Combined use of CLP290 and bumetanide alleviates neuropathic pain and its mechanism after spinal cord injury in rats.

AIM: We aimed to explore whether the combination of CLP290 and bumetanide maximally improves neuropathic pain following spinal cord injury (SCI) and its possible molecular mechanism. METHODS: Rats were randomly divided into five groups: Sham, SCI + vehicle, SCI + CLP290, SCI + bumetanide, and SCI + combination (CLP290 + bumetanide). Drug administration commenced on the 7th day post-injury (7 dpi) and continued for 14 days. All rats underwent behavioral assessments for 56 days to comprehensively evaluate the effects of interventions on mechanical pain, thermal pain, cold pain, motor function, and other relevant parameters. Electrophysiological assessments, immunoblotting, and immunofluorescence detection were performed at different timepoints post-injury, with a specific focus on the expression and changes of KCC2 and NKCC1 proteins in the lumbar enlargement of the spinal cord. RESULTS: CLP290 and bumetanide alleviated SCI-associated hypersensitivity and locomotor function, with the combination providing enhanced recovery. The combined treatment group exhibited the most significant improvement in restoring Rate-Dependent Depression (RDD) levels. In the combined treatment group and the two individual drug administration groups, the upregulation of potassium chloride cotransporter 2 (K+-Cl-cotransporter 2, KCC2) expression and downregulation of sodium potassium chloride cotransporter 1 (Na+-K+-Cl-cotransporter 1, NKCC1) expression in the lumbar enlargement area resulted in a significant increase in the KCC2/NKCC1 ratio compared to the SCI + vehicle group, with the most pronounced improvement seen in the combined treatment group. Compared to the SCI + vehicle group, the SCI + bumetanide group showed no significant paw withdrawal thermal latency (PWTL) improvement at 21 and 35 dpi, but a notable enhancement at 56 dpi. In contrast, the SCI + CLP290 group significantly improved PWTL at 21 days, with non-significant changes at 35 and 56 days. At 21 dpi, KCC2 expression was marginally higher in monotherapy groups versus SCI + vehicle, but not significantly. At 56 dpi, only the SCI + bumetanide group showed a significant difference in KCC2 expression compared to the control group. CONCLUSION: Combined application of CLP290 and bumetanide effectively increases the ratio of KCC2/NKCC1, restores RDD levels, enhances GABAA receptor-mediated inhibitory function in the spinal cord, and relieves neuropathic pain in SCI; Bumetanide significantly improves neuropathic pain in the long term, whereas CLP290 demonstrates a notable short-term effect.

Neuronal repair after spinal cord injury by in vivo astrocyte reprogramming mediated by the overexpression of NeuroD1 and Neurogenin-2.

BACKGROUND: As a common disabling disease, irreversible neuronal death due to spinal cord injury (SCI) is the root cause of functional impairment; however, the capacity for neuronal regeneration in the developing spinal cord tissue is limited. Therefore, there is an urgent need to investigate how defective neurons can be replenished and functionally integrated by neural regeneration; the reprogramming of intrinsic cells into functional neurons may represent an ideal solution. METHODS: A mouse model of transection SCI was prepared by forceps clamping, and an adeno-associated virus (AAV) carrying the transcription factors NeuroD1 and Neurogenin-2(Ngn2) was injected in situ into the spinal cord to specifically overexpress these transcription factors in astrocytes close to the injury site. 5-bromo-2´-deoxyuridine (BrdU) was subsequently injected intraperitoneally to continuously track cell regeneration, neuroblasts and immature neurons marker expression, neuronal regeneration, and glial scar regeneration. In addition, immunoprotein blotting was used to measure the levels of transforming growth factor-ß (TGF-ß) pathway-related protein expression. We also evaluated motor function, sensory function, and the integrity of the blood-spinal cord barrier(BSCB). RESULTS: The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord was achieved by specific AAV vectors. This intervention led to a significant increase in cell regeneration and the proportion of cells with neuroblasts and immature neurons cell properties at the injury site(p < 0.0001). Immunofluorescence staining identified astrocytes with neuroblasts and immature neurons cell properties at the site of injury while neuronal marker-specific staining revealed an increased number of mature astrocytes at the injury site. Behavioral assessments showed that the intervention did not improve The BMS (Basso mouse scale) score (p = 0.0726) and gait (p > 0.05), although the treated mice had more sensory sensitivity and greater voluntary motor ability in open field than the non-intervention mice. We observed significant repair of the BSCB at the center of the injury site (p < 0.0001) and a significant improvement in glial scar proliferation. Electrophysiological assessments revealed a significant improvement in spinal nerve conduction (p < 0.0001) while immunostaining revealed that the levels of TGF-ß protein at the site of injury in the intervention group were lower than control group (p = 0.0034); in addition, P70 s6 and PP2A related to the TGF-ß pathway showed ascending trend (p = 0.0036, p = 0.0152 respectively). CONCLUSIONS: The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord after spinal cord injury can reprogram astrocytes into neurons and significantly enhance cell regeneration at the injury site. The reprogramming of astrocytes can lead to tissue repair, thus improving the reduced threshold and increasing voluntary movements. This strategy can also improve the integrity of the blood-spinal cord barrier and enhance nerve conduction function. However, the simple reprogramming of astrocytes cannot lead to significant improvements in the striding function of the lower limbs.

