrospective imaging analysis and CT findings suggested a foreign body, emphasizing the utility of imaging in suspected cases. Prompt surgical intervention is crucial to prevent complications such as recurrent infections.

Recovery of independent ambulation after complete spinal cord transection in the presence of the neuroprotectant polyethylene glycol in monkeys

ObjectiveDespite the conventional belief that motor function and sensation distal to the site of a complete spinal cord transection are irretrievable, our research has demonstrated significant motor recovery in mice, rats, and dogs by applying polyethylene glycol (PEG) topically via a syringe directly to the contact interface of transected spinal cord. However, before implementing this technology in human subjects, validating PEG's efficacy and enduring impact through experimentation on non-human primates is imperative. MethodsTwo 4-year-old female Macaca fascicularis monkeys underwent complete dorsal cord transection at T10. Postoperative behavioral assessment, electrophysiologic monitoring, and neuroimaging examinations were recorded, and tissues were obtained for histological examination at the end of study. ResultsThe monkey whose spinal cord had been fully transected in the presence of PEG developed useful recovery already at 3 months and near-complete recovery of motor function in the hind-limbs at 18 months. The control animal without PEG remained paralyzed. Cortical somatosensory evoked potentials recovered postoperatively only in PEG-treated monkey vs none in the control. Diffusion tensor imaging showed re-establishment of continuity of the white matter in PEG-treated monkey, but not in the control. Moreover, histology revealed intact neuronal bodies, axons, and myelin tissue at the spinal cord transection site in PEG-treated monkey only. ConclusionThis report suggests that in primates, an acutely transected spinal cord can be re-fused in the presence of PEG with restoration of neural continuity and functional recovery of motor activity distal to the site of transection.

Effect of moxibustion on ATP-sensitive potassium channel (KATP) of bladder in detrusor overactivity rats.

To observe the effect of ginger-salt-partitioned moxibustion on ATP-sensitive potassium (KATP) channel of bladder in detrusor overactivity (DO) rats. Female SD rats were randomly divided into sham operation, model, moxibustion and antagonist groups (n=9 in each group). Thorax (T) 10 spinal cord transection was performed by surgery. Ginger-salt partitioned moxibustion was applied to "Shenque" (CV8) for 3 cones, once daily for 14 consecutive days. Rats of the antagonist group were intraperitoneally injected with KATP channel specific antagonist glibenclamide (10 μg·kg-1·d-1) once daily for 14 consecutive days. Urodynamic tests were performed after treatment. The distribution and expression of KATP channel tetrameric subunit (SUR2B) in the bladder of rats was observed by immunofluorescence. The protein and mRNA expression levels of SUR2B in bladder tissue were detected by Western blot and qPCR respectively. Compared with the sham operation group, rats of the model group showed intensive and large phasic contractions of the detrusor during bladder filling, the frequency and amplitude of phasic contractions of the detrusor 5 min before leakage were significantly increased (P<0.001)；the voiding threshold pressure was significantly decreased (P<0.001)；the bladder perfusion volume was increased (P<0.001)；the SUR2B protein and mRNA expression in bladder tissue were significantly reduced (P<0.001). Compared with the model group and the antagonist group, the above-mentioned indicators in the moxibustion group were all reversed (P<0.01, P<0.001, P<0.05). Ginger-salt partitioned moxibustion can reduce the frequency and amplitude of detrusor phase contraction during bladder filling and prolong the time of first phase contraction in DO rats, which may be associated with up-regulating the expression level of KATP channel protein and mRNA, promoting the outflow of potassium ions, and inhibiting the inflow of calcium ions, thus improve the stability of detrusor during storage.

