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Mensah EO, Chalif JI, Johnston BR, Chalif E, Parker T, Izzy S, He Z, Saigal R, Fehlings MG, Lu Y. Traumatic spinal cord injury: a review of the current state of art and future directions - what do we know and where are we going? NORTH AMERICAN SPINE SOCIETY JOURNAL 2025; 22:100601. [PMID: 40256049 PMCID: PMC12008600 DOI: 10.1016/j.xnsj.2025.100601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 02/07/2025] [Accepted: 02/17/2025] [Indexed: 04/22/2025]
Abstract
Background Traumatic spinal cord injury (SCI) remains a devastating condition, with limited functional recovery despite advancements in clinical management and understanding of its mechanisms. SCI pathophysiology involves primary mechanical trauma and secondary neuroimmune and structural changes, leading to neuronal death and chronic functional deficits. Methods Through a comprehensive literature review of articles published in the PubMed, MEDLINE, Embase, and Cochrane Reviews Library databases, this article provides an update on the current management of traumatic SCI with a focus on these emerging therapeutic strategies that hold potential for future advancements in the field. Results Current management strategies include pre-hospital care, acute clinical interventions, surgical decompression and spine destabilization, and neurorehabilitation. Despite these interventions, SCI patients often fail to fully restore lost functions. Emerging therapies focus on neuroprotection, neuroregeneration, and neuromodulation, leveraging advances in molecular biomarkers, imaging techniques, and cell-based treatments. Neuroprotective agents, including the sodium-glutamate antagonist riluzole, aim to keep cells alive through the secondary injury phase, while regenerative strategies utilize neurotrophic factors and stem cell transplantation or approaches to target inhibitor molecules such as NOGO or RGMa to regenerate new cells, axons, and neural circuits. Neuromodulation techniques, such as electrical and magnetic field stimulation, offer promising avenues for functional recovery. Combining these novel therapies with traditional neurorehabilitation holds potential for improved outcomes. Conclusions While significant strides have been made in understanding the mechanisms underlying SCI and in developing novel therapeutic approaches, the challenge and opportunity will be to tailor treatments to fit the heterogenous clinical presentation of patients with SCI and to better understand the heterogeneity in clinical trajectories.
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Affiliation(s)
- Emmanuel O. Mensah
- Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Joshua I. Chalif
- Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Benjamin R. Johnston
- Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Eric Chalif
- Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Tariq Parker
- Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Saef Izzy
- Divisions of Stroke, Cerebrovascular, and Critical Care Neurology, Department of Neurology, Brigham and Women's Hospital, Boston, MA, United States
| | - Zhigang He
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, United States
- Department of Neurology and Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - Rajiv Saigal
- Department of Neurosurgery, University of California San Francisco, San Francisco, CA, United States
| | - Michael G. Fehlings
- Division of Neurosurgery and Spine Program, University of Toronto, Ontario, Canada
| | - Yi Lu
- Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
- Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
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Hassan OI, Takamiya S, Asgarihafshejani A, Fehlings MG. Bridging the gap: a translational perspective in spinal cord injury. Exp Biol Med (Maywood) 2024; 249:10266. [PMID: 39391076 PMCID: PMC11464315 DOI: 10.3389/ebm.2024.10266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 08/27/2024] [Indexed: 10/12/2024] Open
Abstract
Traumatic spinal cord injury (SCI) is a devastating and complex condition to treat with no curative options. In the past few decades, rapid advancements in our understanding of SCI pathophysiology as well as the mergence of new treatments has created more optimism. Focusing on clinical translation, this paper provides a comprehensive overview of SCI through its epidemiology, pathophysiology, currently employed management strategies, and emerging therapeutic approaches. Additionally, it emphasizes the importance of addressing the heavy quality of life (QoL) challenges faced by SCI patients and their desires, providing a basis to tailor patient-centric forms of care. Furthermore, this paper discusses the frequently encountered barriers in translation from preclinical models to clinical settings. It also seeks to summarize significant completed and ongoing SCI clinical trials focused on neuroprotective and neuroregenerative strategies. While developing a cohesive regenerative treatment strategy remains challenging, even modest improvements in sensory and motor function can offer meaningful benefits and motivation for patients coping with this highly debilitating condition.
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Affiliation(s)
- Omar Imad Hassan
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Soichiro Takamiya
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON, Canada
| | - Azam Asgarihafshejani
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON, Canada
| | - Michael G. Fehlings
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Division of Neurosurgery, Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
- Division of Neurosurgery and Spine Program, Department of Surgery, University of Toronto, Toronto, ON, Canada
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3
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Långsjö J, Jordan S, Laurila S, Paaso M, Thesleff T, Huhtala H, Ronkainen A, Karlsson S, Koskinen E, Luoto T. Traumatic cervical spinal cord injury: Comparison of two different blood pressure targets on neurological recovery. Acta Anaesthesiol Scand 2024; 68:493-501. [PMID: 38228292 DOI: 10.1111/aas.14372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/28/2023] [Accepted: 12/23/2023] [Indexed: 01/18/2024]
Abstract
BACKGROUND Controversy exists whether blood pressure augmentation therapy benefits patients suffering from spinal cord injury (SCI). This retrospective comparative study was designed to assess the impact of two different mean arterial pressure (MAP) targets (85-90 mmHg vs. 65-85 mmHg) on neurological recovery after traumatic cervical SCI. METHODS Fifty-one adult patients with traumatic cervical SCI were retrospectively divided into two groups according to their intensive care unit (ICU) MAP targets: 85-90 mmHg (higher MAP group, n = 32) and 65-85 mmHg (lower MAP group, n = 19). Invasive MAP measurements were stored as 2-min median values for 3-7 days. The severity of SCI (AIS grade and neurological level) was evaluated upon ICU stay and during rehabilitation. Neurological recovery was correlated with individual mean MAP values and with the proportion of MAP values ≥85 mmHg upon the first 3 days (3d-MAP%≥85 ). RESULTS The initial AIS grades were A 29.4%, B 17.6%, C 31.4%, and D 21.6%. AIS grade improved in 24 patients (47.1%). During ICU care, 82.0% and 36.8% of the measured MAP values reached ≥85 mmHg in the higher and the lower MAP groups, respectively (p < .001). The medians of individual mean MAP values were different between the groups (90.2 mmHg vs. 81.4 mmHg, p < .001). Similarly, 3d-MAP%≥85 was higher in the higher MAP group (85.6% vs. 50.0%, p < .001). However, neurological recovery was not different between the groups, nor did it correlate with individual mean MAP values or 3d-MAP%≥85 . CONCLUSION The currently recommended MAP target of 85-90 mmHg was not associated with improved outcomes compared to a lower target in patients with traumatic cervical SCI in this cohort.
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Affiliation(s)
- Jaakko Långsjö
- Department of Intensive Care, Tampere University Hospital, Tampere, Finland
| | - Sofia Jordan
- Department of Anesthesiology, Helsinki University Central Hospital, Helsinki, Finland
| | - Salla Laurila
- Department of Anesthesiology, Tampere University Hospital, Tampere, Finland
| | - Markku Paaso
- Department of Anesthesiology, Tampere University Hospital, Tampere, Finland
| | - Tuomo Thesleff
- Department of Neurosurgery, Tampere University Hospital, Tampere, Finland
| | - Heini Huhtala
- Faculty of Social Sciences, University of Tampere, Tampere, Finland
| | - Antti Ronkainen
- Department of Neurosurgery, Tampere University Hospital, Tampere, Finland
| | - Sari Karlsson
- Department of Intensive Care, Tampere University Hospital, Tampere, Finland
| | - Eerika Koskinen
- Department of Neurology, Tampere University Hospital, Tampere, Finland
| | - Teemu Luoto
- Department of Neurosurgery, Tampere University Hospital, Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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4
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Zhou R, Li J, Wang R, Chen Z, Zhou F. The neurovascular unit in healthy and injured spinal cord. J Cereb Blood Flow Metab 2023; 43:1437-1455. [PMID: 37190756 PMCID: PMC10414016 DOI: 10.1177/0271678x231172008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 02/09/2023] [Accepted: 03/24/2023] [Indexed: 05/17/2023]
Abstract
The neurovascular unit (NVU) reflects the close temporal and spatial link between neurons and blood vessels. However, the understanding of the NVU in the spinal cord is far from clear and largely based on generalized knowledge obtained from the brain. Herein, we review the present knowledge of the NVU and highlight candidate approaches to investigate the NVU, particularly focusing on the spinal cord. Several unique features maintain the highly regulated microenvironment in the NVU. Autoregulation and neurovascular coupling ensure regional blood flow meets the metabolic demand according to the blood supply or local neural activation. The blood-central nervous system barrier partitions the circulating blood from neural parenchyma and facilitates the selective exchange of substances. Furthermore, we discuss spinal cord injury (SCI) as a common injury from the perspective of NVU dysfunction. Hopefully, this review will help expand the understanding of the NVU in the spinal cord and inspire new insights into SCI.
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Affiliation(s)
- Rubing Zhou
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Junzhao Li
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Ruideng Wang
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Zhengyang Chen
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Fang Zhou
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
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Behem CR, Haunschild J, Pinnschmidt HO, Gaeth C, Graessler MF, Trepte CJC, Etz CD, Debus ES, Wipper SH. Effects of fluids vs. vasopressors on spinal cord microperfusion in hemorrhagic shock induced ischemia/reperfusion. Microvasc Res 2022; 143:104383. [PMID: 35605693 DOI: 10.1016/j.mvr.2022.104383] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 05/13/2022] [Accepted: 05/17/2022] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Spinal cord injury induced by ischemia/reperfusion is a devastating complication of aortic repair. Despite developments for prevention and treatment of spinal cord injury, incidence is still considerably high majorly impacting patient outcome. Microcirculation is paramount for tissue perfusion and oxygen supply and often dissociated from macrohemodynamic parameters used to guide resuscitation. Effects of fluids vs. vasopressors in the setting of hemodynamic resuscitation on spinal cord microperfusion are unknown. Aim of this study was to compare the effects of vasopressor and fluid resuscitation on spinal cord microperfusion in a translational acute pig model of hemorrhagic shock induced ischemia/reperfusion injury. METHODS We designed this study as prospective randomized explorative large animal study. We induced hemorrhagic shock in 20 pigs as a model of global ischemia/reperfusion injury. We randomized animals to receive either fluid or vasopressor resuscitation. We measured spinal cord microperfusion using fluorescent microspheres as well as laser-Doppler probes. We monitored and analyzed macrohemodynamic parameters and cerebrospinal fluid pressure. RESULTS Spinal cord microperfusion decreased following hemorrhagic shock induced ischemia/reperfusion injury. Both fluids and vasopressors sufficiently restored spinal cord microperfusion. There were no important changes between groups (percentage changes compared to baseline: fluids 14.0 (0.31-27.6) vs. vasopressors 24.3 (8.12-40.4), p = .340). However, cerebrospinal fluid pressure was higher in animals receiving fluid resuscitation (percentage changes compared to baseline: fluids 27.7 (12.6-42.8) vs. vasopressors -5.56 ((-19.8)-8.72), p = .003). Microcirculatory resuscitation was in line with improvements of macrohemodynamic parameters. CONCLUSIONS Both, fluids and vasopressors, equally restored spinal cord microperfusion in a porcine acute model of hemorrhagic shock induced ischemia/reperfusion injury. However, significant differences in cerebrospinal fluid pressure following resuscitation were present. Future studies should evaluate these effects in perfusion disruption induced ischemia/reperfusion conditions of microcirculatory deterioration.
