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Surgical intervention combined with weight-bearing walking training promotes recovery in patients with chronic spinal cord injury:a randomized controlled study

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Neural Regeneration Research 2024年第12期19卷 2773-2784页

作者： Hui Zhu James D.Guest Sarah Dunlop Jia-Xin Xie Sujuan Gao Zhuojing Luo Joe E.Springer wutian wu Wise Young Wai Sang Poon Song Liu Hongkun Gao Tao Yu Dianchun Wang Libing Zhou Shengping wu Lei Zhong Fang Niu Xiaomei Wang Yansheng Liu Kwok-Fai So Xiao-Ming Xu Kunming Tongren Hospital KunmingYunnan ProvinceChina Neurological Surgery and the Miami Project to Cure ParalysisMiller School of MedicineUniversity of MiamiMiamiFLUSA School of Biological Sciences The University of Western AustraliaPerthWAAustralia Minderoo Foundation PerthWAAustralia Clinical Center for Spinal Cord Injury Kunming General Hospital of Chengdu Military CommandKunmingYunnan ProvinceChina Department of Biostatistics and Health Data Science Indiana University School of MedicineIndianapolisINUSA Department of Orthopedic Spinal Surgery Xijing HospitalFourth Military Medical UniversityXi’anShaanxi ProvinceChina Spinal Cord and Brain Injury Research Center Department of Physical Medicine and RehabilitationUniversity of Kentucky College of MedicineLexingtonKYUSA Guangdong-HongKong-Macao Institute of CNS Regeneration Jinan UniversityGuangzhouGuangdong ProvinceChina W.M.Keck Center for Collaborative Neuroscience Rutgers UniversityPiscatawayNJUSA Neurosurgery Department Chinese University of Hong KongPrince of Wales HospitalHong Kong Special Administration RegionChina Spinal Cord and Brain Injury Research Group Stark Neurosciences Research InstituteDepartment of Neurological SurgeryIndiana University School of MedicineIndianapolisINUSA

For patients with chronic spinal cord injury,the co nventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection,pressure sores,osteoporosis,and deep vein thrombosis.Surgery is rarely perfo rmed on spinal co rd injury in the chronic phase,and few treatments have been proven effective in chronic spinal cord injury patients.Development of effective therapies fo r chronic spinal co rd injury patients is needed.We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal co rd injury to compare intensive rehabilitation(weight-bearing walking training)alone with surgical intervention plus intensive rehabilitation.This clinical trial was registered at ClinicalTrials.gov(NCT02663310).The goal of surgical intervention was spinal cord detethering,restoration of cerebrospinal fluid flow,and elimination of residual spinal cord compression.We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement,reduced spasticity,and more rapid bowel and bladder functional recovery than weight-bearing walking training alone.Overall,the surgical procedures and intensive rehabilitation were safe.American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries.Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.

关键词： chronic spinal cord injury intensive rehabilitation locomotor training neurological recovery surgical intervention weightbearing walking training

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ISP and PAP4 peptides promote motor functional recovery after peripheral nerve injury

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Neural Regeneration Research 2021年第8期16卷 1598-1605页

作者： Shi-Qin Lv wutian wu Guangdong-Hong Kong-Macao Institute of CNS Regeneration Ministry of Education CNS Regeneration Collaborative Joint LaboratoryJinan UniversityGuangzhouGuangdong ProvinceChina Re-Stem Biotechnology Co. Ltd.SuzhouJiangsu ProvinceChina

Both intracellular sigma peptide(ISP) and phosphatase and tensin homolog agonist protein(PAP4) promote nerve regeneration and motor functional recovery after spinal cord injury. However, the role of these two small peptides in peripheral nerve injury remains unclear. A rat model of brachial plexus injury was established by crush of the C6 ventral root. The rats were then treated with subcutaneous injection of PAP4(497 μg/d, twice per day) or ISP(11 μg/d, once per day) near the injury site for 21 successive days. After ISP and PAP treatment, the survival of motoneurons was increased, the number of regenerated axons and neuromuscular junctions was increased, muscle atrophy was reduced, the electrical response of the motor units was enhanced and the motor function of the injured upper limbs was greatly improved in rats with brachial plexus injury. These findings suggest that ISP and PAP4 promote the recovery of motor function after peripheral nerve injury in rats. The animal care and experimental procedures were approved by the Laboratory Animal Ethics Committee of Jinan University of China(approval No. 20111008001) in 2011.