Acute non-traffic traumatic spinal cord injury in the aging population: Analysis of the National Inpatient Sample 2005-2018.

BACKGROUND: This study aimed to determine risk factors for poor in-hospital outcomes in a large cohort of older adult patients with acute non-traffic traumatic spinal cord injury (tSCI). METHODS: This is a population-based, retrospective, observational study. Data of older adults ≥65 years with a primary discharge diagnosis of acute non-traffic tSCI were extracted from the US National Inpatient Sample (NIS) database 2005-2018. Traffic-related tSCI admissions or patients lacking complete data on age, sex and outcomes of interest were excluded. Univariate and multivariate logistic regression analysis was used to determine associations between variables and in-hospital outcomes. RESULTS: Data of 49,449 older patients (representing 246,939 persons in the US) were analyzed. The mean age was 79.9 years. Multivariable analyses revealed that severe International Classification of Disease (ICD)-based injury severity score (ICISS) (adjusted odds ratio [aOR] = 3.14, 95% confidence interval [CI]: 2.77-3.57), quadriplegia (aOR = 2.79, 95%CI: 2.34-3.32), paraplegia (aOR = 2.60, 95%CI:1.89-3.58), cervical injury with vertebral fracture (aOR = 2.19, 95%CI: 1.90-2.52), and severe liver disease (aOR = 2.33, 95%CI: 1.34-4.04) were all strong independent predictors of in-hospital mortality. In addition, malnutrition (aOR = 3.19, 95% CI: 2.93-3.48) was the strongest predictors of prolonged length of stay (LOS). CONCLUSIONS: Several critical factors for in-hospital mortality, unfavorable discharge, and prolonged LOS among US older adults with acute non-traffic tSCI were identified. In addition to the factors associated with initial severity, the presence of severe liver disease and malnutrition emerged as strong predictors of unfavorable outcomes, highlighting the need for special attention for these patient subgroups.

Inhibition of phospholipase D promotes neurological function recovery and reduces neuroinflammation after spinal cord injury in mice.

Introduction: Spinal cord injury (SCI) is a severely disabling disease. Hyperactivation of neuroinflammation is one of the main pathophysiological features of secondary SCI, with phospholipid metabolism playing an important role in regulating inflammation. Phospholipase D (PLD), a critical lipid-signaling molecule, is known to be involved in various physiological processes, including the regulation of inflammation. Despite this knowledge, the specific role of PLD in SCI remains unclear. Methods: In this study, we constructed mouse models of SCI and administered PLD inhibitor (FIPI) treatment to investigate the efficacy of PLD. Additionally, transcriptome sequencing and protein microarray analysis of spinal cord tissues were conducted to further elucidate its mechanism of action. Results: The results showed that PLD expression increased after SCI, and inhibition of PLD significantly improved the locomotor ability, reduced glial scarring, and decreased the damage of spinal cord tissues in mice with SCI. Transcriptome sequencing analysis showed that inhibition of PLD altered gene expression in inflammation regulation. Subsequently, the protein microarray analysis of spinal cord tissues revealed variations in numerous inflammatory factors. Biosignature analysis pointed to an association with immunity, thus confirming the results obtained from transcriptome sequencing. Discussion: Collectively, these observations furnish compelling evidence supporting the anti-inflammatory effect of FIPI in the context of SCI, while also offering important insights into the PLD function which may be a potential therapeutic target for SCI.

