Objective Low back pain is one of the most inextricable problems encountered in clinics. Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible the...Objective Low back pain is one of the most inextricable problems encountered in clinics. Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible therapeutic applications. With the development of genetic technology in pain field, the possibility of mutating specific genes in mice has provided a potent tool for investigating the specific mechanisms of pain. The aim of the present study was to develop a mouse model of chronic compression of dorsal root ganglion （CCD）, in which gene mutation can be applied to facilitate the studies of chronic pain. Methods Chronic compression of L4 and L5 dorsal root ganglia was conducted in mice by inserting fine stainless steel rods into the intervertebral foramina, one at L4 and the other at L5. Mechanical allodynia and thermal hyperalgesia were examined with von Frey filaments and radiating heat stimulator, respectively. Results The CCD mice displayed dramatic mechanical and thermal hyperalgesia as well as tactile allodynia in the hindpaw ipsilateral to CCD. In addition, this mechanical and thermal hyperalgesia as well as tactile allodynia was also found to spread to the contralateral hindpaw. Conclusion This model, combined with the possible genetic modification, will strengthen our knowledge of the underlying mechanisms of low back pain. It also favors the development of new treatment strategies for pain and hyperalgesia after spinal injury and other disorders which affect the dorsal root ganglion in humans.展开更多
Carpal tunnel syndrome is the most common compressive neuropathy,presenting with sensorimotor dysfunction.In carpal tunnel syndrome patients,irregular afferent signals on functional magnetic resonance imaging are asso...Carpal tunnel syndrome is the most common compressive neuropathy,presenting with sensorimotor dysfunction.In carpal tunnel syndrome patients,irregular afferent signals on functional magnetic resonance imaging are associated with changes in neural plasticity during peripheral nerve injury.However,it is difficult to obtain multi-point neuroimaging data of the brain in the clinic.In the present study,a rat model of median nerve compression was established by median nerve ligation,i.e.,carpal tunnel syndrome model.Sensory cortex remodeling was determined by functional magnetic resonance imaging between normal rats and carpal tunnel syndrome models at 2 weeks and 2 months after operation.Stimulation of bilateral paws by electricity for 30 seconds,alternating with 30 seconds of rest period（repeatedly 3 times）,resulted in activation of the contralateral sensorimotor cortex in normal rats.When carpal tunnel syndrome rats received this stimulation,the contralateral cerebral hemisphere was markedly activated at 2 weeks after operation,including the primary motor cortex,cerebellum,and thalamus.Moreover,this activation was not visible at 2 months after operation.These findings suggest that significant remodeling of the cerebral cortex appears at 2 weeks and 2 months after median nerve compression.展开更多
Current animal models of chronic peripheral nerve compression are mainly silicone tube models. However, the cross section of the rat sciatic nerve is not a perfect circle, and there are differences in the diameter of ...Current animal models of chronic peripheral nerve compression are mainly silicone tube models. However, the cross section of the rat sciatic nerve is not a perfect circle, and there are differences in the diameter of the sciatic nerve due to individual differences. The use of a silicone tube with a uniform internal diameter may not provide a reliable and consistent model. We have established a chronic sciatic nerve compression model that can induce demyelination of the sciatic nerve and lead to atrophy of skeletal muscle. In 3-week-old pups and adult rats, the sciatic nerve of the right hind limb was exposed, and a piece of surgical latex glove was gently placed under the nerve. N-butyl-cyanoacrylate was then placed over the nerve, and after it had set, another piece of glove latex was placed on top of the target area and allowed to adhere to the first piece to form a sandwich-like complex. Thus, a chronic sciatic nerve compression model was produced. Control pups with latex or N-butyl-cyanoacrylate were also prepared. Functional changes to nerves were assessed using the hot plate test and electromyography. Immunofluorescence and electron microscopy analyses of the nerves were performed to quantify the degree of neuropathological change. Masson staining was conducted to assess the degree of fibrosis in the gastrocnemius and intrinsic paw muscles. The pup group rats subjected to nerve compression displayed thermal hypoesthesia and a gradual decrease in nerve conduction velocity at 2 weeks after surgery. Neuropathological studies demonstrated that the model caused nerve demyelination and axonal irregularities and triggered collagen deposition in the epineurium and perineurium of the affected nerve at 8 weeks after surgery. The degree of fibrosis in the gastrocnemius and intrinsic paw muscles was significantly increased at 20 weeks after surgery. In conclusion, our novel model can reproduce the functional and histological changes of chronic nerve compression injury that occurs in humans and it will be a useful new tool for investigating the mechanisms underlying chronic nerve compression.展开更多
Chronic spinal cord compression(CSCC)is induced by disc herniation and other reasons,leading to movement and sensation dysfunction,with a serious impact on quality of life.Spontaneous disc herniation rarely occurs in ...Chronic spinal cord compression(CSCC)is induced by disc herniation and other reasons,leading to movement and sensation dysfunction,with a serious impact on quality of life.Spontaneous disc herniation rarely occurs in rodents,and therefore establishing a chronic spinal cord compression(CSCC)animal model is of crucial importance to explore the pathogenesis and treatment of CSCC.The absence of secreted protein,acidic,and rich in cysteine(SPARC)leads to spontaneous intervertebral disc degeneration in mice,which resembles human disc degeneration.In this study,we evaluated whether SPARC-null mice may serve as an animal model for CSCC.We performed rod rotation test,pain threshold test,gait analysis,and Basso Mouse Scale score.Our results showed that the motor function of SPARC-null mice was weakened,and magnetic resonance images revealed compression at different spinal cord levels,particularly in the lumbar segments.Immunofluorescence staining and western blot assay showed that the absence of SPARC induced apoptosis of neurons and oligodendrocytes,activation of microglia/macrophages with M1/M2 phenotype and astrocytes with A1/A2 phenotype;it also activated the expression of the NOD-like receptor protein 3 inflammasome and inhibited brain-derived neurotrophic factor/tyrosine kinase B signaling pathway.Notably,these findings are characteristics of CSCC.Therefore,we propose that SPARC-null mice may be an animal model for studying CSCC caused by disc herniation.展开更多
Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase,followed by partial self-recovery,and ultimately an equilibrium stat...Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase,followed by partial self-recovery,and ultimately an equilibrium state of neurological dysfunction.Ferroptosis is a crucial pathological process in many neurodegenerative diseases;however,its role in chro nic compressive spinal cord injury remains unclear.In this study,we established a chronic compressive spinal cord injury rat model,which displayed its most severe behavioral and electrophysiological dysfunction at 4 wee ks and partial recovery at 8 weeks after compression.Bulk RNA sequencing data identified enriched functional pathways,including ferroptosis,presynapse,and postsynaptic membrane activity at both 4 and 8 wee ks following chro nic compressive spinal co rd injury.Tra nsmission electron microscopy and malondialdehyde quantification assay confirmed that ferroptosis activity peaked at 4 weeks and was attenuated at 8 weeks after chronic compression.Ferro ptosis activity was negatively correlated with behavioral score.Immunofluorescence,quantitative polymerase chain reaction,and western blotting showed that expression of the anti-ferroptosis molecules,glutathione peroxidase 4(GPX4) and MAF BZIP transcription factor G(MafG),in neuro ns was suppressed at 4 weeks and upregulated at 8 weeks following spinal co rd compression.There was a positive correlation between the expression of these two molecules,suggesting that they may work together to contribute to functional recovery following chronic compressive spinal cord injury.In conclusion,our study determined the genome-wide expression profile and fe rroptosis activity of a consistently compressed spinal cord at different time points.The results showed that anti-fe rroptosis genes,specifically GPX4 and MafG,may be involved in spontaneous neurological recovery at 8 weeks of chronic compressive spinal cord injury.These findings contribute to a better understanding of the mechanisms underlying chronic compressive spinal cord injury and may help identify new therapeutic targets for compressive cervical myelopathy.展开更多
Somatosensory evoked potentials(SEPs)have been widely used to assess neurological function in clinical practice.A good understanding of the association between SEP signals and neurological function is helpful for prec...Somatosensory evoked potentials(SEPs)have been widely used to assess neurological function in clinical practice.A good understanding of the association between SEP signals and neurological function is helpful for precise diagnosis of impairment location.Previous studies on SEPs have been reported in animal models.However,few studies have reported the relationships between SEP waveforms in animals and those in humans.In this study,we collected normal SEP waveforms and decomposed them into specific time–frequency components(TFCs).Our results showed three stable TFC distribution regions in intact goats and rats and in humans.After we induced spinal cord injury in the animal models,a greater number of small TFC distribution regions were observed in the injured goat and rat groups than in the normal group.Moreover,there were significant correlations(P<0.05)and linear relationships between the main SEP TFCs of the human group and those of the goat and rat groups.A stable TFC distribution of SEP components was observed in the human,goat and rat groups,and the TFC distribution modes were similar between the three groups.Results in various animal models in this study could be translated to future clinical studies based on SEP TFC analysis.Human studies were approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster(approval No.UM 05-312 T/975)on December 5,2005.Rat experiments were approved by the Committee on the Use of Live Animals in Teaching and Research of Li Ka Shing Faculty of Medicine of the University of Hong Kong(approval No.CULART 2912-12)on January 28,2013.Goat experiments were approved by the Animal Ethics Committee of Affiliated Hospital of Guangdong Medical University(approval No.GDY2002132)on March 5,2018.展开更多
基金supported by the National Natural Science Foundation of China(No.30970971)Fourth Military Medical University Grant(No.00002215)
文摘Objective Low back pain is one of the most inextricable problems encountered in clinics. Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible therapeutic applications. With the development of genetic technology in pain field, the possibility of mutating specific genes in mice has provided a potent tool for investigating the specific mechanisms of pain. The aim of the present study was to develop a mouse model of chronic compression of dorsal root ganglion （CCD）, in which gene mutation can be applied to facilitate the studies of chronic pain. Methods Chronic compression of L4 and L5 dorsal root ganglia was conducted in mice by inserting fine stainless steel rods into the intervertebral foramina, one at L4 and the other at L5. Mechanical allodynia and thermal hyperalgesia were examined with von Frey filaments and radiating heat stimulator, respectively. Results The CCD mice displayed dramatic mechanical and thermal hyperalgesia as well as tactile allodynia in the hindpaw ipsilateral to CCD. In addition, this mechanical and thermal hyperalgesia as well as tactile allodynia was also found to spread to the contralateral hindpaw. Conclusion This model, combined with the possible genetic modification, will strengthen our knowledge of the underlying mechanisms of low back pain. It also favors the development of new treatment strategies for pain and hyperalgesia after spinal injury and other disorders which affect the dorsal root ganglion in humans.
