Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)mode...Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)models were established by colorectal distention in newborn rats aged 8 to 14 days,and visceral hypersensitivity was assessed using electromyogram(EMG).Oxytocin or saclofen was administered intrathecally to evaluate visceral hypersensitivity in the rats.The protein expressions of oxytocin receptor(OTR),γ-aminobutyric acid type B1 receptor(GABAB1),and transient receptor potential vanilloid 1(TRPV1)in the lumbosacral spinal cord regions were measured.IBS rats exhibited a unique spinal cord molecular signature comprising decreased OTR/GABAB1 and increased TRPV1 expression.Intrathecal oxytocin treatment not only normalized these molecular alterations(increasing GABAB1 while decreasing TRPV1)but also ameliorated visceral pain behaviors.Crucially,this therapeutic effect was fully reversed by GABAB1 inhibition,establishing the necessity of intact GABAergic signaling for oxytocin-mediated analgesia.Collectively,these findings indicate that oxytocin relieves visceral hypersensitivity through the regulation of GABAB1 and TRPV1 in the spinal cord of IBS rats.展开更多
Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in s...Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.展开更多
After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the tim...After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the timing of interventions,combined with the limitations of current methods.To address these challenges,various techniques have been developed to aid in the repair and reconstruction of neural circuits at different stages of injury.Notably,neuromodulation has garnered considerable attention for its potential to enhance nerve regeneration,provide neuroprotection,restore neurons,and regulate the neural reorganization of circuits within the cerebral cortex and corticospinal tract.To improve the effectiveness of these interventions,the implementation of multitarget early interventional neuromodulation strategies,such as electrical and magnetic stimulation,is recommended to enhance functional recovery across different phases of nerve injury.This review concisely outlines the challenges encountered following spinal cord injury,synthesizes existing neurostimulation techniques while emphasizing neuroprotection,repair,and regeneration of impaired connections,and advocates for multi-targeted,task-oriented,and timely interventions.展开更多
Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival a...Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.展开更多
Objective To research the direct electrophysiological evidence of discomplete spinal cord injury (SCI) and the effect of 4-aminopyridine on it.Methods Motor evoked potentials (MEPs), both spinal cord recorded MEPs (...Objective To research the direct electrophysiological evidence of discomplete spinal cord injury (SCI) and the effect of 4-aminopyridine on it.Methods Motor evoked potentials (MEPs), both spinal cord recorded MEPs (scMEPs) and extracellularly recorded MEPs (exMEPs) were recorded and characterized on a T13 epidural electrode (scMEPs) and an extracellular microelectrode (exMEPs) for 10 normal rats and 40 rats with lesions of various severity (sham, 35?g*cm force (gcf), 70?gcf, 100?gcf impact injury) at the T8-T9 cord using the Allen's drop model. The incline plane and Tarlov techniques were used to assess clinical neurological function. Results MEPs in the normal rats were elicited by applying transcortical suprathreshold stimulation consisting of 3-4 early negative peaks (N1, N2, N3 and N4) followed by several late waves. The N1 and N2 peaks were largest in the anterior and ventrolateral funiculus, respectively, which was indicative of extrapyramidal pathways. The 100?gcf impact injuries and the cord transection abolished the MEP distal to the lesion, whereas the 35?gcf injuries resulted in a latency shift and amplitude decrement of the MEP peaks. Eighteen of the 20 rats with 70?gcf injuries showed clinical paraplegia. Among them, 7 rats had neurophysiological evidence of residual conduction pathways through the lesioned cord segment, such as the presence of N1 and N2 peaks in the scMEPs or exMEPs. After 4-aminopyridine (4-AP) administrations (1?mg/kg), the amplitude of the spared exMEP increased significantly and spread more widely. Conclusions MEPs evoked by transcortical stimulation travel mostly in the extrapyramidal tract. MEP monitoring could provide an excellent method of detecting the functional integrity of the motor tracts after SCI, and could even detect spared motor fibers after discomplete SCI. Furthermore, the use of 4-AP or other K+ channel blocking agents may be a potential treatment for patients with chronic moderate to severe SCI.展开更多
Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and geneti...Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and genetic mechanisms and can be derived from an individual's somatic cells(e.g.,blood or skin).This enables patient-specific paradigms for precision neurotrauma research,pa rticula rly relevant to the over 300,000 people in the United States living with chronic effects of spinal cord injury(SCI).展开更多