Impact of inflammation and Treg cell regulation on neuropathic pain in spinal cord injury: mechanisms and therapeutic prospects.

Spinal cord injury is a severe neurological trauma that can frequently lead to neuropathic pain. During the initial stages following spinal cord injury, inflammation plays a critical role; however, excessive inflammation can exacerbate pain. Regulatory T cells (Treg cells) have a crucial function in regulating inflammation and alleviating neuropathic pain. Treg cells release suppressor cytokines and modulate the function of other immune cells to suppress the inflammatory response. Simultaneously, inflammation impedes Treg cell activity, further intensifying neuropathic pain. Therefore, suppressing the inflammatory response while enhancing Treg cell regulatory function may provide novel therapeutic avenues for treating neuropathic pain resulting from spinal cord injury. This review comprehensively describes the mechanisms underlying the inflammatory response and Treg cell regulation subsequent to spinal cord injury, with a specific focus on exploring the potential mechanisms through which Treg cells regulate neuropathic pain following spinal cord injury. The insights gained from this review aim to provide new concepts and a rationale for the therapeutic prospects and direction of cell therapy in spinal cord injury-related conditions.

Impact of Frailty on Inpatient Outcomes of Acute Traumatic Spinal Cord Injury: Evidence From US National Inpatient Sample.

OBJECTIVES: Spinal cord injury (SCI) is any spinal cord injury or affliction that results in temporary or permanent impairment of motor or sensory function. This study determined the prevalence of frailty and its impact on in-hospital outcomes of patients admitted with acute traumatic SCI (TSCI). METHODS: This retrospective study extracted data of adults 18 to 85 years with acute TSCI from the US Nationwide Inpatient Sample (NIS) 2016 to 2018. Frailty status were assessed by the 11-factor modified Frailty Index (mFI-11) through claim codes. Patients with an mFI ≥3 were classified as frail. Associations between study variables and in-hospital mortality, discharge status, prolonged length of stay, severe infection, and hospital costs were determined by univariate and multivariable regression analyses. RESULTS: A total of 52,263 TSCI patients were identified, where 12,203 (23.3%) patients were frail. After adjusting for relevant confounders, frailty was independently associated with increased risk for in-hospital mortality [adjusted odds ratio (aOR) = 1.25, 95% CI:1.04-1.49], unfavorable discharge (aOR =1.15, 95% CI: 1.09-1.22), prolonged length of stay (aOR =1.32, 95% CI: 1.24-1.40), and severe infection (aOR =2.52, 95% CI: 2.24-2.83), but not hospital cost. Stratified analyses revealed frailty was associated with higher unfavorable discharge and severe infection regardless of age, Charlson Comorbidity Index, and injury level. CONCLUSIONS: In acute TSCI, frailty is independently associated with increased risk for adverse inpatient outcomes in terms of in-hospital mortality, prolonged hospital stays, unfavorable discharge, and particularly severe infection.

The identification of new roles for nicotinamide mononucleotide after spinal cord injury in mice: an RNA-seq and global gene expression study.

