|
1
|
Doncel-Pérez E, Guízar-Sahagún G, Grijalva-Otero I. From single to combinatorial therapies in spinal cord injuries for structural and functional restoration. Neural Regen Res 2025; 20:660-670. [PMID: 38886932 PMCID: PMC11433899 DOI: 10.4103/nrr.nrr-d-23-01928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 02/21/2024] [Accepted: 03/20/2024] [Indexed: 06/20/2024] Open
Abstract
Spinal cord injury results in paralysis, sensory disturbances, sphincter dysfunction, and multiple systemic secondary conditions, most arising from autonomic dysregulation. All this produces profound negative psychosocial implications for affected people, their families, and their communities; the financial costs can be challenging for their families and health institutions. Treatments aimed at restoring the spinal cord after spinal cord injury, which have been tested in animal models or clinical trials, generally seek to counteract one or more of the secondary mechanisms of injury to limit the extent of the initial damage. Most published works on structural/functional restoration in acute and chronic spinal cord injury stages use a single type of treatment: a drug or trophic factor, transplant of a cell type, and implantation of a biomaterial. Despite the significant benefits reported in animal models, when translating these successful therapeutic strategies to humans, the result in clinical trials has been considered of little relevance because the improvement, when present, is usually insufficient. Until now, most studies designed to promote neuroprotection or regeneration at different stages after spinal cord injury have used single treatments. Considering the occurrence of various secondary mechanisms of injury in the acute and sub-acute phases of spinal cord injury, it is reasonable to speculate that more than one therapeutic agent could be required to promote structural and functional restoration of the damaged spinal cord. Treatments that combine several therapeutic agents, targeting different mechanisms of injury, which, when used as a single therapy, have shown some benefits, allow us to assume that they will have synergistic beneficial effects. Thus, this narrative review article aims to summarize current trends in the use of strategies that combine therapeutic agents administered simultaneously or sequentially, seeking structural and functional restoration of the injured spinal cord.
Collapse
Affiliation(s)
- Ernesto Doncel-Pérez
- Hospital Nacional de Parapléjicos de Toledo, Servicio de Salud de Castilla La Mancha (SESCAM), Toledo, Spain
| | - Gabriel Guízar-Sahagún
- Medical Research Unit for Neurological Diseases, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, México
| | - Israel Grijalva-Otero
- Medical Research Unit for Neurological Diseases, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, México
| |
Collapse
|
|
2
|
de Barros AGC, dos Santos GB, Marcon RM, Cristante AF. Erythropoietin to Treat Spinal Cord Injury: Evaluation of Different Doses and Magnitudes of Trauma in Rats. Global Spine J 2024:21925682241306106. [PMID: 39652832 PMCID: PMC11629366 DOI: 10.1177/21925682241306106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2024] Open
Abstract
STUDY DESIGN Experimental spinal cord lesion study. OBJECTIVES To evaluate the effects of erythropoietin at different doses on neural regeneration in rats undergoing spinal cord injury. METHODS Anesthetized Wistar rats were submitted to standardized spinal cord injury and randomized into eight groups, receiving different magnitudes of trauma and single or repeated doses of intraperitoneal erythropoietin (500 or 5000 IU/kg of body weight). We evaluated motor function using BBB scores and sensorimotor behavior by observing the rats walking on a horizontal ladder (at 2, 4, and 6 weeks) and performed histological analysis of the spinal cord after euthanasia. We compared the scores between groups using analysis of variance (ANOVA) and Bonferroni multiple comparisons. RESULTS The experiments were conducted with 10 animals per group (n = 80), none of which died or were excluded. BBB scores increased over time (meaning recovery) in all groups (P < 0.001 for all). From the fourth week, animals receiving lower trauma and higher erythropoietin doses had higher BBB scores than those receiving lower doses. The total number of steps and correct steps taken on the horizontal ladder increased, and slips decreased over time with treatment in all groups. Although the number of errors was different between moments (P < 0.001), it was not different between groups (P = 0.707). Rats receiving higher impact lesions had more spinal cord necrosis and worse recovery of neuronal fibers than the rest. CONCLUSIONS Animals receiving a higher dose of erythropoietin and suffering minor trauma showed better and faster neurological recovery. Repeating erythropoietin after a week showed no benefit.