Biological sex is increasingly recognized as a crucial factor in evaluating the translational value of preclinical spinal cord injury(SCI)studies.The rising incidence of SCI in females challenges the historical preced...Biological sex is increasingly recognized as a crucial factor in evaluating the translational value of preclinical spinal cord injury(SCI)studies.The rising incidence of SCI in females challenges the historical precedent of SCI being a male-dominated condition.In contrast,most basic science researchers utilize single-sex studies to minimize complications associated with bladder care in males(Stewart et al.,2020).The findings of our recent publication identify sexually dimorphic immune responses to SCI in both mice and pigs(Kumari et al.,2025).Here,we will highlight these findings and discuss the impact of sex on SCI inflammation and recovery.展开更多
The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system.After spinal cord injury,autophagic flux within endothelial cells is disrupted,compromising the integrity of the blood-...The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system.After spinal cord injury,autophagic flux within endothelial cells is disrupted,compromising the integrity of the blood-spinal cord barrier.This disruption facilitates extensive infiltration of inflammatory cells,resulting in exacerbated neuroinflammatory responses,neuronal death,and impaired neuronal regeneration.Previous research has demonstrated that photobiomodulation promotes the regeneration of damaged nerves following spinal cord injury by inhibiting the recruitment of inflammatory cells to the injured site and restoring neuronal mitochondrial function.However,the precise mechanisms by which photobiomodulation regulates neuroinflammation remain incompletely elucidated.In this study,we established a mouse model of spinal cord injury and assessed the effects of photobiomodulation treatment.Photobiomodulation effectively cleared damaged mitochondria from endothelial cells in mice,promoting recovery of hindlimb motor function.Using microvascular endothelial bEnd.3 cells subjected to oxygen-glucose deprivation,we found that the effects of photobiomodulation were mediated through activation of the PINK1/Parkin pathway.Additionally,photobiomodulation reduced mitochondrial oxidative stress levels and increased the expression of tight junction proteins within the blood-spinal cord barrier.Our findings suggest that photobiomodulation activates mitochondrial autophagy in endothelial cells through the PINK1/Parkin pathway,thereby promoting repair of the blood-spinal cord barrier following spinal cord injury.展开更多
The spinal cord links the brain and the peripheral nervous system and has important sensory and motor functions.Impairments in the spinal cord occur in different diseases,such as spinal cord injury,multiple sclerosis,...The spinal cord links the brain and the peripheral nervous system and has important sensory and motor functions.Impairments in the spinal cord occur in different diseases,such as spinal cord injury,multiple sclerosis,pain,motor neuron diseases,and neurodegenerative diseases.Imaging of the spinal cord has been challenging,partly due to its small size and deep anatomical location.Additionally,in an animal model,motion artifacts further influence the in vivo imaging quality of the spinal cord.Recent advances have pushed boundaries for in vivo imaging in living animals(even behaving animals).展开更多
Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathop...Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathophysiology:an initial primary injury(mechanical trauma,axonal disruption,and hemorrhage) is followed by a progressive secondary injury cascade that involves ischemia,neuronal loss,and inflammation.Given the challenges in achieving regeneration of the injured spinal cord,neuroprotection has been at the forefront of clinical research.展开更多
Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenes...Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenesis universally originates from ischemia/reperfusion(I/R)injury affecting the cerebral,spinal cord,and/or retina.展开更多
Traumatic spinal cord injury(SCI)is a debilitating condition characterized by the impairment of neural circuits,leading to the loss of motor and sensory functions and accompanied by severe complications.Substantial re...Traumatic spinal cord injury(SCI)is a debilitating condition characterized by the impairment of neural circuits,leading to the loss of motor and sensory functions and accompanied by severe complications.Substantial research has reported the therapeutic potential of Omega-3 fatty acids for the central nervous system,particularly after traumatic SCI.Omega-3 fatty acids may contribute to improving SCI recovery through their anti-inflammatory,anti-oxidative,neurotrophic,and membrane integrity-preserving properties.These functions of Omega-3 fatty acids are primarily mediated via the activation of G protein-coupled receptor 120(GPR120),commonly known as the fish oil-specific receptor.Advancements in understanding of the molecular mechanisms of GPR120’s recognition of Omega-3 fatty acids and its downstream signaling mechanisms has significantly promoted research on the pharmacological potential of Omega-3 fatty acids and the development of highly selective and high-affinity alternatives.This review aims to provide in-depth analysis of the comprehensive therapeutic potential of Omega-3 fatty acids for SCI and its accompanying complications,and the prospects for developing novel drugs based on the recognition of Omega-3 fatty acids by GPR120.展开更多
Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people...Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people are diagnosed with SCI annually(Singh et al.,2014),and while this number appears quite low,the effect that an SCI has on the patient’s quality of life is drastic,due to the current difficulties to comprehensively treat this illness.The cost of patient care can also be quite costly,amounting to an estimated$1.69 billion in healthcare costs in the USA alone(Mahabaleshwarkar and Khanna,2014).展开更多
Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue r...Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue repair or exacerbate damage.Among macrophage secreted factors,transforming growth factor-beta 1 has emerged as a critical mediator of pathological changes.In this study,we show the pivotal role of macrophage-derived transforming growth factor-beta 1 in driving neuronal senescence and impairing functional recovery after spinal cord injury.In a mouse spinal cord injury model,transforming growth factor-beta 1 levels were significantly increased at the injury site,accompanied by increased mothers against decapentaplegic homolog 2(SMAD2)phosphorylation and upregulation of neuronal senescence markers such as p16INK4a andβ-galactosidase activity.Treatment with LY-364947,a SMAD2 phosphorylation inhibitor,markedly reduced the number of senescent neurons,mitigated tissue degeneration,and improved motor function recovery.Additionally,macrophage depletion using clodronate liposomes lowered transforming growth factor-beta 1 levels at the injury site and attenuated neuronal senescence.These findings highlight the transforming growth factor-beta 1-SMAD2 signaling axis as a potential therapeutic target to reduce neuronal senescence and enhance functional recovery following spinal cord injury.展开更多
Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and g...Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and glia,undergo reactive transformations whose molecular and functional properties are poorly understood2.Here,using multiple transcriptional profiling methods,we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury.展开更多
Chronic pain following a spinal cord injury refers to pain that persists or recurs after the injury.This pain can manifest as burning,stinging,or sensations similar to electric shocks.Recent studies have shown that sp...Chronic pain following a spinal cord injury refers to pain that persists or recurs after the injury.This pain can manifest as burning,stinging,or sensations similar to electric shocks.Recent studies have shown that spinal cord stimulation is an effective way to treat chronic pain after spinal cord injury.The purpose of this review is to introduce the technique of spinal cord stimulation,the clinical manifestations of spinal cord injury,and the role of spinal cord stimulation in the treatment of spinal cord injury.The mechanism and clinical application of spinal cord stimulation in the treatment of pain after spinal cord injury are discussed.The mechanism of spinal cord stimulation primarily involves three aspects:neuromodulation,neurochemical regulation,and anti-inflammatory effects,along with nerve repair.In terms of neuromodulation,spinal cord stimulation is based on the gate control theory of pain.It activates large-diameter amyloid-βnerve fibers to promote the release of inhibitory neurotransmitters by gamma-aminobutyric acidergic inhibitory interneurons in the spinal cord,thereby blocking the transmission of pain signals from small-diameter C fibers.Neurochemical studies indicate that spinal cord stimulation can regulate the balance of neurotransmitters within the spinal cord,increasing the release of inhibitory neurotransmitters such as gamma-aminobutyric acid,serotonin,and acetylcholine while reducing the levels of excitatory neurotransmitters.Additionally,spinal cord stimulation exhibits significant anti-inflammatory and neuroprotective effects,downregulating pro-inflammatory factor levels,upregulating anti-inflammatory factor expression,alleviating neuroinflammatory responses,and repairing damaged neural circuits by promoting the secretion of neurotrophic factors and axonal regeneration.Spinal cord stimulation have demonstrated remarkable efficacy in the clinical treatment of pain after spinal cord injury,but there are still limitations such as small sample size and high heterogeneity in clinical studies,as well as insufficient long-term efficacy data.Future research should conduct multi-center large-sample randomized controlled trials,and establish long-term follow-up mechanisms to improve evidence-based medical evidence.展开更多
Spinal cord injury is a critical event characterized by intricate pathogenic mechanisms.Although recent studies have highlighted tissue exosomes as key mediators of inflammatory responses in diverse organs and tissues...Spinal cord injury is a critical event characterized by intricate pathogenic mechanisms.Although recent studies have highlighted tissue exosomes as key mediators of inflammatory responses in diverse organs and tissues,their role in spinal cord injury has yet to be determined.In this study,we investigated the role and mechanisms of spinal cord tissue exosomes in the inflammatory response following spinal cord injury.We found morphological,concentration,and functional differences between exosomes extracted from injured and normal spinal cord tissues,and identified proinflammatory effects associated with spinal cord injury-generated tissue exosomes but not with exosomes derived from normal spinal cord tissue.Our in vivo and in vitro analyses showed that spinal cord injury-generated tissue exosomes promoted microglial M1 polarization and inflammatory cytokine expression,thereby exacerbating tissue and neuronal injury in the spinal cord.In addition,the combination of exosomal miRNA sequencing and experimental verification showed that the miR-155-5p level was higher in spinal cord injury-generated tissue exosomes than in spinal cord tissue.We further found that spinal cord injury-generated tissue exosomes-derived miR-155-5p induced a significant inhibition of forkhead box O3a phosphorylation and activated the nuclear factor-kappa B pathway,thereby promoting microglial M1 polarization and inflammatory cytokine expression.These findings suggest that injury-induced miR-155-5p-containing exosomes exacerbate spinal cord injury via the promotion of microglial M1 polarization and inflammatory responses.Thus,targeting miR-155-5p expression or exosome secretion could be a novel strategy for attenuating inflammation and reducing secondary injury post-spinal cord injury.展开更多