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Affiliation(s)
- Christoph R Behem
- Department of Anesthesiology, Center of Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Josephina Haunschild
- University Department for Cardiac Surgery, Heart Center Leipzig, Leipzig, Germany
| | - Hans O Pinnschmidt
- Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Catharina Gaeth
- Department of Vascular Medicine, University Heart and Vascular Center Hamburg (UHZ), Hamburg, Germany
| | - Michael F Graessler
- Department of Anesthesiology, Center of Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Constantin J C Trepte
- Department of Anesthesiology, Center of Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian D Etz
- University Department for Cardiac Surgery, Heart Center Leipzig, Leipzig, Germany
| | - E Sebastian Debus
- Department of Vascular Medicine, University Heart and Vascular Center Hamburg (UHZ), Hamburg, Germany
| | - Sabine H Wipper
- Department of Vascular Medicine, University Heart and Vascular Center Hamburg (UHZ), Hamburg, Germany
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6
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Torres-Espín A, Haefeli J, Ehsanian R, Torres D, Almeida CA, Huie JR, Chou A, Morozov D, Sanderson N, Dirlikov B, Suen CG, Nielson JL, Kyritsis N, Hemmerle DD, Talbott JF, Manley GT, Dhall SS, Whetstone WD, Bresnahan JC, Beattie MS, McKenna SL, Pan JZ, Ferguson AR. Topological network analysis of patient similarity for precision management of acute blood pressure in spinal cord injury. eLife 2021; 10:68015. [PMID: 34783309 PMCID: PMC8639149 DOI: 10.7554/elife.68015] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 10/23/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients. Methods: Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods. Results: Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76–[104-117] mmHg associated with neurological recovery. Conclusions: We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention. Funding: NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB); DOE: DE-AC02-05CH11231 (DM). Spinal cord injury is a devastating condition that involves damage to the nerve fibers connecting the brain with the spinal cord, often leading to permanent changes in strength, sensation and body functions, and in severe cases paralysis. Scientists around the world work hard to find ways to treat or even repair spinal cord injuries but few patients with complete immediate paralysis recover fully. Immediate paralysis is caused by direct damage to neurons and their extension in the spinal cord. Previous research has shown that blood pressure regulation may be key in saving these damaged neurons, as spinal cord injuries can break the communication between nerves that is involved in controlling blood pressure. This can lead to a vicious cycle of dysregulation of blood pressure and limit the supply of blood and oxygen to the damaged spinal cord tissue, exacerbating the death of spinal neurons. Management of blood pressure is therefore a key target for spinal cord injury care, but so far, the precise thresholds to enable neurons to recover are poorly understood. To find out more, Torres-Espin, Haefeli et al. used machine learning software to analyze previously recorded blood pressure and heart rate data obtained from 118 patients that underwent spinal cord surgery after acute spinal cord injury. The analyses revealed that patients who suffered from either low or high blood pressure during surgery had poorer prospects of recovery. Statistical models confirming these findings showed that the optimal blood pressure range to ensure recovery lies between 76 to 104-117 mmHg. Any deviation from this narrow window would dramatically worsen the ability to recover. These findings suggests that dysregulated blood pressure during surgery affects to odds of recovery in patients with a spinal cord injury. Torres-Espin, Haefeli et al. provide specific information that could improve current clinical practice in trauma centers. In the future, such machine learning tools and models could help develop real-time models that could predict the likelihood of a patient’s recovery following spinal cord injury and related neurological conditions.
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Affiliation(s)
- Abel Torres-Espín
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - Jenny Haefeli
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - Reza Ehsanian
- Division of Physical Medicine and Rehabilitation, Department of Orthopaedics and Rehabilitation, University of New Mexico School of Medicine, Albuquerque, United States
| | - Dolores Torres
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - Carlos A Almeida
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - J Russell Huie
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States.,San Francisco Veterans Affairs Healthcare System, San Francisco, United States
| | - Austin Chou
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - Dmitriy Morozov
- Computational Research Division, Lawrence Berkeley National Laboratory, Berkeley, United States
| | | | - Benjamin Dirlikov
- Rehabilitation Research Center, Santa Clara Valley Medical Center, San Jose, United States
| | - Catherine G Suen
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - Jessica L Nielson
- Department of Psychiatry and Behavioral Science, and University of Minnesota, Minneapolis, United States.,Institute for Health Informatics, University of Minnesota, Minneapolis, United States
| | - Nikos Kyritsis
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - Debra D Hemmerle
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - Jason F Talbott
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
| | - Geoffrey T Manley
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - Sanjay S Dhall
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - William D Whetstone
- Department of Emergency Medicine, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - Jacqueline C Bresnahan
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States.,San Francisco Veterans Affairs Healthcare System, San Francisco, United States
| | - Michael S Beattie
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States.,San Francisco Veterans Affairs Healthcare System, San Francisco, United States
| | - Stephen L McKenna
- Department of Physical Medicine and Rehabilitation, Santa Clara Valley Medical Center, San Jose, United States.,Department of Neurosurgery, Stanford University, Stanford, United States
| | - Jonathan Z Pan
- Department of Anesthesia and Perioperative Care, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States
| | - Adam R Ferguson
- Weill Institute for Neurosciences; Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, United States.,San Francisco Veterans Affairs Healthcare System, San Francisco, United States
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7
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Zhang Y, Al Mamun A, Yuan Y, Lu Q, Xiong J, Yang S, Wu C, Wu Y, Wang J. Acute spinal cord injury: Pathophysiology and pharmacological intervention (Review). Mol Med Rep 2021; 23:417. [PMID: 33846780 PMCID: PMC8025476 DOI: 10.3892/mmr.2021.12056] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 11/12/2020] [Indexed: 12/12/2022] Open
Abstract
Spinal cord injury (SCI) is one of the most debilitating of all the traumatic conditions that afflict individuals. For a number of years, extensive studies have been conducted to clarify the molecular mechanisms of SCI. Experimental and clinical studies have indicated that two phases, primary damage and secondary damage, are involved in SCI. The initial mechanical damage is caused by local impairment of the spinal cord. In addition, the fundamental mechanisms are associated with hyperflexion, hyperextension, axial loading and rotation. By contrast, secondary injury mechanisms are led by systemic and cellular factors, which may also be initiated by the primary injury. Although significant advances in supportive care have improved clinical outcomes in recent years, a number of studies continue to explore specific pharmacological therapies to minimize SCI. The present review summarized some important pathophysiologic mechanisms that are involved in SCI and focused on several pharmacological and non‑pharmacological therapies, which have either been previously investigated or have a potential in the management of this debilitating injury in the near future.
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Affiliation(s)
- Yi Zhang
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, P.R. China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Abdullah Al Mamun
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Yuan Yuan
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Qi Lu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Jun Xiong
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Shulin Yang
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, P.R. China
| | - Chengbiao Wu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Yanqing Wu
- Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang 325035, P.R. China
| | - Jian Wang
- Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
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8
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Shahsavani N, Kataria H, Karimi-Abdolrezaee S. Mechanisms and repair strategies for white matter degeneration in CNS injury and diseases. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166117. [PMID: 33667627 DOI: 10.1016/j.bbadis.2021.166117] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 12/14/2022]
Abstract
White matter degeneration is an important pathophysiological event of the central nervous system that is collectively characterized by demyelination, oligodendrocyte loss, axonal degeneration and parenchymal changes that can result in sensory, motor, autonomic and cognitive impairments. White matter degeneration can occur due to a variety of causes including trauma, neurotoxic exposure, insufficient blood flow, neuroinflammation, and developmental and inherited neuropathies. Regardless of the etiology, the degeneration processes share similar pathologic features. In recent years, a plethora of cellular and molecular mechanisms have been identified for axon and oligodendrocyte degeneration including oxidative damage, calcium overload, neuroinflammatory events, activation of proteases, depletion of adenosine triphosphate and energy supply. Extensive efforts have been also made to develop neuroprotective and neuroregenerative approaches for white matter repair. However, less progress has been achieved in this area mainly due to the complexity and multifactorial nature of the degeneration processes. Here, we will provide a timely review on the current understanding of the cellular and molecular mechanisms of white matter degeneration and will also discuss recent pharmacological and cellular therapeutic approaches for white matter protection as well as axonal regeneration, oligodendrogenesis and remyelination.
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Affiliation(s)
- Narjes Shahsavani
- Department of Physiology and Pathophysiology, Regenerative Medicine Program, Spinal Cord Research Centre, Children's Hospital Research Institute of Manitoba, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Hardeep Kataria
- Department of Physiology and Pathophysiology, Regenerative Medicine Program, Spinal Cord Research Centre, Children's Hospital Research Institute of Manitoba, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Soheila Karimi-Abdolrezaee
- Department of Physiology and Pathophysiology, Regenerative Medicine Program, Spinal Cord Research Centre, Children's Hospital Research Institute of Manitoba, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
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9
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Fiani B, Kondilis A, Soula M, Tao A, Alvi MA. Novel Methods of Necroptosis Inhibition for Spinal Cord Injury Using Translational Research to Limit Secondary Injury and Enhance Endogenous Repair and Regeneration. Neurospine 2021; 18:261-270. [PMID: 33494555 PMCID: PMC8255772 DOI: 10.14245/ns.2040722.361] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 01/02/2021] [Indexed: 11/19/2022] Open
Abstract
Spinal cord injuries (SCIs) pose an immense challenge from a clinical perspective as current treatments and interventions have been found to provide marginal improvements in clinical outcome (with varying degrees of success) particularly in areas of motor and autonomic function. In this review, the pathogenesis of SCI will be described, particularly as it relates to the necroptotic pathway which has been implicated in limiting recovery of SCI via its roles in neuronal cell death, glial scarring, inflammation, and axonal demyelination and degeneration. Major mediators of the necroptotic pathway including receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed-lineage kinase domain-like will be described in detail regarding their role in facilitating necroptosis. Additionally, due to the rapid accumulation of reactive oxygen species and inflammatory markers, the onset of necroptosis can begin within hours following SCI, thus developing therapeutics that readily cross the blood-brain barrier and inhibit necroptosis during these critical periods of inflammation are imperative in preventing irreversible damage. As such, current therapeutic interventions regarding SCI and targeting of the necroptotic pathway will be explored as will discussion of potential future therapeutics that show promise in minimizing long-term or permanent damage to the spinal cord following severe injury.
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Affiliation(s)
- Brian Fiani
- Department of Neurosurgery, Desert Regional Medical Center, Palm Springs, CA, USA
| | - Athanasios Kondilis
- Michigan State University College of Osteopathic Medicine, East Lansing, MI, USA
| | - Marisol Soula
- New York University Grossman School of Medicine, New York, NY, USA
| | - Anthony Tao
- New York University Grossman School of Medicine, New York, NY, USA
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10
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Zhong W, Wang L, Huang T, Luo X. Risk factors for rapid progressive neurological deterioration in patients with cervical spondylotic myelopathy. J Orthop Surg Res 2021; 16:75. [PMID: 33478509 PMCID: PMC7818545 DOI: 10.1186/s13018-021-02227-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 01/11/2021] [Indexed: 01/04/2024] Open
Abstract
Background The rapid progressive cervical spondylotic myelopathy (rp-CSM) which had a course of CSM less than 1 month and suffered rapidly progressive neurological deterioration had few reports. Therefore, it is important for us to recognize the pathophysiology of CSM especially the rp-CSM. The study aimed to investigate the risk factors for rapidly progressive (rp) neurological deterioration in patients with cervical spondylotic myelopathy (CSM). Methods A total of 159 patients were reviewed and divided into an rp-CSM group and a chronic-CSM (c-CSM) group. Various clinical indexes, including age, sex, Japanese Orthopaedic Association (JOA) score, intramedullary MR T2-hyperintensity, congenital/degenerative spinal stenosis, and local type of ossification of the posterior longitudinal ligament (OPLL), were analyzed, and independent risk factors were investigated. Results Thirty-four of 159 patients (21.4%) were diagnosed with rp-CSM. All patients were followed up for a mean of 68.56 ± 14.00 months in the rp-CSM group and 62.66 ± 19.95 months in the c-CSM group. No significant difference was found in sex, mean age, smoking and drinking status, diabetes mellitus (DM), hypertension, surgery time, blood loss, JOA score, degenerative spinal stenosis, or OPLL (local). Univariate analyses demonstrated that rp-CSM patients tended to have MR T2-hyperintensity, longer hospital stay, shorter waiting time for surgery, more congenital spinal stenosis, and worse neurological function and to prefer more posterior surgeries than c-CSM patients. A multiple logistic regression analysis showed that congenital spinal stenosis and MR T2-hyperintensity were independently related to the presence of rp-CSM. Conclusions MR T2-hyperintensity and congenital spinal stenosis were risk factors for rp-CSM. Although neurological function deteriorates rapidly, early surgical decompression is recommended and can achieve good neurological recovery after surgery, indicating that rp-CSM could be a reversible condition.