关键词： axon brachial plexus injury crush injury intracellular sigma peptide motor function PAP4 peripheral nerve protection regeneration repair

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Are newborn rat-derived neural stem cells more sensitive to lead neurotoxicity?

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Neural Regeneration Research 2013年第7期8卷 581-592页

作者： Yan Ho Chan Mingyong Gao wutian wu Department of Anatomy Li Ka Shing Faculty of Medicine the University of Hong Kong Department of Spine Surgery Renmin Hospital of Wuhan University State Key Laboratory of Brain and Cognitive Sciences Li Ka Shing Faculty of Medicine The University of Hong Kong Research Center of Reproduction Development and Growth Li Ka Shing Faculty of Medicine the University of Hong Kong GHM Institute of Central Nervous System Regeneration Jinan University

Lead ion （Pb2＋） has been proven to be a neurotoxin due to its neurotoxicity on mammalian nervous system, especially for the developing brains of juveniles. However, many reported studies involved the negative effects of Pb2＋ on adult neural cells of humans or other mammals, only few of which have examined the effects of Pb2＋ on neural stem cells. The purpose of this study was to reveal the biological effects of Pb2＋from lead acetate [Pb （0H30OO）2] on viability, proliferation and differentiation of neural stem cells derived from the hippocampus of newborn rats aged 7 days and adult rats aged 90 days, respectively. This study was carried out in three parts. In the first part, 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay （MTT viability assay） was used to detect the effects of Pb2＋ on the cell viability of passage 2 hippocampal neural stem cells after 48-hour exposure to 0-200 pM Pb2＋. In the second part, 10 pM bromodeoxyuridine was added into the culture medium of passage 2 hippocampal neural stem cells after 48-hour exposure to 0- 200 pM Pb2＋, followed by immunocytochemical staining with anti-bromodeoxyuridine to demonstrate the effects of Pb2＋ on cell proliferation. In the last part, passage 2 hippocampal neural stem cells were allowed to grow in the differentiation medium with 0-200 pM Pb2＋. Immunocytochemical staining with anti-microtubule-associated protein 2 （a neuron marker）, anti-glial fibrillary acidic protein （an astrocyte marker）, and anti-RIP （an oligodendrocyte marker） was performed to detect the differentiation commitment of affected neural stem cells after 6 days. The data showed that Pb2~ inhibited not only the viability and proliferation of rat hippocampal neural stem cells, but also their neuronal and oligodendrocyte differentiation in vitro. Moreover, increased activity of astrocyte differentiation of hippocampal neural stem cells from both newborn and adult rats was observed after exposure to high concentration of lead ion in vitro. These findings suggest that hippocampal ne

关键词： neural regeneration stem cells neural stem cells adult neonate mammals Pb2＋ neurotoxicity viability proliferation hippocampus photographs-containing paper neuroregeneration

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Three-dimensional histology:new visual approaches to morphological changes during neural regeneration

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Neural Regeneration Research 2017年第1期12卷 53-55页

作者： Hei Ming Lai Ho Man Ng wutian wu School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong Special Administrative RegionChina State Key Laboratory of Brain and Cognitive Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong Special Administrative RegionChina Research Center of Reproduction Development and GrowthLi Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong Special Administrative RegionChina Guangdong-Hong Kong-Macao Institute of CNS Regeneration Jinan UniversityGuangzhouGuangdong ProvinceChina

Three-dimensional（3D） histology utilizes tissue clearing techniques to turn intact tissues transparent,allowing rapid interrogation of tissue architecture in three dimensions.In this article,we summarized the available tissue clearing methods and classified them according to their physicochemical principles of operation,which provided a framework for one to choose the best techniques for various research settings.Recent attempts in addressing various questions regarding the degenerating and regenerating nervous system have been promising with the use of 3D histological techniques.