Background: Nicotinamide mononucleotide (NMN), an important transforming precursor of nicotinamide adenine dinucleotide (NAD+). Numerous studies have confirmed the neuroprotective effects of NMN in nervous system diseases. However, its role in spinal cord injury (SCI) and the molecular mechanisms involved have yet to be fully elucidated. Methods: We established a moderate-to-severe model of SCI by contusion (70 kdyn) using a spinal cord impactor. The drug was administered immediately after surgery, and mice were intraperitoneally injected with either NMN (500 mg NMN/kg body weight per day) or an equivalent volume of saline for seven days. The central area of the spinal cord was harvested seven days after injury for the systematic analysis of global gene expression by RNA Sequencing (RNA-seq) and finally validated using qRT-PCR. Results: NMN supplementation restored NAD+ levels after SCI, promoted motor function recovery, and alleviated pain. This could potentially be associated with alterations in NAD+ dependent enzyme levels. RNA sequencing (RNA-seq) revealed that NMN can inhibit inflammation and potentially regulate signaling pathways, including interleukin-17 (IL-17), tumor necrosis factor (TNF), toll-like receptor, nod-like receptor, and chemokine signaling pathways. In addition, the construction of a protein-protein interaction (PPI) network and the screening of core genes showed that interleukin 1ß (IL-1ß), interferon regulatory factor 7 (IRF 7), C-X-C motif chemokine ligand 10 (Cxcl10), and other inflammationrelated factors, changed significantly after NMN treatment. qRT-PCR confirmed the inhibitory effect of NMN on inflammatory factors (IL-1ß, TNF-α, IL-17A, IRF7) and chemokines (chemokine ligand 3, Cxcl10) in mice following SCI. Conclusion: The reduction of NAD+ levels after SCI can be compensated by NMN supplementation, which can significantly restore motor function and relieve pain in a mouse model. RNA-seq and qRT-PCR systematically revealed that NMN affected inflammation-related signaling pathways, including the IL-17, TNF, Toll-like receptor, NOD-like receptor and chemokine signaling pathways, by down-regulating the expression of inflammatory factors and chemokines.

The Effect of Glycine and N-Acetylcysteine on Oxidative Stress in the Spinal Cord and Skeletal Muscle After Spinal Cord Injury.

Oxidative stress is a frequently occurring pathophysiological feature of spinal cord injury (SCI) and can result in secondary injury to the spinal cord and skeletal muscle atrophy. Studies have reported that glycine and N-acetylcysteine (GlyNAC) have anti-aging and anti-oxidative stress properties; however, to date, no study has assessed the effect of GlyNAC in the treatment of SCI. In the present work, we established a rat model of SCI and then administered GlyNAC to the animals by gavage at a dose of 200 mg/kg for four consecutive weeks. The BBB scores of the rats were significantly elevated from the first to the eighth week after GlyNAC intervention, suggesting that GlyNAC promoted the recovery of motor function; it also promoted the significant recovery of body weight of the rats. Meanwhile, the 4-week heat pain results also suggested that GlyNAC intervention could promote the recovery of sensory function in rats to some extent. Additionally, after 4 weeks, the levels of glutathione and superoxide dismutase in spinal cord tissues were significantly elevated, whereas that of malondialdehyde was significantly decreased in GlyNAC-treated animals. The gastrocnemius wet weight ratio and total antioxidant capacity were also significantly increased. After 8 weeks, the malondialdehyde level had decreased significantly in spinal cord tissue, while reactive oxygen species accumulation in skeletal muscle had decreased. These findings suggested that GlyNAC can protect spinal cord tissue, delay skeletal muscle atrophy, and promote functional recovery in rats after SCI.

Glycine and N-Acetylcysteine (GlyNAC) Combined with Body Weight Support Treadmill Training Improved Spinal Cord and Skeletal Muscle Structure and Function in Rats with Spinal Cord Injury.

Skeletal muscle atrophy is a frequent complication after spinal cord injury (SCI) and can influence the recovery of motor function and metabolism in affected patients. Delaying skeletal muscle atrophy can promote functional recovery in SCI rats. In the present study, we investigated whether a combination of body weight support treadmill training (BWSTT) and glycine and N-acetylcysteine (GlyNAC) could exert neuroprotective effects, promote motor function recovery, and delay skeletal muscle atrophy in rats with SCI, and we assessed the therapeutic effects of the double intervention from both a structural and functional viewpoint. We found that, after SCI, rats given GlyNAC alone showed an improvement in Basso-Beattie-Bresnahan (BBB) scores, gait symmetry, and results in the open field test, indicative of improved motor function, while GlyNAC combined with BWSTT was more effective than either treatment alone at ameliorating voluntary motor function in injured rats. Meanwhile, the results of the skeletal muscle myofiber cross-sectional area (CSA), hindlimb grip strength, and acetylcholinesterase (AChE) immunostaining analysis demonstrated that GlyNAC improved the structure and function of the skeletal muscle in rats with SCI and delayed the atrophication of skeletal muscle.