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Affiliation(s)
- Weiyang Zhong
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Lin Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Tianji Huang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Xiaoji Luo
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China.
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11
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Machino M, Ando K, Kobayashi K, Nakashima H, Kanbara S, Ito S, Inoue T, Koshimizu H, Ito K, Kato F, Imagama S. Prediction of outcome following laminoplasty of cervical spondylotic myelopathy: Focus on the minimum clinically important difference. J Clin Neurosci 2020; 81:321-327. [PMID: 33222939 DOI: 10.1016/j.jocn.2020.09.065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/13/2020] [Accepted: 09/28/2020] [Indexed: 11/30/2022]
Abstract
The minimum clinically important difference (MCID) of the Japanese Orthopaedic Association (JOA) score has been reported to be around 2.5 points in cervical myelopathy. This study sought to define significant predictive factors on achieving the MCID following laminoplasty in a large series of patients with cervical spondylotic myelopathy (CSM). A total of 485 consecutive patients with CSM (295 males and 190 females; mean age: 67.0 years; age range: 42-91 years) who underwent laminoplasty were prospectively enrolled. The average postoperative follow-up period was 26.6 months (range: 12-66 months). We calculated the achieved JOA score. The relationships between outcomes and various clinical and imaging predictors including comorbidity and quantitative performance tests were examined. Logistic regression analysis was conducted to identify the predictors correlated with a JOA score of 2.5 points or more. Clinically meaningful gains were exhibited in 299 patients (61.6%) with a JOA score of ≥2.5 points, whereas 186 patients (38.4%) achieved a JOA score of <2.5 points. Univariate logistic regression analysis showed the predictive factors with a shorter duration of CSM symptoms, lower preoperative JOA scores, absence of hypertension, no use of anticoagulant/antiplatelet agents, and nonsmoking status. Multivariate logistic regression analysis determined that the duration of CSM symptoms (odds ratio: 0.771, 95% confidence interval: 0.705-0.844; p < 0.01) was the only significant predictive factor for achieving JOA scores of ≥2.5 points. An important predictor of MCID achievement following laminoplasty was shorter duration of CSM symptoms.
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Affiliation(s)
- Masaaki Machino
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kei Ando
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuyoshi Kobayashi
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroaki Nakashima
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shunsuke Kanbara
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Sadayuki Ito
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Taro Inoue
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Koshimizu
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keigo Ito
- Department of Orthopedic Surgery, Chubu Rosai Hospital, Japan Organization of Occupational Health and Safety, Nagoya, Japan.
| | - Fumihiko Kato
- Department of Orthopedic Surgery, Chubu Rosai Hospital, Japan Organization of Occupational Health and Safety, Nagoya, Japan
| | - Shiro Imagama
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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12
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Cheung A, Streijger F, So K, Okon EB, Manouchehri N, Shortt K, Kim KT, Keung MSM, Chan RM, Fong A, Sun J, Griesdale DE, Sehkon MS, Kwon BK. Relationship between Early Vasopressor Administration and Spinal Cord Hemorrhage in a Porcine Model of Acute Traumatic Spinal Cord Injury. J Neurotrauma 2020; 37:1696-1707. [PMID: 32233727 DOI: 10.1089/neu.2019.6781] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Current practice guidelines for acute spinal cord injury (SCI) recommend augmenting mean arterial blood pressure (MAP) for the first 7 days post-injury. After SCI, the cord may be compressed by the bone/ligaments of the spinal column, limiting regional spinal cord blood flow. Following surgical decompression, blood flow may be restored, and can potentially promote a "reperfusion" injury. The effects of MAP augmentation on the injured cord during the compressed and decompressed conditions have not been previously characterized. Here, we used our porcine model of SCI to examine the impact of MAP augmentation on blood flow, oxygenation, hydrostatic pressure, metabolism, and intraparenchymal (IP) hemorrhage within the compressed and then subsequently decompressed spinal cord. Yucatan mini-pigs underwent a T10 contusion injury followed by 2 h of sustained compression. MAP augmentation of ∼20 mm Hg was achieved with norepinephrine (NE). Animals received MAP augmentation either during the period of cord compression (CP), after decompression (DCP), or during both periods (CP-DCP). Probes to monitor spinal cord blood flow (SCBF), oxygenation, pressure, and metabolic responses were inserted into the cord parenchyma adjacent to the injury site to measure these responses. The cord was harvested for histological evaluation. MAP augmentation increased SCBF and oxygenation in all groups. In the CP-DCP group, spinal cord pressure steadily increased and histological analysis showed significantly increased hemorrhage in the spinal cord at and near the injury site. MAP augmentation with vasopressors may improve blood flow and reduce ischemia in the injured cord but may also induce undesirable increases in IP pressure and hemorrhage.
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Affiliation(s)
- Amanda Cheung
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Femke Streijger
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Kitty So
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Elena B Okon
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Neda Manouchehri
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Katelyn Shortt
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Kyoung-Tae Kim
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada.,Department of Neurosurgery, Kyungpook National University Hospital, Kyungpook National University, Daegu, South Korea
| | - Martin Sheung Man Keung
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Ryan M Chan
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Allan Fong
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Jenny Sun
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Donald E Griesdale
- Department of Anesthesiology, Division of Critical Care Medicine, Vancouver General Hospital, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Mypinder S Sehkon
- Department of Medicine, Division of Critical Care Medicine, Vancouver General Hospital, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Brian K Kwon
- International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada.,Vancouver Spine Surgery Institute, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada
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13
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Wu Z, Li L, Xie F, Xu G, Dang D, Yang Q. Enhancing KCNQ Channel Activity Improves Neurobehavioral Recovery after Spinal Cord Injury. J Pharmacol Exp Ther 2020; 373:72-80. [PMID: 31969383 PMCID: PMC7076523 DOI: 10.1124/jpet.119.264010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 01/17/2020] [Indexed: 01/08/2023] Open
Abstract
Spinal cord injury (SCI) usually leads to acute neuronal death and delayed secondary degeneration, resulting in sensory dysfunction, paralysis, and chronic pain. Excessive excitation is one of the critical factors leading to secondary neural damage initiated by various insults. KCNQ/Kv7 channels are highly expressed in spinal neurons and axons and play an important role in controlling their excitability. Enhancing KCNQ channel activity by using its specific opener retigabine could thus be a plausible treatment strategy to reduce the pathology after SCI. We produced contusive SCI at T10 in adult male rats, which then received 10 consecutive days' treatment with retigabine or vehicle starting 3 hours or 3 days after contusion. Two different concentrations and two different delivery methods were applied. Delivery of retigabine via Alzet osmotic pumps, but not intraperitoneal injections 3 hours after contusion, promoted recovery of locomotor function. Remarkably, retigabine delivery in both methods significantly attenuated the development of mechanical stimuli-induced hyperreflexia and spontaneous pain; however, no significant difference in the thermal threshold was observed. Although retigabine delivered 3 days after contusion significantly attenuated the development of mechanical hypersensitivity and spontaneous pain, the locomotor function is not improved by the delayed treatments. Finally, we found that early application of retigabine attenuates the inflammatory activity in the spinal cord and increases the survival of white matter after SCI. Our results suggest that decreasing neuronal excitability by targeting KCNQ/Kv7 channels at acute stage aids the recovery of locomotor function and attenuates the development of neuropathic pain after SCI. SIGNIFICANCE STATEMENT: Several pharmacological interventions have been proposed for spinal cord injury (SCI) treatment, but none have been shown to be both effective and safe in clinical trials. Necrotic neuronal death and chronic pain are often the cost of pathological neural excitation after SCI. We show that early, brief application of retigabine could aid locomotor and sensory neurobehavioral recovery after SCI, supporting the use of this drug in the clinic to promote motor and sensory function in patients with SCI.
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Affiliation(s)
- Zizhen Wu
- The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (Z.W.); Department of Integrative Biology and Pharmacology, McGovern Medical School at UT Health, Houston, Texas (L.L., F.X.); Department of Critical Medicine, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China (F.X.); and Department of Neuroscience, Cell Biology and Anatomy at University of Texas Medical Branch, Galveston, Texas (G.X., D.D., Q.Y.)
| | - Lin Li
- The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (Z.W.); Department of Integrative Biology and Pharmacology, McGovern Medical School at UT Health, Houston, Texas (L.L., F.X.); Department of Critical Medicine, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China (F.X.); and Department of Neuroscience, Cell Biology and Anatomy at University of Texas Medical Branch, Galveston, Texas (G.X., D.D., Q.Y.)
| | - Fuhua Xie
- The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (Z.W.); Department of Integrative Biology and Pharmacology, McGovern Medical School at UT Health, Houston, Texas (L.L., F.X.); Department of Critical Medicine, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China (F.X.); and Department of Neuroscience, Cell Biology and Anatomy at University of Texas Medical Branch, Galveston, Texas (G.X., D.D., Q.Y.)
| | - Guoying Xu
- The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (Z.W.); Department of Integrative Biology and Pharmacology, McGovern Medical School at UT Health, Houston, Texas (L.L., F.X.); Department of Critical Medicine, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China (F.X.); and Department of Neuroscience, Cell Biology and Anatomy at University of Texas Medical Branch, Galveston, Texas (G.X., D.D., Q.Y.)
| | - Danny Dang
- The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (Z.W.); Department of Integrative Biology and Pharmacology, McGovern Medical School at UT Health, Houston, Texas (L.L., F.X.); Department of Critical Medicine, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China (F.X.); and Department of Neuroscience, Cell Biology and Anatomy at University of Texas Medical Branch, Galveston, Texas (G.X., D.D., Q.Y.)
| | - Qing Yang
- The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (Z.W.); Department of Integrative Biology and Pharmacology, McGovern Medical School at UT Health, Houston, Texas (L.L., F.X.); Department of Critical Medicine, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China (F.X.); and Department of Neuroscience, Cell Biology and Anatomy at University of Texas Medical Branch, Galveston, Texas (G.X., D.D., Q.Y.)
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14
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Badhiwala JH, Wilson JR, Kwon BK, Casha S, Fehlings MG. A Review of Clinical Trials in Spinal Cord Injury Including Biomarkers. J Neurotrauma 2019; 35:1906-1917. [PMID: 29888678 DOI: 10.1089/neu.2018.5935] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Acute traumatic spinal cord injury (SCI) entered the arena of prospective, randomized clinical trials almost 40 years ago, with the undertaking of the National Acute Spinal Cord Study (NASCIS) I trial. Since then, a number of clinical trials have been conducted in the field, spurred by the devastating physical, social, and economic consequences of acute SCI for patients, families, and society at large. Many of these have been controversial and attracted criticism. The current review provides a critical summary of select past and current clinical trials in SCI, focusing in particular on the findings of prospective, randomized controlled trials, the challenges and barriers encountered, and the valuable lessons learned that can be applied to future trials.