基金supported by the National Natural Science Foundation of China,No.81371965,81672144a grant from the Shanghai Pujiang Program of China,No.16PJD035
文摘Carpal tunnel syndrome is the most common compressive neuropathy,presenting with sensorimotor dysfunction.In carpal tunnel syndrome patients,irregular afferent signals on functional magnetic resonance imaging are associated with changes in neural plasticity during peripheral nerve injury.However,it is difficult to obtain multi-point neuroimaging data of the brain in the clinic.In the present study,a rat model of median nerve compression was established by median nerve ligation,i.e.,carpal tunnel syndrome model.Sensory cortex remodeling was determined by functional magnetic resonance imaging between normal rats and carpal tunnel syndrome models at 2 weeks and 2 months after operation.Stimulation of bilateral paws by electricity for 30 seconds,alternating with 30 seconds of rest period（repeatedly 3 times）,resulted in activation of the contralateral sensorimotor cortex in normal rats.When carpal tunnel syndrome rats received this stimulation,the contralateral cerebral hemisphere was markedly activated at 2 weeks after operation,including the primary motor cortex,cerebellum,and thalamus.Moreover,this activation was not visible at 2 months after operation.These findings suggest that significant remodeling of the cerebral cortex appears at 2 weeks and 2 months after median nerve compression.
基金supported by the National Natural Science Foundation of China,No.81471270
文摘Current animal models of chronic peripheral nerve compression are mainly silicone tube models. However, the cross section of the rat sciatic nerve is not a perfect circle, and there are differences in the diameter of the sciatic nerve due to individual differences. The use of a silicone tube with a uniform internal diameter may not provide a reliable and consistent model. We have established a chronic sciatic nerve compression model that can induce demyelination of the sciatic nerve and lead to atrophy of skeletal muscle. In 3-week-old pups and adult rats, the sciatic nerve of the right hind limb was exposed, and a piece of surgical latex glove was gently placed under the nerve. N-butyl-cyanoacrylate was then placed over the nerve, and after it had set, another piece of glove latex was placed on top of the target area and allowed to adhere to the first piece to form a sandwich-like complex. Thus, a chronic sciatic nerve compression model was produced. Control pups with latex or N-butyl-cyanoacrylate were also prepared. Functional changes to nerves were assessed using the hot plate test and electromyography. Immunofluorescence and electron microscopy analyses of the nerves were performed to quantify the degree of neuropathological change. Masson staining was conducted to assess the degree of fibrosis in the gastrocnemius and intrinsic paw muscles. The pup group rats subjected to nerve compression displayed thermal hypoesthesia and a gradual decrease in nerve conduction velocity at 2 weeks after surgery. Neuropathological studies demonstrated that the model caused nerve demyelination and axonal irregularities and triggered collagen deposition in the epineurium and perineurium of the affected nerve at 8 weeks after surgery. The degree of fibrosis in the gastrocnemius and intrinsic paw muscles was significantly increased at 20 weeks after surgery. In conclusion, our novel model can reproduce the functional and histological changes of chronic nerve compression injury that occurs in humans and it will be a useful new tool for investigating the mechanisms underlying chronic nerve compression.