Mechanism of skeletal muscle atrophy after spinal cord injury: A narrative review.

Spinal cord injury leads to loss of innervation of skeletal muscle, decreased motor function, and significantly reduced load on skeletal muscle, resulting in atrophy. Factors such as braking, hormone level fluctuation, inflammation, and oxidative stress damage accelerate skeletal muscle atrophy. The atrophy process can result in skeletal muscle cell apoptosis, protein degradation, fat deposition, and other pathophysiological changes. Skeletal muscle atrophy not only hinders the recovery of motor function but is also closely related to many systemic dysfunctions, affecting the prognosis of patients with spinal cord injury. Extensive research on the mechanism of skeletal muscle atrophy and intervention at the molecular level has shown that inflammation and oxidative stress injury are the main mechanisms of skeletal muscle atrophy after spinal cord injury and that multiple pathways are involved. These may become targets of future clinical intervention. However, most of the experimental studies are still at the basic research stage and still have some limitations in clinical application, and most of the clinical treatments are focused on rehabilitation training, so how to develop more efficient interventions in clinical treatment still needs to be further explored. Therefore, this review focuses mainly on the mechanisms of skeletal muscle atrophy after spinal cord injury and summarizes the cytokines and signaling pathways associated with skeletal muscle atrophy in recent studies, hoping to provide new therapeutic ideas for future clinical work.

MicroRNAs in spinal cord injury: A narrative review.

Spinal cord injury (SCI) is a global medical problem with high disability and mortality rates. At present, the diagnosis and treatment of SCI are still lacking. Spinal cord injury has a complex etiology, lack of diagnostic methods, poor treatment effect and other problems, which lead to the difficulty of spinal cord regeneration and repair, and poor functional recovery. Recent studies have shown that gene expression plays an important role in the regulation of SCI repair. MicroRNAs (miRNAs) are non-coding RNA molecules that target mRNA expression in order to silence, translate, or interfere with protein synthesis. Secondary damage, such as oxidative stress, apoptosis, autophagy, and inflammation, occurs after SCI, and differentially expressed miRNAs contribute to these events. This article reviews the pathophysiological mechanism of miRNAs in secondary injury after SCI, focusing on the mechanism of miRNAs in secondary neuroinflammation after SCI, so as to provide new ideas and basis for the clinical diagnosis and treatment of miRNAs in SCI. The mechanisms of miRNAs in neurological diseases may also make them potential biomarkers and therapeutic targets for spinal cord injuries.

In vivo astrocyte-to-neuron reprogramming for central nervous system regeneration: a narrative review.

The inability of damaged neurons to regenerate within the mature central nervous system (CNS) is a significant neuroscientific challenge. Astrocytes are an essential component of the CNS and participate in many physiological processes including blood-brain barrier formation, axon growth regulation, neuronal support, and higher cognitive functions such as memory. Recent reprogramming studies have confirmed that astrocytes in the mature CNS can be transformed into functional neurons. Building on in vitro work, many studies have demonstrated that astrocytes can be transformed into neurons in different disease models to replace damaged or lost cells. However, many findings in this field are controversial, as the source of new neurons has been questioned. This review summarizes progress in reprogramming astrocytes into neurons in vivo in animal models of spinal cord injury, brain injury, Huntington's disease, Parkinson's disease, Alzheimer's disease, and other neurodegenerative conditions.

Sodium selenite promotes neurological function recovery after spinal cord injury by inhibiting ferroptosis.