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Affiliation(s)
- Jetan H Badhiwala
- 1 Division of Neurosurgery, Department of Surgery, University of Toronto , Toronto, Ontario, Canada
| | - Jefferson R Wilson
- 1 Division of Neurosurgery, Department of Surgery, University of Toronto , Toronto, Ontario, Canada
| | - Brian K Kwon
- 2 Vancouver Spine Surgery Institute, Department of Orthopedics, University of British Columbia , Vancouver, British Columbia, Canada
| | - Steven Casha
- 3 Section of Neurosurgery, Department of Clinical Neurosciences, University of Calgary , Calgary, Alberta, Canada
| | - Michael G Fehlings
- 1 Division of Neurosurgery, Department of Surgery, University of Toronto , Toronto, Ontario, Canada
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15
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Risk Factors for Rapidly Progressive Neurological Deterioration in Cervical Spondylotic Myelopathy. Spine (Phila Pa 1976) 2019; 44:E723-E730. [PMID: 30628980 DOI: 10.1097/brs.0000000000002969] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A retrospective single-center study. OBJECTIVE This study sought to clarify the risk factors and to evaluate the surgical outcome in patients with rapidly progressive cervical spondylotic myelopathy (rp-CSM). SUMMARY OF BACKGROUND DATA CSM is a degenerative spine disease presenting a slow development of myelopathy. Some patients, however, show rapidly progressive neurological deterioration (especially gait disturbances) without any trauma. At present, there is little information about this condition. METHODS We studied 71 consecutive CSM patients (52 men, 19 women) with a mean age of 67.1 years, and the follow-up period was 1 year. Patients were divided into two groups: rp-CSM and chronic-CSM (c-CSM) groups. The Japanese Orthopaedic Association score and various clinical differences, including age, sex, comorbidity, the waiting period from symptomatic onset to surgery, cervical range of motion, and intramedullary MR T2-hyperintensity were analyzed, and independent risk factors were determined using a logistic regression analysis. RESULTS Eighteen of 71 patients (25.4%) were diagnosed with rp-CSM. There were no significant differences between the two groups with regard to age, sex, or cervical range of motion. In the rp-CSM group, the preoperative upper/lower extremities and bladder functions were worse, and the waiting period for surgery was shorter (rp-CSM 1.2 mo, c-CSM 25.7 mo). Patients with rp-CSM had a history of cardiovascular event (CVE) (rp-CSM 44.4%, c-CSM 15.1%) and presented with MR T2-hyperintensity (rp-CSM 94.4%, c-CSM 58.5%), especially at the C4/5 disc level. Independent risk factors were a history of CVE (odds ratio = 4.7) and MR T2-hyperintensity (odds ratio = 12.5). The rp-CSM group showed a better neurological recovery after decompression surgery (the Japanese Orthopaedic Association recovery rate: rp-CSM 64.5%, c-CSM 40.7%). CONCLUSION A history of CVE and MR T2-hyperintensity were risk factors for rp-CSM. Despite rapid neurological deterioration, rp-CSM patients showed a good neurological recovery after surgery, and thus indicating that rp-CSM is a reversible condition. LEVEL OF EVIDENCE 4.
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16
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Intraoperative contrast-enhanced ultrasonography for microcirculatory evaluation in rhesus monkey with spinal cord injury. Oncotarget 2018; 8:40756-40764. [PMID: 28489576 PMCID: PMC5522262 DOI: 10.18632/oncotarget.17252] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 04/03/2017] [Indexed: 11/25/2022] Open
Abstract
This study tried to quantify spinal cord perfusion by using contrast-enhanced ultrasound (CEUS) in rhesus monkey models with acute spinal cord injury. Acute spinal cord perfusion after injury was detected by CEUS, coupling with conventional ultrasound (US) and Color Doppler US (CDFI). Time-intensity curves and perfusion parameters were obtained by autotracking contrast quantification (ACQ) software in the epicenter and adjacent regions of injury, respectively. Neurological and histological examinations were performed to confirm the severity of injury. US revealed spinal cords were hypoechoic and homogeneous, whereas dura maters, pia maters, and cerebral aqueducts were hyperechoic. After spinal cord contusion, the injured spinal cord was hyperechoic on US, and intramedullary vessels of adjacent region of injury were increased and dilated on CDFI. On CEUS hypoperfusion were found in the epicenter of injury, while hyperperfusion in its adjacent region. Quantitative analysis showed that peak intensity (PI) decreased in epicenters of injury but significantly increased in adjacent regions at all time points (p < 0.05). Functional evaluation demonstrated significant deterioration compared to pre-contusion (p < 0.05). Quantitative analysis with CEUS is a promising method for monitoring perfusion changes of spinal cord injury in overall views and real-time.
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17
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Sabit B, Zeiler FA, Berrington N. The Impact of Mean Arterial Pressure on Functional Outcome Post-Acute Spinal Cord Injury: A Scoping Systematic Review of Animal Models. J Neurotrauma 2017; 34:2583-2594. [PMID: 27785982 DOI: 10.1089/neu.2016.4735] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The aim of this work was to perform a scoping systematic review on the animal literature surrounding mean arterial blood pressure (MAP) and functional outcomes post-acute spinal cord injury (ASCI). We performed a systematic review of the literature by searching: MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to January 2015. We also performed a hand search of various published meeting proceedings. Through a two-step review process, using two independent reviewers, we selected articles for the final review based on pre-defined inclusion/exclusion criteria. Ten studies were included within the final systematic review. A variety of animal models were used within these studies. All included studies had some objective means of documenting functional outcome post-manipulation of the MAP. Four studies could be considered to be "positive studies," showing some neurological improvement or beneficial effect to having the blood pressure manipulated. Two studies displayed worse functional outcomes secondary to episodes of hypotension. Four studies failed to demonstrate a relationship between MAP and functional outcome within the animal models. This review concludes that, within the animal literature, there is insufficient evidence to draw a conclusion about the effect of MAP on neurological outcome in animal models of ASCI.
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Affiliation(s)
- Behzad Sabit
- 1 Section of Neurosurgery, Department of Surgery, University of Manitoba , Winnipeg, Manitoba, Canada
| | - Frederick A Zeiler
- 1 Section of Neurosurgery, Department of Surgery, University of Manitoba , Winnipeg, Manitoba, Canada
- 2 Clinician Investigator Program, University of Manitoba , Winnipeg, Manitoba, Canada
- 3 Division of Anaesthesia, University of Cambridge , Cambridge, United Kingdom
| | - Neil Berrington
- 1 Section of Neurosurgery, Department of Surgery, University of Manitoba , Winnipeg, Manitoba, Canada
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18
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O'Hare Doig RL, Chiha W, Giacci MK, Yates NJ, Bartlett CA, Smith NM, Hodgetts SI, Harvey AR, Fitzgerald M. Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma. BMC Neurosci 2017; 18:62. [PMID: 28806920 PMCID: PMC5557315 DOI: 10.1186/s12868-017-0380-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 08/05/2017] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca2+ channel inhibitor Lomerizine (Lom), the Ca2+ permeable AMPA receptor inhibitor YM872 and the P2X7 receptor inhibitor oxATP. RESULTS Following partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination. CONCLUSIONS Data indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs.
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Affiliation(s)
- Ryan L O'Hare Doig
- Experimental and Regenerative Neurosciences, School of Biological Sciences, The University of Western Australia, Crawley, WA, 6009, Australia.,Experimental and Regenerative Neurosciences, School of Human Sciences, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Wissam Chiha
- Experimental and Regenerative Neurosciences, School of Biological Sciences, The University of Western Australia, Crawley, WA, 6009, Australia.,Experimental and Regenerative Neurosciences, School of Human Sciences, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Marcus K Giacci
- Experimental and Regenerative Neurosciences, School of Biological Sciences, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Nathanael J Yates
- Experimental and Regenerative Neurosciences, School of Biological Sciences, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Carole A Bartlett
- Experimental and Regenerative Neurosciences, School of Biological Sciences, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Nicole M Smith
- Experimental and Regenerative Neurosciences, School of Biological Sciences, The University of Western Australia, Crawley, WA, 6009, Australia.,Experimental and Regenerative Neurosciences, School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Stuart I Hodgetts
- Experimental and Regenerative Neurosciences, School of Human Sciences, The University of Western Australia, Crawley, WA, 6009, Australia.,Perron Institute for Neurological and Translational Science, Verdun St, Nedlands, WA, 6009, Australia
| | - Alan R Harvey
- Experimental and Regenerative Neurosciences, School of Human Sciences, The University of Western Australia, Crawley, WA, 6009, Australia.,Perron Institute for Neurological and Translational Science, Verdun St, Nedlands, WA, 6009, Australia
| | - Melinda Fitzgerald
- Experimental and Regenerative Neurosciences, School of Biological Sciences, The University of Western Australia, Crawley, WA, 6009, Australia. .,Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia. .,Perron Institute for Neurological and Translational Science, Verdun St, Nedlands, WA, 6009, Australia.
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Abstract
Spinal cord injury (SCI) has been considered an incurable condition and it often causes devastating sequelae. In terms of the pathophysiology of SCI, reducing secondary damage is the key to its treatment. Various researches and clinical trials have been performed, and some of them showed promising results; however, there is still no gold standard treatment with sufficient evidence. Two therapeutic concepts for SCI are neuroprotective and neuroregenerative strategies. The neuroprotective strategy modulates the pathomechanism of SCI. The purpose of neuroprotective treatment is to minimize secondary damage following direct injury. The aim of neuroregenerative treatment is to enhance the endogenous regeneration process and to alter the intrinsic barrier. With advancement in biotechnology, cell therapy using cell transplantation is currently under investigation. This review discusses the pathophysiology of SCI and introduces the therapeutic candidates that have been developed so far.
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Affiliation(s)
- Young-Hoon Kim
- Department of Orthopaedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kee-Yong Ha
- Department of Orthopaedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sang-Il Kim
- Department of Orthopaedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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20
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O'Hare Doig RL, Bartlett CA, Smith NM, Hodgetts SI, Dunlop SA, Hool L, Fitzgerald M. Specific combinations of ion channel inhibitors reduce excessive Ca 2+ influx as a consequence of oxidative stress and increase neuronal and glial cell viability in vitro. Neuroscience 2016; 339:450-462. [PMID: 27725216 DOI: 10.1016/j.neuroscience.2016.10.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 09/15/2016] [Accepted: 10/02/2016] [Indexed: 01/02/2023]
Abstract
Combinations of Ca2+ channel inhibitors have been proposed as an effective means to prevent excess Ca2+ flux and death of neurons and glia following neurotrauma in vivo. However, it is not yet known if beneficial outcomes such as improved viability have been due to direct effects on intracellular Ca2+ concentrations. Here, the effects of combinations of Lomerizine (Lom), 2,3-dioxo-7-(1H-imidazol-1-yl)6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]acetic acid monohydrate (YM872), 3,5-dimethyl-1-adamantanamine (memantine (Mem)) and/or adenosine 5'-triphosphate periodate oxidized sodium salt (oxATP) to block voltage-gated Ca2+ channels, Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, NMDA receptors and purinergic P2X7 receptors (P2X7R) respectively, on Ca2+ concentration and viability of rat primary mixed cortical (MC) cultures exposed to hydrogen peroxide (H2O2) insult, were assessed. The contribution of ryanodine-sensitive intracellular stores to intracellular Ca2+ concentration was also assessed. Live cell calcium imaging revealed that a 30min H2O2 insult induced a slow increase in intracellular Ca2+, in part from intracellular sources, associated with loss of cell viability by 6h. Most combinations of inhibitors that included oxATP significantly decreased Ca2+ influx and increased cell viability when administered simultaneously with H2O2. However, reductions in intracellular Ca2+ concentration were not always linked to improved cell viability. Examination of the density of specific cell subpopulations demonstrated that most combinations of inhibitors that included oxATP preserved NG2+ non-oligodendroglial cells, but preservation of astrocytes and neurons required additional inhibitors. Olig2+ oligodendroglia and ED-1+ activated microglia/macrophages were not preserved by any of the inhibitor combinations. These data indicate that following H2O2 insult, limiting intracellular Ca2+ entry via P2X7R is generally associated with increased cell viability. Protection of NG2+ non-oligodendroglial cells by Ca2+ channel inhibitor combinations may contribute to observed beneficial outcomes in vivo.