Oxidative stress significantly contributes to secondary damage after spinal cord injury.Despite its importance,research on oxidative stress in spinal cord injury remains limited.Investigating the expression and regula...Oxidative stress significantly contributes to secondary damage after spinal cord injury.Despite its importance,research on oxidative stress in spinal cord injury remains limited.Investigating the expression and regulation of oxidative stress-related genes could enhance the diagnosis and treatment of spinal cord injury.In this study,we analyzed the sequencing data of human blood samples and injured mouse spinal cord tissue that were sourced from GEO databases and identified diagnostic biomarkers associated with the severity of spinal cord injury.We also explored the expression patterns of oxidative stress-related genes,potential regulatory mechanisms,and therapeutic drugs.To validate our findings,we performed immunofluorescence and quantitative polymerase chain reaction to assess gene expression in the injured spinal cord.Our results revealed biomarkers associated with oxidative stress and immune responses across different levels of spinal cord injury in humans.We identified differentially expressed oxidative stress-related genes and key hub genes in injured mouse spinal cord tissue and revealed their temporal expression patterns at both the tissue and single-cell levels.We also clarified the signaling pathways associated with oxidative stress and identified ligand-receptor pairs among various cell types at different time points after injury.Furthermore,we discovered microRNAs,long non-coding RNAs,and transcription factors that regulate these hub genes and revealed their roles in modulating gene expression at various stages after spinal cord injury.We also identified drugs targeting these hub genes.The findings from this study not only aid in identifying diagnostic biomarkers that reflect the severity of spinal cord injury,but also provide insights into the expression dynamics of oxidative stress-related genes.In addition,the study reveals potential regulatory mechanisms and identifies potential drugs to treat patients with spinal cord injury.展开更多
Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate followin...Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate following injury.Understanding the mechanisms that underlie this difference is key to developing treatments for CNS neurological diseases and injuries characterized by axonal damage.To initiate repair after peripheral nerve injury,dorsal root ganglion(DRG) neurons mobilize a pro-regenerative gene expression program,which facilitates axon outgrowth.展开更多
The inter-related pathological cascades following a traumatic spinal cord injury(tSCI)disrupt multiple cell types and physiological processes.Subsequently,motor and sensory functions are disrupted by breakdowns in cel...The inter-related pathological cascades following a traumatic spinal cord injury(tSCI)disrupt multiple cell types and physiological processes.Subsequently,motor and sensory functions are disrupted by breakdowns in cellular interactions and circuitry.Therapeutic interventions seek to modify some aspects of the injury course to enable the re-establishment of functional circuitry.Interventions often target one cell type(e.g.,promoting neuroprotection or neural regeneration)or one process(e.g.,modulating inflammation,affecting astrocytic,microglial,or macrophage responses.)Many axons in the spinal cord are myelinated,and after injury oligodendrocyte death causes demyelination.Promoting remyelination of spared or new axons to re-establish conduction seems a logical choice as a therapeutic target.展开更多
基金supported by the National Natural Science Foundation of China(No.82471229)Science and Technology Collaborative Innovation Fund of Fujian Province(No.2021Y9172)the Natural Science Foundation of Fujian Province,China(No.2023J01169)。
文摘Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)models were established by colorectal distention in newborn rats aged 8 to 14 days,and visceral hypersensitivity was assessed using electromyogram(EMG).Oxytocin or saclofen was administered intrathecally to evaluate visceral hypersensitivity in the rats.The protein expressions of oxytocin receptor(OTR),γ-aminobutyric acid type B1 receptor(GABAB1),and transient receptor potential vanilloid 1(TRPV1)in the lumbosacral spinal cord regions were measured.IBS rats exhibited a unique spinal cord molecular signature comprising decreased OTR/GABAB1 and increased TRPV1 expression.Intrathecal oxytocin treatment not only normalized these molecular alterations(increasing GABAB1 while decreasing TRPV1)but also ameliorated visceral pain behaviors.Crucially,this therapeutic effect was fully reversed by GABAB1 inhibition,establishing the necessity of intact GABAergic signaling for oxytocin-mediated analgesia.Collectively,these findings indicate that oxytocin relieves visceral hypersensitivity through the regulation of GABAB1 and TRPV1 in the spinal cord of IBS rats.