Ferroptosis is a recently discovered form of iron-dependent cell death, which occurs during the pathological process of various central nervous system diseases or injuries, including secondary spinal cord injury. Selenium has been shown to promote neurological function recovery after cerebral hemorrhage by inhibiting ferroptosis. However, whether selenium can promote neurological function recovery after spinal cord injury as well as the underlying mechanism remain poorly understood. In this study, we injected sodium selenite (3 µL, 2.5 µM) into the injury site of a rat model of T10 vertebral contusion injury 10 minutes after spinal cord injury modeling. We found that sodium selenite treatment greatly decreased iron concentration and levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal. Furthermore, sodium selenite increased the protein and mRNA expression of specificity protein 1 and glutathione peroxidase 4, promoted the survival of neurons and oligodendrocytes, inhibited the proliferation of astrocytes, and promoted the recovery of locomotive function of rats with spinal cord injury. These findings suggest that sodium selenite can improve the locomotive function of rats with spinal cord injury possibly through the inhibition of ferroptosis via the specificity protein 1/glutathione peroxidase 4 pathway.

Combined selective peripheral neurotomy in the treatment of spastic lower limbs of spinal cord injury patients.

OBJECTIVE: To explore the therapeutic effect of combined selective peripheral neurotomy (cSPN) on the spasm of the lower limbs after spinal cord injury. METHODS: A prospective intervention (before-after trial) with an observational design was conducted in 14 spinal cord injury patients with severe lower limbs spasticity by cSPN. Given the severe spasm of hip adductor, triceps surae, and hamstring muscles in these patients, a total of 26 obturator nerve branches, 26 tibia nerve branches, and 4 sciatic nerve branches partial neurotomy were performed. The modified Ashworth scale, composite spasticity scale, surface electromyography, gait analysis, functional ambulation category, spinal cord independence measure, and modified spinal cord injury-spasticity evaluation tool were used before and after surgery. RESULTS: Compared with preoperative, the spasm of the hip adductor, triceps surae, and hamstrings of the lower limbs in the postoperative patients decreased significantly. The abnormal gait of knee flexion and varus in the standing stage were significantly reduced. The grading of walking ability and activities of daily living were significantly improved. CONCLUSIONS: Combined selective peripheral neurotomy can significantly reduce the spasm of lower limbs post spinal cord injury, improve abnormal gait, and improve motor function and activities of daily living. TRIAL REGISTRATION: ChiCTR1800019003 (2018-10-20).

The Overexpression of Insulin-Like Growth Factor-1 and Neurotrophin-3 Promote Functional Recovery and Alleviate Spasticity After Spinal Cord Injury.

Objective: This study was conducted to investigate the effects of the exogenous overexpression of nerve growth factors NT-3 and IGF-1 on the recovery of nerve function after spinal cord injury (SCI) and identify the potential mechanism involved. Methods: Sixty-four female SD rats were randomly divided into four groups: an SCI group, an adeno-associated viral (AAV)-RFP and AAV-GFP injection group, an AAV-IGF-1 and AAV-NT-3 injection group, and a Sham group. After grouping, the rats were subjected to a 10-week electrophysiological and behavioral evaluation to comprehensively evaluate the effects of the intervention on motor function, spasticity, mechanical pain, and thermal pain. Ten weeks later, samples were taken for immunofluorescence (IF) staining and Western blot (WB) detection, focusing on the expression of KCC2, 5-HT2A, and 5-HT2C receptors in motor neurons and the spinal cord. Results: Electrophysiological and behavioral data indicated that the AAV-IGF-1 and AAV-NT-3 groups showed better recovery of motor function (P < 0.05 from D14 compared with the AAV-RFP + AAV-GFP group; P < 0.05 from D42 compared with SCI group) and less spasticity (4-10 weeks, at 5 Hz all P < 0.05 compared with SCI group and AAV- RFP + AAV-GFP group) but with a trend for more pain sensitivity. Compared with the SCI group, the von Frey value result of the AAV-IGF-1 and AAV-NT-3 groups showed a lower pain threshold (P < 0.05 at 4-8 weeks), and shorter thermal pain threshold (P < 0.05 at 8-10 weeks). IF staining further suggested that compared with the SCI group, the overexpression of NT-3 and IGF-1 in the SCI-R + G group led to increased levels of KCC2 (p < 0.05), 5-HT2A (p < 0.05), and 5-HT2C (p < 0.001) in motor neurons. WB results showed that compared with the SCI group, the SCI-R + G group exhibited higher expression levels of CHAT (p < 0.01), 5-HT2A (p < 0.05), and 5-HT2C (p < 0.05) proteins in the L2-L6 lumbar enlargement. Conclusion: Data analysis showed that the overexpression of NT-3 and IGF-1 may improve motor function after SCI and alleviate spasms in a rat model; however, these animals were more sensitive to mechanical pain and thermal pain. These behavioral changes may be related to increased numbers of KCC2, 5-HT2A, and 5-HT2C receptors in the spinal cord tissue. The results of this study may provide a new theoretical basis for the clinical treatment of SCI.