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Affiliation(s)
- Ryan L O'Hare Doig
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, Western Australia, Australia; School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia; School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Western Australia, Australia
| | - Carole A Bartlett
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, Western Australia, Australia; School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia
| | - Nicole M Smith
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, Western Australia, Australia; School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia; School of Chemistry and Biochemistry, The University of Western Australia, Crawley, Western Australia, Australia
| | - Stuart I Hodgetts
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, Western Australia, Australia; School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Western Australia, Australia
| | - Sarah A Dunlop
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, Western Australia, Australia; School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia
| | - Livia Hool
- School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Western Australia, Australia; Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
| | - Melinda Fitzgerald
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, Western Australia, Australia; School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia.
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21
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Yılmaz T, Kaptanoğlu E. Current and future medical therapeutic strategies for the functional repair of spinal cord injury. World J Orthop 2015; 6:42-55. [PMID: 25621210 PMCID: PMC4303789 DOI: 10.5312/wjo.v6.i1.42] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Spinal cord injury (SCI) leads to social and psychological problems in patients and requires costly treatment and care. In recent years, various pharmacological agents have been tested for acute SCI. Large scale, prospective, randomized, controlled clinical trials have failed to demonstrate marked neurological benefit in contrast to their success in the laboratory. Today, the most important problem is ineffectiveness of nonsurgical treatment choices in human SCI that showed neuroprotective effects in animal studies. Recently, attempted cellular therapy and transplantations are promising. A better understanding of the pathophysiology of SCI started in the early 1980s. Research had been looking at neuroprotection in the 1980s and the first half of 1990s and regeneration studies started in the second half of the 1990s. A number of studies on surgical timing suggest that early surgical intervention is safe and feasible, can improve clinical and neurological outcomes and reduce health care costs, and minimize the secondary damage caused by compression of the spinal cord after trauma. This article reviews current evidence for early surgical decompression and nonsurgical treatment options, including pharmacological and cellular therapy, as the treatment choices for SCI.
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22
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Alshareef M, Krishna V, Ferdous J, Alshareef A, Kindy M, Kolachalama VB, Shazly T. Effect of spinal cord compression on local vascular blood flow and perfusion capacity. PLoS One 2014; 9:e108820. [PMID: 25268384 PMCID: PMC4182502 DOI: 10.1371/journal.pone.0108820] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 09/05/2014] [Indexed: 11/18/2022] Open
Abstract
Spinal cord injury (SCI) can induce prolonged spinal cord compression that may result in a reduction of local tissue perfusion, progressive ischemia, and potentially irreversible tissue necrosis. Due to the combination of risk factors and the varied presentation of symptoms, the appropriate method and time course for clinical intervention following SCI are not always evident. In this study, a three-dimensional finite element fluid-structure interaction model of the cervical spinal cord was developed to examine how traditionally sub-clinical compressive mechanical loads impact spinal arterial blood flow. The spinal cord and surrounding dura mater were modeled as linear elastic, isotropic, and incompressible solids, while blood was modeled as a single-phased, incompressible Newtonian fluid. Simulation results indicate that anterior, posterior, and anteroposterior compressions of the cervical spinal cord have significantly different ischemic potentials, with prediction that the posterior component of loading elevates patient risk due to the concomitant reduction of blood flow in the arterial branches. Conversely, anterior loading compromises flow through the anterior spinal artery but minimally impacts branch flow rates. The findings of this study provide novel insight into how sub-clinical spinal cord compression could give rise to certain disease states, and suggest a need to monitor spinal artery perfusion following even mild compressive loading.
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Affiliation(s)
- Mohammed Alshareef
- College of Medicine, Medical University of South Carolina, Charleston, SC, United States of America
| | - Vibhor Krishna
- Department of Neurosciences, Medical University of South Carolina, Charleston, SC, United States of America
| | - Jahid Ferdous
- Biomedical Engineering Program, University of South Carolina, Columbia, SC, United States of America
| | - Ahmed Alshareef
- Department of Biomedical Engineering, Duke University, Durham, NC, United States of America
| | - Mark Kindy
- Department of Neurosciences, Medical University of South Carolina, Charleston, SC, United States of America
- Ralph H. Johnson VA Medical Center, Charleston, SC, United States of America
| | | | - Tarek Shazly
- Biomedical Engineering Program, University of South Carolina, Columbia, SC, United States of America
- Department of Mechanical Engineering, University of South Carolina, Columbia, SC, United States of America
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Arundic acid (ONO-2506) inhibits secondary injury and improves motor function in rats with spinal cord injury. J Neurol Sci 2014; 337:186-92. [DOI: 10.1016/j.jns.2013.12.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 11/26/2013] [Accepted: 12/04/2013] [Indexed: 11/17/2022]
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Soubeyrand M, Dubory A, Laemmel E, Court C, Vicaut E, Duranteau J. Effect of norepinephrine on spinal cord blood flow and parenchymal hemorrhage size in acute-phase experimental spinal cord injury. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2013; 23:658-65. [PMID: 24232597 DOI: 10.1007/s00586-013-3086-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 10/25/2013] [Accepted: 10/26/2013] [Indexed: 10/26/2022]
Abstract
PURPOSE In the acute phase of spinal cord injury (SCI), ischemia and parenchymal hemorrhage are believed to worsen the primary lesions induced by mechanical trauma. To minimize ischemia, keeping the mean arterial blood pressure above 85 mmHg for at least 1 week is recommended, and norepinephrine is frequently administered to achieve this goal. However, no experimental study has assessed the effect of norepinephrine on spinal cord blood flow (SCBF) and parenchymal hemorrhage size. We have assessed the effect of norepinephrine on SCBF and parenchymal hemorrhage size within the first hour after experimental SCI. METHODS A total of 38 animals were included in four groups according to whether SCI was induced and norepinephrine injected. SCI was induced at level Th10 by dropping a 10-g weight from a height of 10 cm. Each experiment lasted 60 min. Norepinephrine was started 15 min after the trauma. SCBF was measured in the ischemic penumbra zone surrounding the trauma epicenter using contrast-enhanced ultrasonography. Hemorrhage size was measured repeatedly on parasagittal B-mode ultrasonography slices. RESULTS SCI was associated with significant decreases in SCBF (P = 0.0002). Norepinephrine infusion did not significantly modify SCBF. Parenchymal hemorrhage size was significantly greater in the animals given norepinephrine (P = 0.0002). CONCLUSION In the rat, after a severe SCI at the Th10 level, injection of norepinephrine 15 min after SCI does not modify SCBF and increases the size of the parenchymal hemorrhage.
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Affiliation(s)
- Marc Soubeyrand
- "Microcirculation, Bioénergétique, Inflammation et Insuffisance Circulatoire Aiguë", Equipe Universitaire 3509 Paris VII-Paris XI-Paris XIII, Paris, France,
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25
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Tei R, Kaido T, Nakase H, Sakaki T. Secondary spinal cord hypoperfusion of circumscribed areas after injury in rats. Neurol Res 2013; 27:403-8. [PMID: 15949238 DOI: 10.1179/016164105x25180] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
OBJECTIVES The evaluation of the spatial spread of ischemia following spinal cord injury (SCI) is important for planning therapeutic strategies for secondary injury. The purpose of this study was to investigate in detail the change in regional spinal cord blood flow (rSCBF) after SCI. METHODS Thirty-four male Wistar rats were used, for which laminectomies of the T11-13 vertebrae were performed. SCI was produced by a directed impact through a laminectomy site at the level of the Th12 using a pneumatic impact device. We measured the sequential and spatial changes of rSCBF using a laser Doppler scanning technique before and after SCI in rats not only at the injured myelomere but also at the circumferent myelomeres. SCBF mapping was carried out before and after SCI on each site. RESULTS After SCI, the rSCBF value gradually decreased for each site for the SCI group (n=26), while it globally decreased at the epicenter. Moreover, a decrease in SCBF was observed at the caudal and rostral sites. The mean value of the %SCBF 120 minutes after SCI for each site was 63.6+/-2.3% (Th11), 74.4+/-4.5% (Th12), 75.8+/-3.2% (Th13), and was significantly lower for the rostral site compared with the caudal site (p<0.05, one-way analysis of variance). DISCUSSION This study found that SCBF is significantly decreased not only at the injured myelomere but also at the circumferent myelomeres. Circumferentially extending ischemia after SCI is related to secondary injury after SCI. The improvement in SCBF after SCI, therefore, can be attributed to the treatment of SCI.
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Affiliation(s)
- Rinsei Tei
- Department of Neurosurgery, Nara Medical University, Nara, Japan
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26
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Muradov JM, Hagg T. Intravenous infusion of magnesium chloride improves epicenter blood flow during the acute stage of contusive spinal cord injury in rats. J Neurotrauma 2013; 30:840-52. [PMID: 23302047 PMCID: PMC3660110 DOI: 10.1089/neu.2012.2670] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Vasospasm, hemorrhage, and loss of microvessels at the site of contusive or compressive spinal cord injury lead to infarction and initiate secondary degeneration. Here, we used intravenous injection of endothelial-binding lectin followed by histology to show that the number of perfused microvessels at the injury site is decreased by 80-90% as early as 20 min following a moderate T9 contusion in adult female rats. Hemorrhage within the spinal cord also was maximal at 20 min, consistent with its vasoconstrictive actions in the central nervous system (CNS). Microvascular blood flow recovered to up to 50% of normal volume in the injury penumbra by 6 h, but not at the epicenter. A comparison with an endothelial cell marker suggested that many microvessels fail to be reperfused up to 48 h post-injury. The ischemia was probably caused by vasospasm of vessels penetrating the parenchyma, because repeated Doppler measurements over the spinal cord showed a doubling of total blood flow over the first 12 h. Moreover, intravenous infusion of magnesium chloride, used clinically to treat CNS vasospasm, greatly improved the number of perfused microvessels at 24 and 48 h. The magnesium treatment seemed safe as it did not increase hemorrhage, despite the improved parenchymal blood flow. However, the treatment did not reduce acute microvessel, motor neuron or oligodendrocyte loss, and when infused for 7 days did not affect functional recovery or spared epicenter white matter over a 4 week period. These data suggest that microvascular blood flow can be restored with a clinically relevant treatment following spinal cord injury.