基金supported by the National Natural Science Foundation of China,Nos.82072165 and 82272256(both to XM)the Key Project of Xiangyang Central Hospital,No.2023YZ03(to RM)。
文摘Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
基金supported by the National Key Research and Development Program of China,No.2023YFC3603705(to DX)the National Natural Science Foundation of China,No.82302866(to YZ).
文摘After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the timing of interventions,combined with the limitations of current methods.To address these challenges,various techniques have been developed to aid in the repair and reconstruction of neural circuits at different stages of injury.Notably,neuromodulation has garnered considerable attention for its potential to enhance nerve regeneration,provide neuroprotection,restore neurons,and regulate the neural reorganization of circuits within the cerebral cortex and corticospinal tract.To improve the effectiveness of these interventions,the implementation of multitarget early interventional neuromodulation strategies,such as electrical and magnetic stimulation,is recommended to enhance functional recovery across different phases of nerve injury.This review concisely outlines the challenges encountered following spinal cord injury,synthesizes existing neurostimulation techniques while emphasizing neuroprotection,repair,and regeneration of impaired connections,and advocates for multi-targeted,task-oriented,and timely interventions.
基金supported by the National Research Foundation of Korea,Nos.2021R1A2C2006110,2021M3E5D9021364,2019R1A5A2026045(to BGK)the Korea Initiative for Fostering University of Research and Innovation(KIURI)Program of the NRF funded by the MSIT(to HK),No.NRF2021M3H1A104892211(to HSK)。
文摘Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.
基金thegrantsfromtheAdvanceDepartment FoundationfromtheMedicalMinistryofShanghai China! (No 1995 Ⅲ 0 0 8)
文摘Objective To research the direct electrophysiological evidence of discomplete spinal cord injury (SCI) and the effect of 4-aminopyridine on it.Methods Motor evoked potentials (MEPs), both spinal cord recorded MEPs (scMEPs) and extracellularly recorded MEPs (exMEPs) were recorded and characterized on a T13 epidural electrode (scMEPs) and an extracellular microelectrode (exMEPs) for 10 normal rats and 40 rats with lesions of various severity (sham, 35?g*cm force (gcf), 70?gcf, 100?gcf impact injury) at the T8-T9 cord using the Allen's drop model. The incline plane and Tarlov techniques were used to assess clinical neurological function. Results MEPs in the normal rats were elicited by applying transcortical suprathreshold stimulation consisting of 3-4 early negative peaks (N1, N2, N3 and N4) followed by several late waves. The N1 and N2 peaks were largest in the anterior and ventrolateral funiculus, respectively, which was indicative of extrapyramidal pathways. The 100?gcf impact injuries and the cord transection abolished the MEP distal to the lesion, whereas the 35?gcf injuries resulted in a latency shift and amplitude decrement of the MEP peaks. Eighteen of the 20 rats with 70?gcf injuries showed clinical paraplegia. Among them, 7 rats had neurophysiological evidence of residual conduction pathways through the lesioned cord segment, such as the presence of N1 and N2 peaks in the scMEPs or exMEPs. After 4-aminopyridine (4-AP) administrations (1?mg/kg), the amplitude of the spared exMEP increased significantly and spread more widely. Conclusions MEPs evoked by transcortical stimulation travel mostly in the extrapyramidal tract. MEP monitoring could provide an excellent method of detecting the functional integrity of the motor tracts after SCI, and could even detect spared motor fibers after discomplete SCI. Furthermore, the use of 4-AP or other K+ channel blocking agents may be a potential treatment for patients with chronic moderate to severe SCI.
基金supported by the Belle Carnell Regenerative Neurorehabilitation Fundthe National Institutes of Health(R01NS113935 to CKF)。
文摘Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and genetic mechanisms and can be derived from an individual's somatic cells(e.g.,blood or skin).This enables patient-specific paradigms for precision neurotrauma research,pa rticula rly relevant to the over 300,000 people in the United States living with chronic effects of spinal cord injury(SCI).
基金supported by University of Kentucky-SCoBIRC Endowed Chair#5Craig H.Neilsen 1173493 and NIH RF1NS135504(to JCG).
文摘Biological sex is increasingly recognized as a crucial factor in evaluating the translational value of preclinical spinal cord injury(SCI)studies.The rising incidence of SCI in females challenges the historical precedent of SCI being a male-dominated condition.In contrast,most basic science researchers utilize single-sex studies to minimize complications associated with bladder care in males(Stewart et al.,2020).The findings of our recent publication identify sexually dimorphic immune responses to SCI in both mice and pigs(Kumari et al.,2025).Here,we will highlight these findings and discuss the impact of sex on SCI inflammation and recovery.