Urinary dysfunction after spinal cord injury: Comparing outcomes after thoracic spinal transection and contusion in the rat

Spinal cord injury (SCI) above the lumbosacral spinal cord induces loss of voluntary control over micturition. Spinal cord transection (SCT) was the gold standard method to reproduce SCI in rodents, but its translational value is arguable and other experimental SCI methods need to be better investigated, including spinal cord contusion (SCC). At present, it is not fully investigated if urinary impairments arising after transection and contusion are comparable. To explore this, we studied bladder-reflex activity and lower urinary tract (LUT) and spinal cord innervation after SCT and different severities of SCC. Severe-contusion animals presented a longer spinal shock period and the tendency for higher residual volumes, followed by SCT and mild-contusion animals. Urodynamics showed that SCT animals presented higher basal and peak bladder pressures. Immunostaining against growth-associated protein-43 (GAP43) and calcitonin gene-related peptide (CGRP) at the lumbosacral spinal cord demonstrated that afferent sprouting is dependent on the injury model, reflecting the severity of the lesion, with a higher expression in SCT animals. In LUT organs, the expression of GAP43, CGRP cholinergic (vesicular acetylcholine transporter (VAChT)) and noradrenergic (tyrosine hydroxylase (TH)) markers was reduced after SCI in the LUT and lumbosacral cord, but only the lumbosacral expression of VAChT was dependent on the injury model. Overall, our findings demonstrate that changes in LUT innervation and function after contusion and transection are similar but result from distinct neuroplastic processes at the lumbosacral spinal cord. This may impact the development of new therapeutic options for urinary impairment arising after spinal cord insult.

Involvement of vimentin- and BLBP-positive glial cells and their MMP expression in axonal regeneration after spinal cord transection in goldfish.

In goldfish, spinal cord injury triggers the formation of a fibrous scar at the injury site. Regenerating axons are able to penetrate the scar tissue, resulting in the recovery of motor function. Previous findings suggested that regenerating axons enter the scar through tubular structures surrounded by glial elements with laminin-positive basement membranes and that glial processes expressing glial fibrillary acidic protein (GFAP) are associated with axonal regeneration. How glia contribute to promoting axonal regeneration, however, is unknown. Here, we revealed that glial processes expressing vimentin or brain lipid-binding protein (BLBP) also enter the fibrous scar after spinal cord injury in goldfish. Vimentin-positive glial processes were more numerous than GFAP- or BLBP-positive glial processes in the scar tissue. Regenerating axons in the scar tissue were more closely associated with vimentin-positive glial processes than GFAP-positive glial processes. Vimentin-positive glial processes co-expressed matrix metalloproteinase (MMP)-14. Our findings suggest that vimentin-positive glial processes closely associate with regenerating axons through tubular structures entering the scar after spinal cord injury in goldfish. In intact spinal cord, ependymo-radial glial cell bodies express BLBP and their radial processes express vimentin, suggesting that vimentin-positive glial processes derive from migrating ependymo-radial glial cells. MMP-14 expressed in vimentin-positive glial cells and their processes might provide a beneficial environment for axonal regeneration.

Transplantation of Predegenerated Peripheral Nerves after Complete Spinal Cord Transection in Rats: Effect of Neural Precursor Cells and Pharmacological Treatment with the Sulfoglycolipid Tol-51.

Following spinal cord injury (SCI), the regenerative capacity of the central nervous system (CNS) is severely limited by the failure of axonal regeneration. The regeneration of CNS axons has been shown to occur by grafting predegenerated peripheral nerves (PPNs) and to be promoted by the transplantation of neural precursor cells (NPCs). The introduction of a combinatorial treatment of PPNs and NPCs after SCI has to address the additional problem of glial scar formation, which prevents regenerating axons from leaving the implant and making functional connections. Previously, we discovered that the synthetic sulfoglycolipid Tol-51 inhibits astrogliosis. The objective was to evaluate axonal regeneration and locomotor function improvement after SCI in rats treated with a combination of PPN, NPC, and Tol-51. One month after SCI, the scar tissue was removed and replaced with segments of PPN or PPN+Tol-51; PPN+NPC+Tol-51. The transplantation of a PPN segment favors regenerative axonal growth; in combination with Tol-51 and NPC, 30% of the labeled descending corticospinal axons were able to grow through the PPN and penetrate the caudal spinal cord. The animals treated with PPN showed significantly better motor function. Our data demonstrate that PPN implants plus NPC and Tol-51 allow successful axonal regeneration in the CNS.