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Affiliation(s)
- Johongir M. Muradov
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky
- Department of Neurological Surgery, University of Louisville, Louisville, Kentucky
| | - Theo Hagg
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky
- Department of Neurological Surgery, University of Louisville, Louisville, Kentucky
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky
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27
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Varma AK, Das A, Wallace G, Barry J, Vertegel AA, Ray SK, Banik NL. Spinal cord injury: a review of current therapy, future treatments, and basic science frontiers. Neurochem Res 2013; 38:895-905. [PMID: 23462880 DOI: 10.1007/s11064-013-0991-6] [Citation(s) in RCA: 174] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 01/17/2013] [Accepted: 01/29/2013] [Indexed: 12/12/2022]
Abstract
The incidence of acute and chronic spinal cord injury (SCI) in the United States is more than 10,000 per year, resulting in 720 cases per million persons enduring permanent disability each year. The economic impact of SCI is estimated to be more than 4 billion dollars annually. Preclinical studies, case reports, and small clinical trials suggest that early treatment may improve neurological recovery. To date, no proven therapeutic modality exists that has demonstrated a positive effect on neurological outcome. Emerging data from recent preclinical and clinical studies offer hope for this devastating condition. This review gives an overview of current basic research and clinical studies for the treatment of SCI.
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Affiliation(s)
- Abhay K Varma
- Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
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28
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Dulin JN, Moore ML, Grill RJ. The dual cyclooxygenase/5-lipoxygenase inhibitor licofelone attenuates p-glycoprotein-mediated drug resistance in the injured spinal cord. J Neurotrauma 2013; 30:211-26. [PMID: 22947335 DOI: 10.1089/neu.2012.2587] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
There are currently no proven effective treatments that can improve recovery of function in spinal cord injury (SCI) patients. Many therapeutic compounds have shown promise in pre-clinical studies, but clinical trials have been largely unsuccessful. P-glycoprotein (Pgp, Abcb1b) is a drug efflux transporter of the blood-spinal cord barrier that limits spinal cord penetration of blood-borne xenobiotics. Pathological Pgp upregulation in diseases such as cancer causes heightened resistance to a broad variety of therapeutic drugs. Importantly, several drugs that have been evaluated for the treatment of SCI, such as riluzole, are known substrates of Pgp. We therefore examined whether Pgp-mediated pharmacoresistance diminishes delivery of riluzole to the injured spinal cord. Following moderate contusion injury at T10 in male Sprague-Dawley rats, we observed a progressive, spatial spread of increased Pgp expression from 3 days to 10 months post-SCI. Spinal cord uptake of i.p.-delivered riluzole was significantly reduced following SCI in wild type but not Abcb1a-knockout rats, highlighting a critical role for Pgp in mediating drug resistance following SCI. Because inflammation can drive Pgp upregulation, we evaluated the ability of the new generation dual anti-inflammatory drug licofelone to promote spinal cord delivery of riluzole following SCI. We found that licofelone both reduced Pgp expression and enhanced riluzole bioavailability within the lesion site at 72 h post-SCI. This work highlights Pgp-mediated drug resistance as an important obstacle to therapeutic drug delivery for SCI, and suggests licofelone as a novel combinatorial treatment strategy to enhance therapeutic drug delivery to the injured spinal cord.
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Affiliation(s)
- Jennifer N Dulin
- Department of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, TX 77030, USA
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29
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Wilson JR, Forgione N, Fehlings MG. Emerging therapies for acute traumatic spinal cord injury. CMAJ 2012; 185:485-92. [PMID: 23228995 DOI: 10.1503/cmaj.121206] [Citation(s) in RCA: 144] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Jefferson R Wilson
- Department of Surgery, Division of Neurosurgery and Spinal Program, University of Toronto, Toronto, Ont
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30
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Cao HQ, Dong ED. An update on spinal cord injury research. Neurosci Bull 2012; 29:94-102. [PMID: 23124646 DOI: 10.1007/s12264-012-1277-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Accepted: 07/26/2012] [Indexed: 02/06/2023] Open
Abstract
Spinal cord injury (SCI) can have a range of debilitating effects and permanently alter the capabilities and quality of life of survivors. The first specialized centers of care for SCI were established in 1944 and since then an increasing amount of research has been carried out in this area. Despite this, the present treatment and care levels for SCI are not comparable to those in other areas of medicine. In the clinic, the aim of SCI treatment is primarily to limit secondary damage by reducing compression in trauma spots and stabilizing the spinal column. Currently, no effective strategy for functional recovery is offered. In this review, we focus on research progress on the molecular mechanisms underlying SCI, and assess the treatment outcomes of SCI in animal models, i.e., neurotrophins and stem cells are discussed as pre-clinical therapies in animal models. We also assess the resources available and national research projects carried out on SCI in China in recent years, as well as making recommendations for the future allocation of funds in this area.
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Affiliation(s)
- He-Qi Cao
- Division of Neurological Disorders and Mental Health, Department of Health Sciences, National Natural Science Foundation of China, Beijing, 100085, China.
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31
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Quantitative assessment of spinal cord perfusion by using contrast-enhanced ultrasound in a porcine model with acute spinal cord contusion. Spinal Cord 2012; 51:196-201. [PMID: 23045300 DOI: 10.1038/sc.2012.111] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVES To quantify spinal cord perfusion by using contrast-enhanced ultrasound (CEUS) in a porcine model with acute spinal cord injury. METHODS Microcirculatory changes of acute spinal cord injury were shown by CEUS in a porcine model with spinal cord contusion at three selected time points, coupling with conventional ultrasound (US) and Color Doppler US (CDFI). Time-intensity curves and perfusion parameters were also obtained by autotracking contrast quantification (ACQ) software in the epicenter of contusion site, adjacent region and distant region, respectively. Neurologic and histologic examinations were used to confirm the severity of injury. RESULTS Conventional US revealed the spinal cord was hypoechoic and homogeneous, whereas the dura mater, pia mater and cerebral aqueduct were hyperechoic. On CDFI intramedullary blood vessels were displayed as segmental and columnar. It was homogeneous on CEUS. After spinal cord contusion, the injured region on gray scale US was hyperechoic. CDFI demonstrated intramedullary blood vessels of adjacent region had increased and dilated during the observation period. On CEUS the epicenter of contusion site was hypoperfusion, whereas its adjacent region was hyperperfusion compared with the distant region. Quantitative analysis showed that peak intensity decreased in epicenters of contusion but increased in adjacent regions significantly at all time points (P<0.05). Evaluation of neurological function for post-contusion demonstrated significantly deterioration in comparison before injury (P<0.05). CONCLUSIONS CEUS is a practical technique that provides overall views for evaluating microcirculatory pattern in spinal cord injury. Quantitative analysis shows the efficacy in assessment of perfusion changes after spinal cord injury.
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Tator CH, Hashimoto R, Raich A, Norvell D, Fehlings MG, Harrop JS, Guest J, Aarabi B, Grossman RG. Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury. J Neurosurg Spine 2012; 17:157-229. [DOI: 10.3171/2012.5.aospine12116] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
There is a need to enhance the pipeline of discovery and evaluation of neuroprotective pharmacological agents for patients with spinal cord injury (SCI). Although much effort and money has been expended on discovering effective agents for acute and subacute SCI, no agents that produce major benefit have been proven to date. The deficiencies of all aspects of the pipeline, including the basic science input and the clinical testing output, require examination to determine remedial strategies. Where has the neuroprotective/pharmacotherapy preclinical process failed and what needs to be done to achieve success? These are the questions raised in the present review, which has 2 objectives: 1) identification of articles that address issues related to the translational readiness of preclinical SCI pharmacological therapies; and 2) examination of the preclinical studies of 5 selected agents evaluated in animal models of SCI (including blunt force trauma, penetrating trauma, or ischemia). The 5 agents were riluzole, glyburide, magnesium sulfate, nimodipine, and minocycline, and these were selected because of their promise of translational readiness as determined by the North American Clinical Trials Network Consortium.
The authors found that there are major deficiencies in the effort that has been extended to coordinate and conduct preclinical neuroprotection/pharmacotherapy trials in the SCI field. Apart from a few notable exceptions such as the NIH effort to replicate promising strategies, this field has been poorly coordinated. Only a small number of articles have even attempted an overall evaluation of the neuroprotective/pharmacotherapy agents used in preclinical SCI trials. There is no consensus about how to select the agents for translation to humans on the basis of their preclinical performance and according to agreed-upon preclinical performance criteria.
In the absence of such a system and to select the next agent for translation, the Consortium has developed a Treatment Strategy Selection Committee, and this committee selected the most promising 5 agents for potential translation. The results show that the preclinical work on these 5 agents has left numerous gaps in knowledge about their preclinical performance and confirm the need for significant changes in preclinical neuroprotection/pharmacotherapy trials in SCI. A recommendation is made for the development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI.
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Affiliation(s)
- Charles H. Tator
- 1Division of Neurosurgery and Spinal Program, Toronto Western Hospital and University of Toronto, Ontario, Canada
| | | | - Annie Raich
- 2Spectrum Research, Inc., Tacoma, Washington
| | | | - Michael G. Fehlings
- 1Division of Neurosurgery and Spinal Program, Toronto Western Hospital and University of Toronto, Ontario, Canada
| | - James S. Harrop
- 3Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - James Guest
- 4Department of Neurological Surgery and the Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Florida
| | - Bizhan Aarabi
- 5Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland; and
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Molecular and cellular mechanisms underlying the role of blood vessels in spinal cord injury and repair. Cell Tissue Res 2012; 349:269-88. [PMID: 22592628 DOI: 10.1007/s00441-012-1440-6] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 04/24/2012] [Indexed: 02/07/2023]
Abstract
Spinal cord injury causes immediate damage of nervous tissue accompanied by the loss of motor and sensory function. The limited self-repair ability of damaged nervous tissue underlies the need for reparative interventions to restore function after spinal cord injury. Blood vessels play a crucial role in spinal cord injury and repair. Injury-induced loss of local blood vessels and a compromised blood-brain barrier contribute to inflammation and ischemia and thus to the overall damage to the nervous tissue of the spinal cord. Lack of vasculature and leaking blood vessels impede endogenous tissue repair and limit prospective repair approaches. A reduction of blood vessel loss and the restoration of blood vessels so that they no longer leak might support recovery from spinal cord injury. The promotion of new blood vessel formation (i.e., angio- and vasculogenesis) might aid repair but also incorporates the danger of exacerbating tissue loss and thus functional impairment. The delicate interplay between cells and molecules that govern blood vessel repair and formation determines the extent of damage and the success of reparative interventions. This review deals with the cellular and molecular mechanisms underlying the role of blood vessels in spinal cord injury and repair.
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Robins-Steele S, Nguyen DH, Fehlings MG. The delayed post-injury administration of soluble fas receptor attenuates post-traumatic neural degeneration and enhances functional recovery after traumatic cervical spinal cord injury. J Neurotrauma 2012; 29:1586-99. [PMID: 22260324 DOI: 10.1089/neu.2011.2005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Spinal cord injury (SCI) is a devastating condition that currently lacks clinically-relevant and effective neuroprotective therapeutic options. Optimal therapeutic agents for clinical translation should show efficacy in a cervical compression/contusion model using a clinically-relevant post-injury therapeutic time window. To date, few compounds have met that rigorous standard. The objective of this work was to evaluate the efficacy of delayed post-injury administration of soluble Fas receptor (sFasR) via intrathecal catheter following acute cervical SCI in a clinically-relevant contusion/compression model. Female Wistar rats were given a C7-T1 moderately severe clip compression injury, followed by either 8-h or 24-h delayed treatment initiation. Long-term neurobehavioral analysis of motor recovery and neuropathic pain development was undertaken. The extent of oligodendrocyte and neuron survival was assessed in peri-lesional cord sections 8 weeks post-SCI. This was complemented by an evaluation of the level of tissue preservation at and adjacent to the site of injury. In animals treated with sFasR delayed 8 h post-injury, significant behavioral effects were observed, coinciding with enhanced cell survival, peri-lesional tissue sparing, and enhanced integrity of descending fiber tracts compared to control treatments. Animals treated with sFasR delayed by 24 h showed more modest improvements in behavioral recovery, and had consistent improvements in cell survival and tissue preservation. This work has shown for the first time that the Fas-mediated apoptotic pathway can be therapeutically targeted in a clinically-relevant time window post-SCI.