The role of KCC2 and NKCC1 in spinal cord injury: From physiology to pathology.

The balance of ion concentrations inside and outside the cell is an essential homeostatic mechanism in neurons and serves as the basis for a variety of physiological activities. In the central nervous system, NKCC1 and KCC2, members of the SLC12 cation-chloride co-transporter (CCC) family, participate in physiological and pathophysiological processes by regulating intracellular and extracellular chloride ion concentrations, which can further regulate the GABAergic system. Over recent years, studies have shown that NKCC1 and KCC2 are essential for the maintenance of Cl- homeostasis in neural cells. NKCC1 transports Cl- into cells while KCC2 transports Cl- out of cells, thereby regulating chloride balance and neuronal excitability. An imbalance of NKCC1 and KCC2 after spinal cord injury will disrupt CI- homeostasis, resulting in the transformation of GABA neurons from an inhibitory state into an excitatory state, which subsequently alters the spinal cord neural network and leads to conditions such as spasticity and neuropathic pain, among others. Meanwhile, studies have shown that KCC2 is also an essential target for motor function reconstruction after spinal cord injury. This review mainly introduces the physiological structure and function of NKCC1 and KCC2 and discusses their pathophysiological roles after spinal cord injury.

Effects of highly selective sympathectomy on neurogenic bowel dysfunction in spinal cord injury rats.

Neurogenic bowel dysfunction, including hyperreflexic and areflexic bowel, is a common complication in patients with spinal cord injury (SCI). We hypothesized that removing part of the colonic sympathetic innervation can alleviate the hyperreflexic bowel, and investigated the effect of sympathectomy on the hyperreflexic bowel of SCI rats. The peri-arterial sympathectomy of the inferior mesenteric artery (PSIMA) was performed in T8 SCI rats. The defecation habits of rats, the water content of fresh faeces, the intestinal transmission function, the defecation pressure of the distal colon, and the down-regulation of Alpha-2 adrenergic receptors in colon secondary to PSIMA were evaluated. The incidence of typical hyperreflexic bowel was 95% in SCI rats. Compared to SCI control rats, PSIMA increased the faecal water content of SCI rats by 5-13% (P < 0.05), the emptying rate of the faeces in colon within 24 h by 14-40% (P < 0.05), and the defecation pressure of colon by 10-11 mmHg (P < 0.05). These effects lasted for at least 12 weeks after PSIMA. Immunofluorescence label showed the secondary down-regulation of Alpha-2 adrenergic receptors after PSIMA occurred mainly in rats' distal colon. PSIMA mainly removes the sympathetic innervation of the distal colon, and can relieve the hyperreflexic bowel in rats with SCI. The possible mechanism is to reduce the inhibitory effect of sympathetic activity, and enhance the regulatory effect of parasympathetic activity on the colon. This procedure could potentially be used for hyperreflexic bowel in patients with SCI.

Effect of electromyographic biofeedback training on motor function of quadriceps femoris in patients with incomplete spinal cord injury: A randomized controlled trial.