Changes in contractile characteristics of rat skeletal muscles associated with P2-receptor activation after spinal cord transection

Introduction. Traumatic spinal cord and peripheral-nerve injury is associated with release of proinflammatory cytokines and chemokines, which may stimulate neuronal activity. Adenosine triphosphoric acid (ATP) is an important pain mediator involved in the acute and chronic neuropathic pain development. Its excessive release from primary injured tissue leads to activation of P2-receptors, which may further start secondary injury mechanisms. Although the effects of ATP on the peripheral nervous system are relatively well studied, the pathophysiological role of purinergic signaling after spinalization remains unclear. The study was aimed at assessing the post-spinalization effects of P2-receptors on the contractile characteristics of rat skeleton muscles. Materials and methods. The objects of the study were the soleus muscle, the extensor digitorum longus (EDL) muscle, and diaphragm in intact rats and spinalized rats. Seven days after laminectomy followed by spinal cord transection, animals were anesthetized, exsanguinated, and their muscles with nerve stumps were isolated. Contractile response parameters were recorded using mechanomyography (MMG). To study effects of ATP on ligand binding, ATP was added to a bath and mechanical responses in the rat muscles were assessed 7 min after. After washing with Krebs–Henseleit solution, the preparations were incubated with suramin solution for 20 min with subsequent ATP application. Then the mechanical responses in the muscles were again recorded. Statistical significance was assessed using Student's t-test for independent (unpaired) and paired samples. Results. We found a significant (p 0.05) decrease in the modulating activity of ATP, as the main endogenous signaling agent, in the cholinergic synapse of the soleus muscle from 32.4 to 5.8% and from 13.7 to 5.6% for the EDL muscle after the spinalization (spinal cord injury at the Th6–Th7 level) compared with intact animals. No such dramatic changes were observed in the diaphragm. Conclusions. Abnormal ATP-mediated modulation of neuromuscular transmission demonstrated in this study supports the involvement of purinergic signaling in the neurotrophic control and functioning of various motor units.

Regeneration of Propriospinal Axons in Rat Transected Spinal Cord Injury through a Growth-Promoting Pathway Constructed by Schwann Cells Overexpressing GDNF.

Unsuccessful axonal regeneration in transected spinal cord injury (SCI) is mainly attributed to shortage of growth factors, inhibitory glial scar, and low intrinsic regenerating capacity of severely injured neurons. Previously, we constructed an axonal growth permissive pathway in a thoracic hemisected injury by transplantation of Schwann cells overexpressing glial-cell-derived neurotrophic factor (SCs-GDNF) into the lesion gap as well as the caudal cord and proved that this novel permissive bridge promoted the regeneration of descending propriospinal tract (dPST) axons across and beyond the lesion. In the current study, we subjected rats to complete thoracic (T11) spinal cord transections and examined whether these combinatorial treatments can support dPST axons' regeneration beyond the transected injury. The results indicated that GDNF significantly improved graft-host interface by promoting integration between SCs and astrocytes, especially the migration of reactive astrocyte into SCs-GDNF territory. The glial response in the caudal graft area has been significantly attenuated. The astrocytes inside the grafted area were morphologically characterized by elongated and slim process and bipolar orientation accompanied by dramatically reduced expression of glial fibrillary acidic protein. Tremendous dPST axons have been found to regenerate across the lesion and back to the caudal spinal cord which were otherwise difficult to see in control groups. The caudal synaptic connections were formed, and regenerated axons were remyelinated. The hindlimb locomotor function has been improved.

Integrating hydrogels manipulate ECM deposition after spinal cord injury for specific neural reconnections via neuronal relays.