关键词： three-dimensional histology tissue clearing neuronal morphology neuronal network

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Functional self-assembling peptide nanofiber hydrogel for peripheral nerve regeneration

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Regenerative Biomaterials 2017年第1期4卷 21-30页

作者： Xiaoli wu Liumin He Wen Li Heng Li Wai-Man Wong Seeram Ramakrishna wutian wu Department of Anatomy School of Biomedical ScienceLKS Faculty of MedicineThe University of Hong Kong21 Sassoon RoadHong Kong SARChina State Key Laboratory of Brain and Cognitive Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulam21 Sassoon RoadHong Kong SARChina Joint Laboratory of Jinan University and the University of Hong Kong GHM Institute of CNS RegenerationJinan University601 Huangpu Avenue WestGuangzhou510632China Department of Mechanical Engineering Faculty of EngineeringCenter for Nanofibers and NanotechnologyNational University of Singapore117576SingaporeSingapore.

Peripheral nerves are fragile and easily damaged,usually resulting in nervous tissue loss,motor and sensory function loss.Advances in neuroscience and engineering have been significantly contributing to bridge the damage nerve and create permissive environment for axonal regrowth across lesions.We have successfully designed two self-assembling peptides by modifying RADA 16-I with two functional motifs IKVAV and RGD.Nanofiber hydrogel formed when combing the two neutral solutions together,defined as RADA 16-Mix that overcomes the main drawback of RADA16-I associated with low pH.In the present study,we transplanted the RADA 16-Mix hydrogel into the transected rat sciatic nerve gap and effect on axonal regeneration was examined and compared with the traditional RADA16-I hydrogel.The regenerated nerves were found to grow along the walls of the large cavities formed in the graft of RADA16-I hydrogel,while the nerves grew into the RADA 16-Mix hydrogel toward distal position.RADA 16-Mix hydrogel induced more axons regeneration and Schwann cells immigration than RADA16-I hydrogel,resulting in better functional recovery as determined by the gait-stance duration percentage and the formation of new neuromuscular junction structures.Therefore,our results indicated that the functional SAP RADA16-Mix nanofibrous hydrogel provided a better environment for peripheral nerve regeneration than RADA16-I hydrogel and could be potentially used in peripheral nerve injury repair.

关键词： Peripheral nerve regeneration self-assembling peptide IKVAV RGD nanofibrous hydrogel

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P75 and phosphorylated c-Jun are differentially regulated in spinal motoneurons following axotomy in rats

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Neural Regeneration Research 2012年第26期7卷 2005-2011页

作者： Qiuju Yuan Huanxing Su wutian wu Zhi-Xiu Lin School of Chinese Medicine Faculty of Science the Chinese University of Hong Kong Shatin N. T Hong Kong Special AdministrativeRegion China Department ofAnatomy Li Ka Shing Faculty of Medicine the University of Hong Kong Pokfulam Hong Kong Special Administrative Region China State Key Laboratory of Brain and Cognitive Sciences Li Ka Shing Faculty of Medicine the University ofHong Kong Pokfulam Hong KongSpecial Administrative Region China Research Center of Reproduction Development and Growth Li Ka Shing Faculty of Medicine the University of Hong Kong Pokfulam HongKoncl Special Administrative Reqion China Joint Laboratory for Brain Function and Health (BFAH) Jinan University and the University of Hong Kong Guangzhou China