BACKGROUND: Electromyographic biofeedback (EMG BF) training is an effective method of promoting motor learning and control in neurorehabilitation, but its effect on quadriceps femoris muscle in individuals with spinal cord injury (SCI) is unknown. OBJECTIVE: The aim of the study was to investigate the therapeutic effect of EMG BF training on motor function of quadriceps femoris in patients with incomplete SCI. METHODS: Thirty-three incomplete paraplegic patients with quadriceps femoris strength ranging grade 1 to grade 3 less than 6 months post-injury were enrolled. Control group (n = 16) received conventional physical therapy to enhance quadriceps femoris strength, while intervention group (n = 17) was treated with conventional physical therapy and EMG BF training. All received treatment once a day for 30 days. Surface electromyograph (sEMG), muscle strength and thigh circumference size were assessed to evaluate motor function of quadriceps femoris. Activities of daily living (ADL) was evaluated by Modified Barthel Index (MBI). All the measures evaluated three times in total. RESULTS: Compared to the control group, intervention group significantly improved on sEMG values and strength of quadriceps femoris (PsEMG < 0.001, Pstrength < 0.05). sEMG values of quadriceps femoris increased earlier than strength of quadriceps femoris in intervention group (Prest = 0.07, Pactive = 0.031). There were no statistical differences in thigh circumference size and ADL scores between groups (Pthigh > 0.05, PADL = 0.423). CONCLUSIONS: EMG BF training appeared to be a useful tool to enhance motor function of quadriceps femoris in patients with incomplete SCI. sEMG could quantify the changes of single muscle myodynamia precisely before visible or touchable changes occur.

Cortical morphometric changes associated with completeness, level, and duration of spinal cord injury in humans: A case-control study.

OBJECTIVE: This study investigated how the injury completeness, level, and duration of spinal cord injury (SCI) affect cortical morphometric changes in humans. METHODS: T1-weighted images were acquired from 59 SCI patients and 37 healthy controls. Voxel-based morphometry analyses of the gray matter volume (GMV) were performed between SCI patients and healthy controls, complete SCI and incomplete SCI, and tetraplegia and paraplegia. Correlation analyses were performed to explore the associations between GMV and clinical variables in SCI patients. RESULTS: Compared to healthy controls, SCI patients showed decreased GMV in bilateral middle frontal gyrus, left superior frontal gyrus (SFG), left medial frontal gyrus in the whole-brain analysis, while increased GMV in right supplementary motor area and right pallidum in ROI analysis. The complete SCI had lower GMV in left primary somatosensory cortex (S1) and higher GMV in left primary motor cortex compared with incomplete SCI. Lower GMV was identified in left thalamus and SFG in tetraplegia than that in paraplegia. Moreover, time since injury was positive with the GMV in right pallidum, positive correlations were observed between the GMV in bilateral S1 and total motor and sensory scores, whereas the GMV in left cuneus was negatively correlated with total motor and sensory scores in SCI patients. CONCLUSIONS: The study provided imaging evidence for identifying cerebral structural abnormalities in SCI patients and significant differences in complete/incomplete and paraplegia/tetraplegia subgroups. These results suggested brain structural changes occur after SCI and these changes may depend on the injury completeness, level, and duration.

The changing demographics of traumatic spinal cord injury in Beijing, China: a single-centre report of 2448 cases over 7 years.

STUDY DESIGN: Retrospective study. OBJECTIVES: To investigate the epidemiological changes in persons with traumatic spinal cord injury (TSCI) over the past 7 years in Beijing Bo'ai Hospital, China Rehabilitation Research Center, China. SETTING: Beijing Bo'ai Hospital, China Rehabilitation Research Center (CRRC). METHODS: A database containing the records of all persons treated with SCI from 1 January 2013 to 31 December 2019 was reviewed. Variables including demographic and clinical data were analysed. Comparisons were made with data previously published in 2002. RESULTS: During the study period, 2448 persons with recent TSCI were included in the analysis. The mean age at the time of injury increased from 38.1 years to 40.2 years (P = 0.025). The percentage of elderly persons increased (8.8-14.6%, P = 0.036) and was higher than that in 2002. The percentage of retirees increased. Transport related injuries were the leading cause of injury and the percentage of TSCI due to low falls increased 6%. Low falls were the most common cause for elderly persons (y ≥ 60) and were even higher for elderly women. Persons with cervical injuries increased compared to the 2002-data (44.1% vs 4.9%). The percentage of persons with incomplete SCI increased significantly over the study duration. CONCLUSIONS: Persons with TSCI are becoming older, and the percentage of elderly persons is increasing year by year. These changes are likely due to a combination of population ageing in the region and changes in aetiology, with corresponding changes including an increase in persons with cervical TSCI and persons with incomplete injury.