基金supported by the National Natural Science Foundation of China,Nos.82074454(to XJC),82174409(to MY),81930116(to YJW),81873317(to XJC)the National Key R&D Program of China,No.2018YFC1704300(to YJW)the Natural Science Foundation of Shanghai,No.20ZR1459000(to MY)。
文摘Chronic spinal cord compression(CSCC)is induced by disc herniation and other reasons,leading to movement and sensation dysfunction,with a serious impact on quality of life.Spontaneous disc herniation rarely occurs in rodents,and therefore establishing a chronic spinal cord compression(CSCC)animal model is of crucial importance to explore the pathogenesis and treatment of CSCC.The absence of secreted protein,acidic,and rich in cysteine(SPARC)leads to spontaneous intervertebral disc degeneration in mice,which resembles human disc degeneration.In this study,we evaluated whether SPARC-null mice may serve as an animal model for CSCC.We performed rod rotation test,pain threshold test,gait analysis,and Basso Mouse Scale score.Our results showed that the motor function of SPARC-null mice was weakened,and magnetic resonance images revealed compression at different spinal cord levels,particularly in the lumbar segments.Immunofluorescence staining and western blot assay showed that the absence of SPARC induced apoptosis of neurons and oligodendrocytes,activation of microglia/macrophages with M1/M2 phenotype and astrocytes with A1/A2 phenotype;it also activated the expression of the NOD-like receptor protein 3 inflammasome and inhibited brain-derived neurotrophic factor/tyrosine kinase B signaling pathway.Notably,these findings are characteristics of CSCC.Therefore,we propose that SPARC-null mice may be an animal model for studying CSCC caused by disc herniation.
文摘Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase,followed by partial self-recovery,and ultimately an equilibrium state of neurological dysfunction.Ferroptosis is a crucial pathological process in many neurodegenerative diseases;however,its role in chro nic compressive spinal cord injury remains unclear.In this study,we established a chronic compressive spinal cord injury rat model,which displayed its most severe behavioral and electrophysiological dysfunction at 4 wee ks and partial recovery at 8 weeks after compression.Bulk RNA sequencing data identified enriched functional pathways,including ferroptosis,presynapse,and postsynaptic membrane activity at both 4 and 8 wee ks following chro nic compressive spinal co rd injury.Tra nsmission electron microscopy and malondialdehyde quantification assay confirmed that ferroptosis activity peaked at 4 weeks and was attenuated at 8 weeks after chronic compression.Ferro ptosis activity was negatively correlated with behavioral score.Immunofluorescence,quantitative polymerase chain reaction,and western blotting showed that expression of the anti-ferroptosis molecules,glutathione peroxidase 4(GPX4) and MAF BZIP transcription factor G(MafG),in neuro ns was suppressed at 4 weeks and upregulated at 8 weeks following spinal co rd compression.There was a positive correlation between the expression of these two molecules,suggesting that they may work together to contribute to functional recovery following chronic compressive spinal cord injury.In conclusion,our study determined the genome-wide expression profile and fe rroptosis activity of a consistently compressed spinal cord at different time points.The results showed that anti-fe rroptosis genes,specifically GPX4 and MafG,may be involved in spontaneous neurological recovery at 8 weeks of chronic compressive spinal cord injury.These findings contribute to a better understanding of the mechanisms underlying chronic compressive spinal cord injury and may help identify new therapeutic targets for compressive cervical myelopathy.
基金supported by the National Natural Science Foundation of China,No.81871768(to YH)the Natural Science Foundation of Tianjin of China,No.18JCYBJC29600(to HYC)High Level-Hospital Program,Health Commission of Guangdong Province of China,No.HKUSZH201902011(to YH).
文摘Somatosensory evoked potentials(SEPs)have been widely used to assess neurological function in clinical practice.A good understanding of the association between SEP signals and neurological function is helpful for precise diagnosis of impairment location.Previous studies on SEPs have been reported in animal models.However,few studies have reported the relationships between SEP waveforms in animals and those in humans.In this study,we collected normal SEP waveforms and decomposed them into specific time–frequency components(TFCs).Our results showed three stable TFC distribution regions in intact goats and rats and in humans.After we induced spinal cord injury in the animal models,a greater number of small TFC distribution regions were observed in the injured goat and rat groups than in the normal group.Moreover,there were significant correlations(P<0.05)and linear relationships between the main SEP TFCs of the human group and those of the goat and rat groups.A stable TFC distribution of SEP components was observed in the human,goat and rat groups,and the TFC distribution modes were similar between the three groups.Results in various animal models in this study could be translated to future clinical studies based on SEP TFC analysis.Human studies were approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster(approval No.UM 05-312 T/975)on December 5,2005.Rat experiments were approved by the Committee on the Use of Live Animals in Teaching and Research of Li Ka Shing Faculty of Medicine of the University of Hong Kong(approval No.CULART 2912-12)on January 28,2013.Goat experiments were approved by the Animal Ethics Committee of Affiliated Hospital of Guangdong Medical University(approval No.GDY2002132)on March 5,2018.