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Affiliation(s)
- Sherri Robins-Steele
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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Vascular Pathology as a Potential Therapeutic Target in SCI. Transl Stroke Res 2011; 2:556-74. [PMID: 24323683 DOI: 10.1007/s12975-011-0128-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 10/21/2011] [Accepted: 10/25/2011] [Indexed: 10/15/2022]
Abstract
Acute traumatic spinal cord injury (SCI) is characterized by a progressive secondary degeneration which exacerbates the loss of penumbral tissue and neurological function. Here, we first provide an overview of the known pathophysiological mechanisms involving injured microvasculature and molecular regulators that contribute to the loss and dysfunction of existing and new blood vessels. We also highlight the differences between traumatic and ischemic injuries which may yield clues as to the more devastating nature of traumatic injuries, possibly involving toxicity associated with hemorrhage. We also discuss known species differences with implications for choosing models, their relevance and utility to translate new treatments towards the clinic. Throughout this review, we highlight the potential opportunities and proof-of-concept experimental studies for targeting therapies to endothelial cell-specific responses. Lastly, we comment on the need for vascular mechanisms to be included in drug development and non-invasive diagnostics such as serum and cerebrospinal fluid biomarkers and imaging of spinal cord pathology.
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Wang Y, Tang P, Zhang L, Wan W, He C, Tang J. Gray-scale contrast-enhanced ultrasonography for quantitative evaluation of the blood perfusion of the sciatic nerves with crush injury. Acad Radiol 2011; 18:1285-91. [PMID: 21784669 DOI: 10.1016/j.acra.2011.06.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 06/06/2011] [Accepted: 06/08/2011] [Indexed: 12/24/2022]
Abstract
RATIONALE AND OBJECTIVES Blood perfusion of peripheral nerves plays an important role in regeneration after nerve injury. Functional recovery after a peripheral nerve injury depends not only on the survival of the affected neurons but also on the recovered blood perfusion. Previous studies have shown that it is possible to quantitatively assess blood perfusion of tissue using contrast-enhanced ultrasound (CEUS). The aim of this study was to evaluate the usefulness of CEUS for the quantitative evaluation of blood perfusion of the sciatic nerves with crush injury. MATERIALS AND METHODS Crush injuries were created in the left sciatic nerve of 30 New Zealand white rabbits. CEUS of the bilateral sciatic nerves was performed in six experimental rabbits at 3 days, 1 week, 2 weeks, 4 weeks, and 8 weeks after injury. Pulse-inversion harmonic imaging was used for real-time CEUS. The other six rabbits were used as a control group. Serial laser Doppler measurements of blood flow and quantitative histologic evaluation were performed parallel to CEUS on all animals. RESULTS Quantitative analysis of CEUS showed that the perfusion index of the crushed sciatic nerves was increased at 3 days after injury, with a peak at 1 week after injury (P = .000). The area under the curve for the crushed sites was increased at 3 days after injury, with a peak at 2 weeks after injury (P = .000). The mean transit time and maximum intensity of the crushed site of the left sciatic nerves were not significantly changed during the 2 months after injury (P = .335 and P = .157 respectively). The perfusion indices measured by CEUS correlated well with those measured by laser Doppler (r = 0.791, P = .000). Marked Wallerian degeneration was found at the crushed site of sciatic nerves at 3 days after injury. The percentage of degenerated myelinated axons was increased during the first 2 weeks after injury and then decreased during the following period. Regenerated axons with small diameter and thin myelin sheaths were found at 2 weeks after injury and during the following period. CONCLUSIONS CEUS may provide a new imaging method to quantitatively analyze blood perfusion of injured peripheral nerves.
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Affiliation(s)
- Yuexiang Wang
- Department of Ultrasound, Chinese People's Liberation Army General Hospital, Beijing, China
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Current and future therapeutic strategies for functional repair of spinal cord injury. Pharmacol Ther 2011; 132:57-71. [DOI: 10.1016/j.pharmthera.2011.05.006] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Accepted: 05/09/2011] [Indexed: 12/26/2022]
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Abstract
Spinal cord injury (SCI) is characterized by secondary degeneration, which leads to tissue loss at the epicenter and subsequent functional deficits. This review provides insight into the pathophysiology of microvascular dysfunction and endothelial cell loss, which are among the earliest responses during the first postinjury day. The enigmatic role of the angiogenic response in the penumbra around the lost tissue, which occurs during the first 2 weeks, is also discussed. The importance of stabilizing and rescuing the injured vasculature is now well-recognized, and several pharmacological and genetic treatments have emerged in the past few years. We conclude with suggestions for future experimental research, including development of vascular-selective treatments and exploitation of genetic models. In summary, vascular dysfunction following SCI is an important contributor to neurological deficits, as proposed long ago. However, there now appears to be new and potentially powerful opportunities for treating acute SCI by targeting the vascular responses.
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Affiliation(s)
- Janelle M. Fassbender
- Kentucky Spinal Cord Injury Research Center, School of Medicine, University of Louisville, Louisville, KY 40292 USA
- M.D./Ph.D. Program, Louisville, KY 40292 USA
- Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, KY 40292 USA
| | - Scott R. Whittemore
- Kentucky Spinal Cord Injury Research Center, School of Medicine, University of Louisville, Louisville, KY 40292 USA
- Department of Neurological Surgery, School of Medicine, University of Louisville, Louisville, KY 40292 USA
- Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, KY 40292 USA
| | - Theo Hagg
- Kentucky Spinal Cord Injury Research Center, School of Medicine, University of Louisville, Louisville, KY 40292 USA
- Department of Neurological Surgery, School of Medicine, University of Louisville, Louisville, KY 40292 USA
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY 40292 USA
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Torres BBJ, Caldeira FMC, Gomes MG, Serakides R, de Marco Viott A, Bertagnolli AC, Fukushima FB, de Oliveira KM, Gomes MV, de Melo EG. Effects of dantrolene on apoptosis and immunohistochemical expression of NeuN in the spinal cord after traumatic injury in rats. Int J Exp Pathol 2010; 91:530-6. [PMID: 21039984 DOI: 10.1111/j.1365-2613.2010.00738.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Dantrolene has been shown to be neuroprotective by reducing neuronal apoptosis after brain injury in several animal models of neurological disorders. In this study, we investigated the effects of dantrolene on experimental spinal cord injury (SCI). Forty-six male Wistar rats were laminectomized at T13 and divided in six groups: GI (n = 7) underwent SCI with placebo and was euthanized after 32 h; GII (n = 7) underwent laminectomy alone with placebo and was euthanized after 32 h; GIII (n = 8) underwent SCI with dantrolene and was euthanized after 32 h; GIV (n = 8) underwent SCI with placebo and was euthanized after 8 days; GV (n = 8) underwent laminectomy alone with placebo and was euthanized after 8 days; and GVI (n = 8) underwent SCI with dantrolene and was euthanized after 8 days. A compressive trauma was performed to induce SCI. After euthanasia, the spinal cord was evaluated using light microscopy, TUNEL staining and immunochemistry with anti-Caspase-3 and anti-NeuN. Animals treated with dantrolene showed a smaller number of TUNEL-positive and caspase-3-positive cells and a larger number of NeuN-positive neurons, both at 32 h and 8 days (P ≤ 0.05). These results showed that dantrolene protects spinal cord tissue after traumatic SCI by decreasing apoptotic cell death.
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Affiliation(s)
- Bruno Benetti Junta Torres
- Departament of Veterinary Medicine and Surgery, School of Veterinary, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Abstract
STUDY DESIGN Literature review of basic scientific and clinical research in spinal cord injury (SCI). OBJECTIVE To provide physicians with an overview of the neurobiologic challenges of SCI, the current status of investigation for novel therapies that have been translated to human clinical trials, and the preclinical, scientific basis for each of these therapies. SUMMARY OF BACKGROUND DATA An abundance of recent scientific and clinical research activity has revealed numerous insights into the neurobiology of SCI, and has generated an abundance of potential therapies. An increasing number of such therapies are being translated into human SCI trials. Clinicians who attend to SCI patients are increasingly asked about potential treatments and clinical trials. METHODS Published data review of novel treatments that are either currently in human clinical trials for acute SCI or about to initiate clinical evaluation. RESULTS A number of treatments have bridged the "translational gap" and are currently either in the midst of human SCI trials, or are about to begin such clinical evaluation. These include minocycline, Cethrin, anti-Nogo antibodies, systemic hypothermia, Riluzole, magnesium chloride in polyethylene glycol, and human embryonic stem cell derived oligodendrocyte progenitors. A systematic review of the preclinical literature on these specific therapies reveals promising results in a variety of different SCI injury models. CONCLUSION The SCI community is encouraged by the progression of novel therapies from "bench to bedside" and the initiation of clinical trials for a number of different treatments. The task of clinical evaluation, however, is substantial, and many years will be required before the actual efficacy of the treatments currently in evaluation will be determined.
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Han S, Arnold SA, Sithu SD, Mahoney ET, Geralds JT, Tran P, Benton RL, Maddie MA, D'Souza SE, Whittemore SR, Hagg T. Rescuing vasculature with intravenous angiopoietin-1 and alpha v beta 3 integrin peptide is protective after spinal cord injury. Brain 2010; 133:1026-42. [PMID: 20375135 DOI: 10.1093/brain/awq034] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Blood vessel loss and inflammation cause secondary degeneration following spinal cord injury. Angiopoietin-1 through the Tie2 receptor, and other ligands through alphavbeta3 integrin, promote endothelial cell survival during developmental or tumour angiogenesis. Here, daily intravenous injections with an alphavbeta3-binding peptide named C16 or an angiopoietin-1 mimetic following a spinal cord contusion at thoracic level 9 in mice rescued epicentre blood vessels, white matter and locomotor function, and reduced detrimental inflammation. Preserved vascularity and reduced inflammation correlated with improved outcomes. C16 and angiopoietin-1 reduced leukocyte transmigration in vitro. Growth factor receptors and integrins facilitate each others' function. Therefore, angiopoietin-1 and C16 were combined and the effects were additive, resulting in almost complete functional recovery. The treatment had lasting effects when started 4 h following injury and terminated after one week. These results identify alphavbeta3 integrin and the endothelial-selective angiopoietin-1 as vascular and inflammatory regulators that can be targeted in a clinically relevant manner for neuroprotection after central nervous system trauma.
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Affiliation(s)
- Shu Han
- Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, 511 S. Floyd St., MDR Building Room 616, University of Louisville, Louisville, KY 40292, USA
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A systematic review of the evidence supporting a role for vasopressor support in acute SCI. Spinal Cord 2009; 48:356-62. [DOI: 10.1038/sc.2009.150] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Hawryluk GWJ, Rowland J, Kwon BK, Fehlings MG. Protection and repair of the injured spinal cord: a review of completed, ongoing, and planned clinical trials for acute spinal cord injury. Neurosurg Focus 2009; 25:E14. [PMID: 18980474 DOI: 10.3171/foc.2008.25.11.e14] [Citation(s) in RCA: 185] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Over the past 2 decades, advances in understanding the pathophysiology of spinal cord injury (SCI) have stimulated the recent emergence of several therapeutic strategies that are being examined in Phase I/II clinical trials. Ten randomized controlled trials examining methylprednisolone sodium succinate, tirilizad mesylate, monosialotetrahexosylganglioside, thyrotropin releasing hormone, gacyclidine, naloxone, and nimodipine have been completed. Although the primary outcomes in these trials were laregely negative, a secondary analysis of the North American Spinal Cord Injury Study II demonstrated that when administered within 8 hours of injury, methylprednisolone sodium succinate was associated with modest clinical benefits, which need to be weighed against potential complications. Thyrotropin releasing hormone (Phase II trial) and monosialotetrahexosylganglioside (Phase II and III trials) also showed some promise, but we are unaware of plans for future trials with these agents. These studies have, however, yielded many insights into the conduct of clinical trials for SCI. Several current or planned clinical trials are exploring interventions such as early surgical decompression (Surgical Treatment of Acute Spinal Cord Injury Study) and electrical field stimulation, neuroprotective strategies such as riluzole and minocycline, the inactivation of myelin inhibition by blocking Nogo and Rho, and the transplantation of various cellular substrates into the injured cord. Unfortunately, some experimental and poorly characterized SCI therapies are being offered outside a formal investigational structure, which will yield findings of limited scientific value and risk harm to patients with SCI who are understandably desperate for any intervention that might improve their function. Taken together, recent advances suggest that optimism for patients and clinicians alike is justified, as there is real hope that several safe and effective therapies for SCI may become available over the next decade.