基金supported by the National Natural Science Foundation of China,No.82471411(to ZW and TD)the Key Research and DevelopmentProgram of Shaanxi Province,No.2023-ZDLSF-12(to TD).
文摘The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system.After spinal cord injury,autophagic flux within endothelial cells is disrupted,compromising the integrity of the blood-spinal cord barrier.This disruption facilitates extensive infiltration of inflammatory cells,resulting in exacerbated neuroinflammatory responses,neuronal death,and impaired neuronal regeneration.Previous research has demonstrated that photobiomodulation promotes the regeneration of damaged nerves following spinal cord injury by inhibiting the recruitment of inflammatory cells to the injured site and restoring neuronal mitochondrial function.However,the precise mechanisms by which photobiomodulation regulates neuroinflammation remain incompletely elucidated.In this study,we established a mouse model of spinal cord injury and assessed the effects of photobiomodulation treatment.Photobiomodulation effectively cleared damaged mitochondria from endothelial cells in mice,promoting recovery of hindlimb motor function.Using microvascular endothelial bEnd.3 cells subjected to oxygen-glucose deprivation,we found that the effects of photobiomodulation were mediated through activation of the PINK1/Parkin pathway.Additionally,photobiomodulation reduced mitochondrial oxidative stress levels and increased the expression of tight junction proteins within the blood-spinal cord barrier.Our findings suggest that photobiomodulation activates mitochondrial autophagy in endothelial cells through the PINK1/Parkin pathway,thereby promoting repair of the blood-spinal cord barrier following spinal cord injury.
文摘The spinal cord links the brain and the peripheral nervous system and has important sensory and motor functions.Impairments in the spinal cord occur in different diseases,such as spinal cord injury,multiple sclerosis,pain,motor neuron diseases,and neurodegenerative diseases.Imaging of the spinal cord has been challenging,partly due to its small size and deep anatomical location.Additionally,in an animal model,motion artifacts further influence the in vivo imaging quality of the spinal cord.Recent advances have pushed boundaries for in vivo imaging in living animals(even behaving animals).
文摘Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathophysiology:an initial primary injury(mechanical trauma,axonal disruption,and hemorrhage) is followed by a progressive secondary injury cascade that involves ischemia,neuronal loss,and inflammation.Given the challenges in achieving regeneration of the injured spinal cord,neuroprotection has been at the forefront of clinical research.
基金supported by the National Natural Science Foundation of China(Grant nos.62576136 to Yan Huang82372507,82572869 to Kun Xiongthe National Natural Science Foundation of Hunan Province(Grant no.2026JJ30177).
文摘Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenesis universally originates from ischemia/reperfusion(I/R)injury affecting the cerebral,spinal cord,and/or retina.
基金supported by the National Key Research and Development Project of Stem Cell and Transformation Research(2019YFA0112100)Taishan Scholars Programof Shandong Province-Young Taishan Scholars(tsqn201909197)+1 种基金Cutting Edge Development Fund of Advanced Medical Research Institute(Shandong University)National Natural Science Foundation of China(82220108005)。
文摘Traumatic spinal cord injury(SCI)is a debilitating condition characterized by the impairment of neural circuits,leading to the loss of motor and sensory functions and accompanied by severe complications.Substantial research has reported the therapeutic potential of Omega-3 fatty acids for the central nervous system,particularly after traumatic SCI.Omega-3 fatty acids may contribute to improving SCI recovery through their anti-inflammatory,anti-oxidative,neurotrophic,and membrane integrity-preserving properties.These functions of Omega-3 fatty acids are primarily mediated via the activation of G protein-coupled receptor 120(GPR120),commonly known as the fish oil-specific receptor.Advancements in understanding of the molecular mechanisms of GPR120’s recognition of Omega-3 fatty acids and its downstream signaling mechanisms has significantly promoted research on the pharmacological potential of Omega-3 fatty acids and the development of highly selective and high-affinity alternatives.This review aims to provide in-depth analysis of the comprehensive therapeutic potential of Omega-3 fatty acids for SCI and its accompanying complications,and the prospects for developing novel drugs based on the recognition of Omega-3 fatty acids by GPR120.
基金supported by the Irish Research Council under the Government of Ireland Postdoctoral Fellowship Project ID-GOIPD/2023/1431(to AS).
文摘Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people are diagnosed with SCI annually(Singh et al.,2014),and while this number appears quite low,the effect that an SCI has on the patient’s quality of life is drastic,due to the current difficulties to comprehensively treat this illness.The cost of patient care can also be quite costly,amounting to an estimated$1.69 billion in healthcare costs in the USA alone(Mahabaleshwarkar and Khanna,2014).