A bioinspired hydrogel composed of hyaluronic acid-graft-dopamine (HADA) and a designer peptide HGF-(RADA)4-DGDRGDS (HRR) was presented to enhance tissue integration following spinal cord injury (SCI). The HADA/HRR hydrogel manipulated the infiltration of PDGFRβ+ cells in a parallel pattern, transforming dense scars into an aligned fibrous substrate that guided axonal regrowth. Further incorporation of NT3 and curcumin promoted axonal regrowth and survival of interneurons at lesion borders, which served as relays for establishing heterogeneous axon connections in a target-specific manner. Notable improvements in motor, sensory, and bladder functions resulted in rats with complete spinal cord transection. The HADA/HRR + NT3/Cur hydrogel promoted V2a neuron accumulation in ventral spinal cord, facilitating the recovery of locomotor function. Meanwhile, the establishment of heterogeneous neural connections across the hemisected lesion of canines was documented in a target-specific manner via neuronal relays, significantly improving motor functions. Therefore, biomaterials can inspire beneficial biological activities for SCI repair.

Effects of low-intensity extracorporeal shock wave on bladder and urethral dysfunction in spinal cord injured rats.

To investigate the effects of low-intensity extracorporeal shock wave therapy (LiESWT) on bladder and urethral dysfunction with detrusor overactivity and detrusor sphincter dyssynergia (DSD) resulting from spinal cord injury (SCI). At 3 weeks after Th9 spinal cord transection, LiESWT was performed on the bladder and urethra of adult female Sprague Dawley rats with 300 shots of 2Hz and an energy flux density of 0.12mJ/mm2, repeated four times every 3 days, totaling 1200 shots. Six weeks postoperatively, a single cystometrogram (CMG) and an external urethral sphincter electromyogram (EUS-EMG) were simultaneously recorded in awake animals, followed by histological evaluation. Voiding efficiency significantly improved in the LiESWT group (71.2%) compared to that in the control group (51.8%). The reduced EUS activity ratio during voiding (duration of reduced EUS activity during voiding/EUS contraction duration with voiding + duration of reduced EUS activity during voiding) was significantly higher in the LiESWT group (66.9%) compared to the control group (46.3%). Immunohistochemical examination revealed that fibrosis in the urethral muscle layer was reduced, and S-100 stained-positive area, a Schwann cell marker, was significantly increased in the urethra of the LiESWT group. LiESWT targeting the urethra after SCI can restore the EUS-EMG tonic activity during voiding, thereby partially ameliorating DSD. Therefore, LiESWT is a promising approach for treating bladder and urethral dysfunction following SCI.

An injectable COL6-crosslinked HA-DTPH hydrogel promotes spinal tract-like structure organization during spinal cord regeneration

Serious spinal cord injury (SCI) often leads to disorganized axon regeneration, impeding the accurate projection of neural signals. This study aims to rebuild spinal tracts by targeting the collagen VI (COL6)-induced axonal fasciculation pathway, which is active during spinal cord development but diminishes in regenerating spinal cord. A thiol-modified hyaluronic acid hydrogel crosslinked with COL6 (HAPC) is proposed to reactivate spinal tract morphogenesis for regeneration. Neurites cultured on the HAPC substrate exhibited a straight-bundled pattern, contrasting with the straggly pattern observed in control groups that lacked COL6. The dynamics of axonal aggregation and proximal retraction are determined to drive the formation of straight axon bundles. Experiments on a rat spinal cord transection model demonstrates that treatment with HAPC significantly induces the organization of spinal tract-like structures and promotes the targeted projection of 5-Hydroxytryptamine (5-HT) axons, along with improved functional recovery. These findings highlight the role of COL6 in spinal tract self-organization and the potential of HAPC for treating clinical SCI.

Disruption of Core Stress Granule Protein Aggregates Promotes CNS Axon Regeneration.