The neurotrophin receptor （p75） activates the c-Jun N-terminal kinase （JNK） pathway. Activation of JNK and its substrate c-Jun can cause apoptosis. Here we evaluate the role of p75 in spinal motoneurons by comparing immunoreactivity for p75 and phosphorylated c-Jun （p-c-Jun）, the production of JNK activation in axotomized motoneurons in postnatal day （PN）I, PN7, PN14 and adult rats. Intensive p-c-Jun was induced in axotomized motoneurons in PN1 and PN7. In PN14, p-c-Jun expression was sharply reduced after the same injury. The decreased expression of p-c-Jun at this age coincided with a developmental switch of re-expression of p75 in axotomized cells. In adult animals, no p-c-Jun but intensive p75 was detected in axotomized motoneurons. These results indicate differential expression or turnover of phosphorylation of c-Jun and p75 in immature versus mature spinal motoneurons in response to axonal injury. The non-co-occurrence of p75 and p-c-Jun in injured motoneurons indicated that p75 may not activate JNK pathway, suggesting that the p75 may not be involved in cell death in axotomized motoneurons.

关键词： apoptosis transcription factor c-Jun N-terminal kinase nerve growth factor receptor motoneuron spinal cord axotomy neonatal adult axonal regeneration

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Self-assembling peptide nanofibrous hydrogel as a promising strategy in nerve repair after traumatic injury in the nervous system

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Neural Regeneration Research 2016年第5期11卷 717-718页

作者： Na Zhang Liumin He wutian wu Guangdong-Hongkong-Macao Institute of CNS Regeneration Jinan University Guangzhou Guangdong Province China School of Biomedical Science LKS Faculty of Medicine the University of Hong Kong Pokfulam Hong Kong Special Administrative Region China State Key Laboratory of Brain and Cognitive Sciences The University of Hong Kong Pokfulam Hong Kong Special Administrative Region China Key Laboratory of Biomaterials of Guangdong Higher Education Institutes Department of Biomedical Engineering College of Life Science and Technology Jinan University Guangzhou Guangdong Province China

Following injury in central nervous system（CNS）,there are pathological changes in the injured region,which include neuronal death,axonal damage and demyelination,inflammatory response and activation of glial cells.T... 详细信息

关键词： NSCs Self-assembling peptide nanofibrous hydrogel as a promising strategy in nerve repair after traumatic injury in the nervous system RGD

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Contrasting neuropathology and functional recovery after spinal cord injury in developing and adult rats

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Neuroscience Bulletin 2013年第4期29卷 509-516页

作者： Qiuju Yuan Huanxing Su Kin Chiu wutian wu Zhi-Xiu Lin Department of Anatomy The University of Hong Kong School of Chinese Medicine Faculty of Science The Chinese University of Hong Kong State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences University of Macao State Key Laboratory of Brain and Cognitive Sciences Development and Growth Li Ka Shing Faculty of Medicine The University of Hong Kong Research Center of Reproduction Development and Growth Li Ka Shing Faculty of Medicine The University of Hong Kong GHM Institute of CNS Regeneration Jinan University

Conflicting findings exist regarding the link between functional recovery and the regrowth of spinal tracts across the lesion leading to the restoration of functional contacts. In the present study, we investigated whether functional locomotor recovery was attributable to anatomical regeneration at postnatal day 1 （PN1）, PN7, PN14 and in adult rats two months after transection injury at the tenth thoracic segment of the spinal cord. The Basso, Beattie, and Bresnahan scores showed that transection led to a failure of hindlimb locomotor function in PN14 and adult rats. However, PN1 and PN7 rats showed a significant level of stepping function after complete spinal cord transection. Unexpectedly, unlike the transected PN14 and adult rats in which the spinal cord underwent limited secondary degeneration and showed a scar at the lesion site, the rats transected at PN1 and PN7 showed massive secondary degeneration both anterograde and retrograde, leaving a 〉5-mm gap between the two stumps. Furthermore, retrograde tracing with fluorogold （FG） also showed that FG did not cross the transection site in PN1 and PN7rats as in PN14 and adult rats, and re-transection of the cord caused no apparent loss in locomotor performance in the rats transected at PN1. Thus, these three lines of evidence strongly indicated that the functional recovery after transection in neonatal rats is independent of regrowth of spinal tracts across the lesion site. Our results support the notion that the recovery of locomotor function in developing rats may be due to intrinsic adaptations in the spinal circuitry below the lesion that control hindlimb locomotor activity rather than the regrowth of spinal tracts across the lesion. The difference in secondary degeneration between neonatal and adult rats remains to be explored.