基金supported by grants from Tianjin Key Medical Discipline(Specialty)Construct Project,No.TJYXZDXK-027A(to SF)National Key Research and Development Project of Stem Cell and Transformation Research,No.2019YFA0112100(to SF)+3 种基金the National Natural Science Foundation of China,Nos.81930070(to SF),82402825(to XS)Tianjin Health Science and Technology Project Key Discipline Special Project,No.hUCMSC preferred subgroup,No.TJWJ2022XK002(to SF)2022 Beijing-Tianjin-Hebei Basic Research Cooperation Project,No.22JCZXJC00050(to SF)Youth Research Incubation Fund of School of Basic Medical Sciences,Tianjin Medical University,No.023FY05(to XS).
文摘Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue repair or exacerbate damage.Among macrophage secreted factors,transforming growth factor-beta 1 has emerged as a critical mediator of pathological changes.In this study,we show the pivotal role of macrophage-derived transforming growth factor-beta 1 in driving neuronal senescence and impairing functional recovery after spinal cord injury.In a mouse spinal cord injury model,transforming growth factor-beta 1 levels were significantly increased at the injury site,accompanied by increased mothers against decapentaplegic homolog 2(SMAD2)phosphorylation and upregulation of neuronal senescence markers such as p16INK4a andβ-galactosidase activity.Treatment with LY-364947,a SMAD2 phosphorylation inhibitor,markedly reduced the number of senescent neurons,mitigated tissue degeneration,and improved motor function recovery.Additionally,macrophage depletion using clodronate liposomes lowered transforming growth factor-beta 1 levels at the injury site and attenuated neuronal senescence.These findings highlight the transforming growth factor-beta 1-SMAD2 signaling axis as a potential therapeutic target to reduce neuronal senescence and enhance functional recovery following spinal cord injury.
文摘Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and glia,undergo reactive transformations whose molecular and functional properties are poorly understood2.Here,using multiple transcriptional profiling methods,we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury.
基金supported by Key Tackling Project of the Education Department of Liaoning Province,No.2024C011the Medical-Industrial Joint Innovation Funding Project of the First Hospital of Dalian Medical University and Dalian Institute of Chemical Physics,No.DMU-1&DICP UN202311(both to ZL).
文摘Chronic pain following a spinal cord injury refers to pain that persists or recurs after the injury.This pain can manifest as burning,stinging,or sensations similar to electric shocks.Recent studies have shown that spinal cord stimulation is an effective way to treat chronic pain after spinal cord injury.The purpose of this review is to introduce the technique of spinal cord stimulation,the clinical manifestations of spinal cord injury,and the role of spinal cord stimulation in the treatment of spinal cord injury.The mechanism and clinical application of spinal cord stimulation in the treatment of pain after spinal cord injury are discussed.The mechanism of spinal cord stimulation primarily involves three aspects:neuromodulation,neurochemical regulation,and anti-inflammatory effects,along with nerve repair.In terms of neuromodulation,spinal cord stimulation is based on the gate control theory of pain.It activates large-diameter amyloid-βnerve fibers to promote the release of inhibitory neurotransmitters by gamma-aminobutyric acidergic inhibitory interneurons in the spinal cord,thereby blocking the transmission of pain signals from small-diameter C fibers.Neurochemical studies indicate that spinal cord stimulation can regulate the balance of neurotransmitters within the spinal cord,increasing the release of inhibitory neurotransmitters such as gamma-aminobutyric acid,serotonin,and acetylcholine while reducing the levels of excitatory neurotransmitters.Additionally,spinal cord stimulation exhibits significant anti-inflammatory and neuroprotective effects,downregulating pro-inflammatory factor levels,upregulating anti-inflammatory factor expression,alleviating neuroinflammatory responses,and repairing damaged neural circuits by promoting the secretion of neurotrophic factors and axonal regeneration.Spinal cord stimulation have demonstrated remarkable efficacy in the clinical treatment of pain after spinal cord injury,but there are still limitations such as small sample size and high heterogeneity in clinical studies,as well as insufficient long-term efficacy data.Future research should conduct multi-center large-sample randomized controlled trials,and establish long-term follow-up mechanisms to improve evidence-based medical evidence.
基金supported by the Joint Funds for the Innovation of Science and Technology,Fujian Province,No.2023Y9233(to HH)the QuanzhouScience and Technology Project,No.2022C036R(to HH)+1 种基金the Science and Technology Bureau of Quanzhou,No.2020CT003(to SL)the Quanzhou MunicipalMedical and Health Guiding Science and Technology Project,No.2023N066S(to YZhou).