Depletion or inhibition of core stress granule proteins, G3BP1 in mammals and TIAR-2 in C. elegans , increases axon regeneration in injured neurons that show spontaneous regeneration. Inhibition of G3BP1 by expression of its acidic or 'B-domain' accelerates axon regeneration after nerve injury bringing a potential therapeutic intervention to promote neural repair in the peripheral nervous system. Here, we asked if G3BP1 inhibition is a viable strategy to promote regeneration in the injured mammalian central nervous system where axons do not regenerate spontaneously. G3BP1 B-domain expression was found to promote axon regeneration in both the mammalian spinal cord and optic nerve. Moreover, a cell permeable peptide to a subregion of G3BP1's B-domain (rodent G3BP1 amino acids 190-208) accelerated axon regeneration after peripheral nerve injury and promoted the regrowth of reticulospinal axons into the distal transected spinal cord through a bridging peripheral nerve graft. The rodent and human G3BP1 peptides promoted axon growth from rodent and human neurons cultured on permissive substrates, and this function required alternating Glu/Asp-Pro repeats that impart a unique predicted tertiary structure. These studies point to G3BP1 granules as a critical impediment to CNS axon regeneration and indicate that G3BP1 granule disassembly represents a novel therapeutic strategy for promoting neural repair after CNS injury.

Complete cervical spinal cord transection cephalad to noncontiguous sub-axial vertical distraction injury: a rare complex injury case report, surgical technique and literature review

Complete cervical spinal cord transection cephalad to noncontiguous sub-axial vertical distraction injury: a rare complex injury case report, surgical technique and literature review

Developing preclinical dog models for reconstructive severed spinal cord continuity via spinal cord fusion technique

BackgroundSpinal cord injury (SCI) is a severe impairment of the central nervous system, leading to motor, sensory, and autonomic dysfunction. The present study investigates the efficacy of the polyethylene glycol (PEG)-mediated spinal cord fusion (SCF) techniques, demonstrating efficacious in various animal models with complete spinal cord transection at the T10 level. This research focuses on a comparative analysis of three SCF treatment models in beagles: spinal cord transection (SCT), vascular pedicle hemisected spinal cord transplantation (vSCT), and vascularized allograft spinal cord transplantation (vASCT) surgical model. MethodsSeven female beagles were included in the SCT surgical model, while four female dogs were enrolled in the vSCT surgical model. Additionally, twelve female dogs underwent vASCT in a paired donor-recipient setup. Three surgical model were evaluated and compared through electrophysiology, imaging and behavioral recovery. ResultsThe results showed a progressive recovery in the SCT, vSCT and vASCT surgical models, with no statistically significant differences observed in cBBB scores at both 2-month and 6-month post-operation (both P>0.05). Neuroimaging analysis across the SCT, vSCT and vASCT surgical models revealed spinal cord graft survival and fiber regrowth across transection sites at 6 months postoperatively. Also, positive MEP waveforms were recorded in all three surgical models at 6-month post-surgery. ConclusionThe study underscores the clinical relevance of PEG-mediated SCF techniques in promoting nerve fusion, repair, and motor functional recovery in SCI. SCT, vSCT, and vASCT, tailored to specific clinical characteristics, demonstrated similar effective therapeutic outcomes.

Improved Recovery of Complete Spinal Cord Transection by a Plasma-Modified Fibrillar Scaffold.

Complete spinal cord injury causes an irreversible disruption in the central nervous system, leading to motor, sensory, and autonomic function loss, and a secondary injury that constitutes a physical barrier preventing tissue repair. Tissue engineering scaffolds are presented as a permissive platform for cell migration and the reconnection of spared tissue. Iodine-doped plasma pyrrole polymer (pPPy-I), a neuroprotective material, was applied to polylactic acid (PLA) fibers and implanted in a rat complete spinal cord transection injury model to evaluate whether the resulting composite implants provided structural and functional recovery, using magnetic resonance (MR) imaging, diffusion tensor imaging and tractography, magnetic resonance spectroscopy, locomotion analysis, histology, and immunofluorescence. In vivo, MR studies evidenced a tissue response to the implant, demonstrating that the fibrillar composite scaffold moderated the structural effects of secondary damage by providing mechanical stability to the lesion core, tissue reconstruction, and significant motor recovery. Histologic analyses demonstrated that the composite scaffold provided a permissive environment for cell attachment and neural tissue guidance over the fibers, reducing cyst formation. These results supply evidence that pPPy-I enhanced the properties of PLA fibrillar scaffolds as a promising treatment for spinal cord injury recovery.