关键词： neonatal spinal cord injury regeneration functional recovery rat

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Spinal root avulsion:an excellent model for studying motoneuron degeneration and regeneration after severe axonal injury

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Neural Regeneration Research 2014年第2期9卷 117-118页

作者： Carolin Ruven Tak-Kwong Chan wutian wu Department of Anatomy LKS Faculty of MedicineThe University of Hong KongHong Kong Special Administrative Region GHM Institute of CNS regeneration Jinan University and The University of Hong Kong

Spinal root avulsion is an excellent model for studying the re- sponse of motoneurons to severe injury to their axons （Koliat- sos et al., 1994）. In this model （‘Avulsion Model＇）, spinal roots are torn off from spinal cord without removing the vertebra at different levels of spinal segments, usually at cervical and lum- bar segments. Step-by-step procedures are described in detail elsewhere （Chu and wu, 2009）. The Avulsion Model resembles very well brachial plexus injuries in human beings. Around 70% of severe brachial plexus injuries in human involved avulsion of one or more roots （Narakas, 1985） and the main causes of traumatic brachial plexus injuries were motor vehicle accidents, sport injuries and difficult deliveries （Terzis et al., 2001）. The Avulsion Model involves injury to both central nervous system （CNS） and peripheral nervous system （PNS） while nerve axoto- my, transection and crush injuries only involve PNIS.

关键词： root GDNF Spinal root avulsion

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Substance P mRNA expression in the rat spinal cord following selective brachial plexus injury

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Neural Regeneration Research 2008年第12期3卷 1324-1327页

作者： Na Liu Longju Chen Feng Li wutian wu Department of Anatomy Zhongshan Medical College Sun Yat-sen University Guangzhou 510080 Guangdong Province China Medical College Foshan University Foshan 528000 Guangdong Province China Department of Anatomy Yunyang Medical College Shiyan 442000 Hubei Province China Department of Anatomy Medical College The University of Hong Kong Hong Kong Special Administrative Region 999077 China

BACKGROUND： The neuropeptide, substance P, has various bioactivities and is widely distributed in the central nervous system. Substance P participates in neural transmission in the spinal cord and plays an important role in regeneration and repair of nerve injury. OBJECTIVE： To investigate substance P mRNA expression in the anterior horn of the spinal cord following brachial plexus injury. DESIGN, TIME AND SETTING： A molecular cell biology randomized controlled study was performed at the Department of Anatomy, Zhongshan Medical College, Sun Yat-sen University and the DaAn Gene Laboratory in May 2005. MATERIALS： A total of 29 adult male Sprague Dawley rats were randomly assigned to a control group （n = 5） and an injury group （n = 24）. METHODS： The injury group was divided into three subgroups. In subgroup A, the right seventh cervical vertebra （C7） anterior root was avulsed, and the residual nerve root at the distal end was removed. In subgroup B, the right C7 anterior root was avulsed, and the right C5 first thoracic vertebrae （T1） posterior root was incised. Thus afferent pathways of the posterior root that connected with the anterior horn motor neurons were blocked. In subgroup C, the right C7 anterior root was avulsed, and a right C56 hemisection was performed. Thus the descending fiber pathways of the cortex that connected with anterior horn motor neurons were blocked. In the control group, the C5-T1 vertebral plate was opened, and then the skin was sutured. MAIN OUTCOME MEASURE： Substance P mRNA expression in the anterior horn of the spinal cord was quantified using fluorescent quantitative reverse transcription-polymerase chain reaction. RESULTS： Substance P mRNA expression was low in the anterior horn of the rat spinal cord in the control group. Substance P mRNA expression in the anterior horn of the spinal cord was upregulated and was significantly higher in the injury group compared with the control group （P 〈 0.01）. Substance P mRNA expression was highest in subgroup B. CONCLUSION： Brachial plexus anter

关键词： brachial plexus injury substance P reverse transcription-polymerase chain reaction

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