文摘Spinal cord injury is a critical event characterized by intricate pathogenic mechanisms.Although recent studies have highlighted tissue exosomes as key mediators of inflammatory responses in diverse organs and tissues,their role in spinal cord injury has yet to be determined.In this study,we investigated the role and mechanisms of spinal cord tissue exosomes in the inflammatory response following spinal cord injury.We found morphological,concentration,and functional differences between exosomes extracted from injured and normal spinal cord tissues,and identified proinflammatory effects associated with spinal cord injury-generated tissue exosomes but not with exosomes derived from normal spinal cord tissue.Our in vivo and in vitro analyses showed that spinal cord injury-generated tissue exosomes promoted microglial M1 polarization and inflammatory cytokine expression,thereby exacerbating tissue and neuronal injury in the spinal cord.In addition,the combination of exosomal miRNA sequencing and experimental verification showed that the miR-155-5p level was higher in spinal cord injury-generated tissue exosomes than in spinal cord tissue.We further found that spinal cord injury-generated tissue exosomes-derived miR-155-5p induced a significant inhibition of forkhead box O3a phosphorylation and activated the nuclear factor-kappa B pathway,thereby promoting microglial M1 polarization and inflammatory cytokine expression.These findings suggest that injury-induced miR-155-5p-containing exosomes exacerbate spinal cord injury via the promotion of microglial M1 polarization and inflammatory responses.Thus,targeting miR-155-5p expression or exosome secretion could be a novel strategy for attenuating inflammation and reducing secondary injury post-spinal cord injury.
基金supported by Shenzhen Science and Technology Program, No. JCYJ20230807110259002 (to JL)The Seventh Affiliated Hospital of Sun Yat-sen University, No. ZSQYRSFPD0050 (to JL)The Postdoctoral Fellowship Program of CPSF, No. GZC20242074 (to KT)
文摘Oxidative stress significantly contributes to secondary damage after spinal cord injury.Despite its importance,research on oxidative stress in spinal cord injury remains limited.Investigating the expression and regulation of oxidative stress-related genes could enhance the diagnosis and treatment of spinal cord injury.In this study,we analyzed the sequencing data of human blood samples and injured mouse spinal cord tissue that were sourced from GEO databases and identified diagnostic biomarkers associated with the severity of spinal cord injury.We also explored the expression patterns of oxidative stress-related genes,potential regulatory mechanisms,and therapeutic drugs.To validate our findings,we performed immunofluorescence and quantitative polymerase chain reaction to assess gene expression in the injured spinal cord.Our results revealed biomarkers associated with oxidative stress and immune responses across different levels of spinal cord injury in humans.We identified differentially expressed oxidative stress-related genes and key hub genes in injured mouse spinal cord tissue and revealed their temporal expression patterns at both the tissue and single-cell levels.We also clarified the signaling pathways associated with oxidative stress and identified ligand-receptor pairs among various cell types at different time points after injury.Furthermore,we discovered microRNAs,long non-coding RNAs,and transcription factors that regulate these hub genes and revealed their roles in modulating gene expression at various stages after spinal cord injury.We also identified drugs targeting these hub genes.The findings from this study not only aid in identifying diagnostic biomarkers that reflect the severity of spinal cord injury,but also provide insights into the expression dynamics of oxidative stress-related genes.In addition,the study reveals potential regulatory mechanisms and identifies potential drugs to treat patients with spinal cord injury.
基金supported by the Canada Foundation for Innovation (Project#44220)the Natural Sciences and Engineering Research Council of Canada (RGPIN-2024-03986)+3 种基金the Michael Smith Foundation for Health Research BCthe financial support of Health Canada,through the Canada Brain Research Fund,an innovative partnership between the Government of Canada (through Health Canada),Brain Canada Foundationthe Azrieli Foundationsupported by a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship–Master’s Award。
文摘Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate following injury.Understanding the mechanisms that underlie this difference is key to developing treatments for CNS neurological diseases and injuries characterized by axonal damage.To initiate repair after peripheral nerve injury,dorsal root ganglion(DRG) neurons mobilize a pro-regenerative gene expression program,which facilitates axon outgrowth.
基金supported by Grant 3195 from Paralyzed Veterans of America Research Foundation (to BRK)
文摘The inter-related pathological cascades following a traumatic spinal cord injury(tSCI)disrupt multiple cell types and physiological processes.Subsequently,motor and sensory functions are disrupted by breakdowns in cellular interactions and circuitry.Therapeutic interventions seek to modify some aspects of the injury course to enable the re-establishment of functional circuitry.Interventions often target one cell type(e.g.,promoting neuroprotection or neural regeneration)or one process(e.g.,modulating inflammation,affecting astrocytic,microglial,or macrophage responses.)Many axons in the spinal cord are myelinated,and after injury oligodendrocyte death causes demyelination.Promoting remyelination of spared or new axons to re-establish conduction seems a logical choice as a therapeutic target.