Improvement of lower urinary tract dysfunction by a monoacylglycerol lipase inhibitor in mice with spinal cord injury.

Activation of the endocannabinoid system by monoacylglycerol lipase (MAGL) blockade may affect the lower urinary tract function. We investigated the effect of an MAGL inhibitor, MJN110, on neurogenic lower urinary tract dysfunction (LUTD) in the mouse model of spinal cord injury (SCI). Female C57BL/6 mice that underwent spinal cord transection at T8-10 level were divided into three groups consisting of (1) vehicle-treated SCI mice, (2) 5 mg/kg, or (3) 10 mg/kg of MJN110-treated SCI mice. MJN110 and vehicle were administered intraperitoneally for 7 days from 4 weeks after spinal cord transection. We then conducted awake cystometrograms and compared urodynamic parameters between three groups. The expression of cannabinoid (CB) receptors, TRP receptors, and inflammatory cytokines in L6-S1 dorsal root ganglia (DRG) or the bladder mucosa were evaluated and compared among three groups. Changes in the level of serum 2-arachidonoylglycerol (2-AG) and bladder MAGL were also evaluated. In the cystometrogram, detrusor overactivity (DO) parameters, such as the number of nonvoiding contraction (NVC), a ratio of time to the 1st NVC to intercontraction interval (ICI), and NVC integrals were improved by MJN110 treatment, and some effects were dose dependent. Although MJN110 did not improve voiding efficiency, it decreased bladder capacity, ICI, and residual urine volume compared to vehicle injection. MJN110 treatment groups had lower CB2, TRPV1, TRPA1, and inflammatory cytokines mRNA levels in DRG and bladder mucosa. Serum 2-AG was increased,and bladder MAGL was decreased after MAGL inhibitor treatment. MAGL inhibition improved LUTD including attenuation of DO after SCI. Thus, MAGL can be a therapeutic target for neurogenic LUTD after SCI.

The Left-Right Side-Specific Neuroendocrine Signaling from Injured Brain: An Organizational Principle.

A neurological dogma is that the contralateral effects of brain injury are set through crossed descending neural tracts. We have recently identified a novel topographic neuroendocrine system (T-NES) that operates via a humoral pathway and mediates the left-right side-specific effects of unilateral brain lesions. In rats with completely transected thoracic spinal cords, unilateral injury to the sensorimotor cortex produced contralateral hindlimb flexion, a proxy for neurological deficit. Here, we investigated in acute experiments whether T-NES consists of left and right counterparts and whether they differ in neural and molecular mechanisms. We demonstrated that left- and right-sided hormonal signaling is differentially blocked by the δ-, κ- and µ-opioid antagonists. Left and right neurohormonal signaling differed in targeting the afferent spinal mechanisms. Bilateral deafferentation of the lumbar spinal cord abolished the hormone-mediated effects of the left-brain injury but not the right-sided lesion. The sympathetic nervous system was ruled out as a brain-to-spinal cord-signaling pathway since hindlimb responses were induced in rats with cervical spinal cord transections that were rostral to the preganglionic sympathetic neurons. Analysis of gene-gene co-expression patterns identified the left- and right-side-specific gene co-expression networks that were coordinated via the humoral pathway across the hypothalamus and lumbar spinal cord. The coordination was ipsilateral and disrupted by brain injury. These findings suggest that T-NES is bipartite and that its left and right counterparts contribute to contralateral neurological deficits through distinct neural mechanisms, and may enable ipsilateral regulation of molecular and neural processes across distant neural areas along the neuraxis.