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Affiliation(s)
- Gregory W J Hawryluk
- Division of Genetics and Development, Toronto Western Research Institute, Toronto, Ontario, Canada
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Oria M, Chatauret N, Raguer N, Córdoba J. A new method for measuring motor evoked potentials in the awake rat: effects of anesthetics. J Neurotrauma 2008; 25:266-75. [PMID: 18352840 DOI: 10.1089/neu.2007.0393] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The goal of this investigation was to develop a method to study the neurophysiological integrity of the central motor tract using motor evoked potentials in the awake rat and assess the effects of different anesthetics in this model. Rats were implanted with six subcutaneous electrodes (pediatric myocardial pacing leads) and one cranial screw. Motor evoked potentials of the hind limb were elicited after cranial and sciatic nerve stimulation. Experiments were repeated on different days during three weeks studying the effect of three different anesthetics (propofol, ketamine/xylazine, pentobarbital) at three different doses. Stimulation of motor evoked potentials in the awake rat was well tolerated with no effects on behavior. The electrodes could be kept chronically in place without signs of infection. The repeated recordings on different days showed high reproducibility after the fourth day following implantation of the electrodes. All three anesthetics induced an increase in the latency and a decrease in the amplitude of the motor evoked potentials which were dose dependent. Propofol (up to 1 mg/kg x min(1)) affected motor evoked potentials to a lesser extent than the other anesthetics. Based upon these findings, we believe that our approach provides a new method of chronically implanting electrodes in the rat to assess the neurophysiological function of the motor tract without the need of anesthetics. This model may prove useful in the investigation of various diseases that affect the motor pathways without the confounding effects of anesthesia.
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Affiliation(s)
- Marc Oria
- Servicio de Medicina Interna-Hepatología, Hospital Vall d'Hebron, Barcelona, Spain
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MUKAINO M, NAKAMURA M, OKADA S, TOYAMA Y, LIU M, OKANO H. Role of IL-6 in regulation of inflammation and stem cell differentiation in CNS trauma. ACTA ACUST UNITED AC 2008; 31:93-8. [DOI: 10.2177/jsci.31.93] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Masahiko MUKAINO
- Dept Physiology, Keio Univ. Sch. Med
- Dept Rehabilitation Medicine, Keio Univ. Sch. Med
| | - Masaya NAKAMURA
- Dept Physiology, Keio Univ. Sch. Med
- Dept Orthopaedic Surgery Keio Univ. Sch. Med
| | | | | | - Meigen LIU
- Dept Rehabilitation Medicine, Keio Univ. Sch. Med
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Chu GKT, Yu W, Fehlings MG. The p75 neurotrophin receptor is essential for neuronal cell survival and improvement of functional recovery after spinal cord injury. Neuroscience 2007; 148:668-82. [PMID: 17706365 DOI: 10.1016/j.neuroscience.2007.05.028] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2006] [Revised: 05/03/2007] [Accepted: 05/17/2007] [Indexed: 01/08/2023]
Abstract
The mechanisms initiating post-spinal cord injury (SCI) apoptotic cell death remain incompletely understood. The p75 neurotrophin receptor (p75(NTR)) has been shown to exert both pro-survival and pro-apoptotic effects on neural cells in vitro. While a previous study had shown that there is decreased oligodendrocyte apoptosis distal to a clean partial transection injury of the cord in mice with nonfunctional p75(NTR), most human spinal cord injuries do not involve partial transections but are rather due to compression/contusion injuries with significant perilesional ischemia. Therefore, we sought to examine the role of the p75(NTR) in a clinically relevant clip compression model of SCI in p75 null mice with an exon III mutation. Mice with a functional p75(NTR) had increased caspase-9 activation at 3 days after SCI in comparison to the functionally deficient p75(NTR) mice. However, at 7 days following SCI there was no difference in the activation of the effector caspases (caspase-3 and caspase-6) at the spinal cord lesion. Moreover, at 7 days after injury, there was increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end (TUNEL) positive cell death at the injury site in the functionally deficient p75(NTR) mice. Using double labeling with TUNEL and cell specific markers we showed that the absence of p75(NTR) function increased the extent of neuronal but not oligodendroglial cell death at the injury site. This selective loss of neuronal cells after SCI was confirmed with a decrease in levels of microtubule-associated protein 2 in the p75 null mice. Furthermore, the wild-type animals had dramatically improved survival and enhanced locomotor recovery at 8 weeks after SCI when compared with the p75(NTR) null mice. Also at 8 weeks, there were significantly more neurons present at the injury site of wild-type mice when compared with p75 null mice. We conclude that the p75(NTR) receptor is integral to neuronal cell survival and endogenous reparative mechanisms after compressive/contusive SCI.
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Affiliation(s)
- G K T Chu
- Division of Neurosurgery, Toronto Western Research Institute, The Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, University of Toronto, McLaughlin Pavilion, McL 12-407, Toronto, Ontario, Canada M5T 2S8
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Urdzíková L, Jendelová P, Glogarová K, Burian M, Hájek M, Syková E. Transplantation of bone marrow stem cells as well as mobilization by granulocyte-colony stimulating factor promotes recovery after spinal cord injury in rats. J Neurotrauma 2006; 23:1379-91. [PMID: 16958589 DOI: 10.1089/neu.2006.23.1379] [Citation(s) in RCA: 164] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Emerging clinical studies of treating brain and spinal cord injury (SCI) with autologous adult stem cells led us to compare the effect of an intravenous injection of mesenchymal stem cells (MSCs), an injection of a freshly prepared mononuclear fraction of bone marrow cells (BMCs) or bone marrow cell mobilization induced by granulocyte colony stimulating factor (G-CSF) in rats with a balloon- induced spinal cord compression lesion. MSCs were isolated from rat bone marrow by their adherence to plastic, labeled with iron-oxide nanoparticles and expanded in vitro. Seven days after injury, rats received an intravenous injection of MSCs or BMCs or a subcutaneous injection of GCSF (from day 7 to 11 post-injury). Functional status was assessed weekly for 5 weeks after SCI, using the Basso-Beattie-Bresnehan (BBB) locomotor rating score and the plantar test. Animals with SCI treated with MSCs, BMCs, or G-CSF had higher BBB scores and better recovery of hind limb sensitivity than controls injected with saline. Morphometric measurements showed an increase in the spared white matter. MR images of the spinal cords were taken ex vivo 5 weeks after SCI using a Bruker 4.7-T spectrometer. The lesions populated by grafted MSCs appeared as dark hypointense areas. Histology confirmed a large number of iron-containing and PKH 26-positive cells in the lesion site. We conclude that treatment with three different bone marrow cell populations had a positive effect on behavioral outcome and histopathological assessment after SCI, which was most pronounced after MSC injection.
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Affiliation(s)
- Lucia Urdzíková
- Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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Abstract
Acute traumatic spinal cord injury (SCI) results in a devastating loss of neurological function below the level of injury and adversely affects multiple systems within the body. The pathobiology of SCI involves a primary mechanical insult to the spinal cord and activation of a delayed secondary cascade of events, which ultimately causes progressive degeneration of the spinal cord. Whereas cell death from the mechanical injury is predominated by necrosis, secondary injury events trigger a continuum of necrotic and apoptotic cell death mechanisms. These secondary events include vascular abnormalities, ischemia-reperfusion, glutamate excitotoxicity and disturbances in ionic homeostasis, oxidative cell injury, and a robust inflammatory response. No gold standard therapy for SCI has been established, although clinical trials with methylprednisolone (NASCIS II and III) and GM-1 ganglioside (Maryland and Sygen) have demonstrated modest, albeit potentially important therapeutic benefits. In light of the overwhelming impact of SCI on the individual, other therapeutic interventions are urgently needed. A number of promising pharmacological therapies are currently under investigation for neuroprotective abilities in animal models of SCI. These include the sodium (Na+) channel blocker riluzole, the tetracycline derivative minocycline, the fusogen copolymer polyethylene glycol (PEG), and the tissue-protective hormone erythropoietin (EPO). Moreover, clinical trials investigating the putative neuroprotective and neuroregenerative properties ascribed to the Rho pathway antagonist, Cethrin (BioAxone Therapeutic, Inc.), and implantation of activated autologous macrophages (ProCord; Proneuron Biotechnologies) in patients with thoracic and cervical SCI are now underway. We anticipate that these studies will harken an era of renewed interest in translational clinical trials. Ultimately, due to the multi-factorial pathophysiology of traumatic SCI, effective therapies will require combined approaches.
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Affiliation(s)
- Darryl C Baptiste
- Division of Cell and Molecular Biology, Toronto Western Research Institute and Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
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Cetin A, Nas K, Büyükbayram H, Ceviz A, Olmez G. The effects of systemically administered methylprednisolone and recombinant human erythropoietin after acute spinal cord compressive injury in rats. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2006; 15:1539-44. [PMID: 16547753 DOI: 10.1007/s00586-006-0091-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2005] [Revised: 01/06/2006] [Accepted: 02/16/2006] [Indexed: 11/25/2022]
Abstract
The study design was to decrease the damage of spinal cord on the experimentally induced acute spinal cord injury in rats. The objective of this study was to evaluate whether recombinant human erythropoietin (rHu-EPO) and methylprednisolone (MPSS) improve neurological function and histopathological changes if systemically administered after traumatic spinal cord injury. This study included 48 rats that underwent experimental SCI. Forty-eight animals were randomly divided into six groups. Animals constituted a moderate compression of 0.6 N that was produced by application of an aneurysm clip at level T3 for 1 min. rHu-EPO (1,000 and 3,000 U (Unit) per kg of body weight i.p.) and MPSS (30 mg/kg) were administered 5 min after injury, and control group was saline treated. (1) Control group (n=8), (2) MPSS group (n=8), (3) rHu-EPO 1,000 U group (n=8), (4) MPSS + rHu-EPO 1,000 U group (n=8), (5) rHu-EPO 3,000 U group (n=8), and (6) MPSS + rHu-EPO 3,000 U group (n=8). The neurological function and histopathology were evaluated at 24 and 72 h. According to the neurological functional test scores significant improvements between the control group and the other groups that had taken medical treatment were observed (P<0.001). Histopathologically severe ischemic findings were observed in the control group. A significant decrease in ischemic damage was detected in MPSS + rHu-EPO 3,000 U group (P<0.001). The most significant neurological functional and histopathological improvements were observed after systemical administration of MPSS + rHu-EPO 3,000 U and rHu-EPO 3,000 U. Furthermore, the MPSS + rHu-EPO 3,000 U group provides the most improved neurological functional and histopathological recovery.
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Affiliation(s)
- Abdurrahman Cetin
- Department of Neurosurgery, Dicle University, School of Medicine, Diyarbakir, Turkey
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