Collapse
Affiliation(s)
- Alderico Girão Campos de Barros
- Department of Orthopedics and Traumatology, University of São Paulo Institute of Orthopedics and Traumatology, São Paulo, Brasil
| | - Gustavo Bispo dos Santos
- Department of Orthopedics and Traumatology, University of São Paulo Institute of Orthopedics and Traumatology, São Paulo, Brasil
| | - Raphael Martus Marcon
- Department of Orthopedics and Traumatology, University of São Paulo Institute of Orthopedics and Traumatology, São Paulo, Brasil
| | - Alexandre Fogaça Cristante
- Department of Orthopedics and Traumatology, University of São Paulo Institute of Orthopedics and Traumatology, São Paulo, Brasil
| |
Collapse
|
|
3
|
Zhang YY, Yao M, Zhu K, Xue RR, Xu JH, Cui XJ, Mo W. Neurological recovery and antioxidant effect of erythropoietin for spinal cord injury: A systematic review and meta-analysis. Front Neurol 2022; 13:925696. [PMID: 35928137 PMCID: PMC9343731 DOI: 10.3389/fneur.2022.925696] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundTo critically evaluate the neurological recovery effects and antioxidant effects of erythropoietin (EPO) in rat models of spinal cord injury (SCI).MethodsThe PubMed, EMBASE, MEDLINE, ScienceDirect, and Web of Science were searched for animal experiments applying EPO to treat SCI to January 2022. We included studies which examined neurological function by the Basso, Beattie, and Bresnahan (BBB) scale, as well as cavity area and spared area, and determining the molecular-biological analysis of antioxidative effects by malondialdehyde (MDA) levels in spinal cord tissues. Meta-analysis were performed with Review Manager 5.4 software.ResultsA total of 33 studies were included in this review. The results of the meta-analysis showed that SCI rats receiving EPO therapy showed a significant locomotor function recovery after 14 days compared with control, then the superiority of EPO therapy maintained to 28 days from BBB scale. Compared with the control group, the cavity area was reduced [4 studies, weighted mean difference (WMD) = −16.65, 95% CI (−30.74 to −2.55), P = 0.02] and spared area was increased [3 studies, WMD =11.53, 95% CI (1.34 to 21.72), P = 0.03] by EPO. Meanwhile, MDA levels [2 studies, WMD = −0.63 (−1.09 to −0.18), P = 0.007] were improved in the EPO treatment group compared with control, which indicated its antioxidant effect. The subgroup analysis recommended 5,000 UI/kg is the most effective dose [WMD = 4.05 (2.23, 5.88), P < 0.0001], although its effect was not statistically different from that of 1,000 UI/kg. Meanwhile, the different rat strains (Sprague-Dawley vs. Wistar), and models of animals, as well as administration method (single or multiple administration) of EPO did not affect the neuroprotective effect of EPO for SCI.ConclusionsThis systematic review indicated that EPO can promote the recovery of the locomotor function of SCI rats. The mechanism exploration of EPO needs to be verified by experiments, and then carefully designed randomized controlled trials are needed to explore its neural recovery effects.
Collapse
Affiliation(s)
- Ya-yun Zhang
- Department of Orthopaedics, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Min Yao
- Department of Orthopaedics, Spine Disease Institute, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ke Zhu
- Department of Orthopaedics, Spine Disease Institute, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rui-rui Xue
- Department of Orthopaedics, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jin-hai Xu
- Department of Orthopaedics, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Xue-jun Cui
| | - Xue-jun Cui
- Department of Orthopaedics, Spine Disease Institute, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Jin-hai Xu
| | - Wen Mo
- Department of Orthopaedics, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Wen Mo
| |
Collapse
|
|
4
|
Biglari B, Heller RA, Hörner M, Sperl A, Bock T, Reible B, Haubruck P, Grützner PA, Moghaddam A. Novel approach to an early assessment of a patient's potential for neurological remission after acute spinal cord injury: Analysis of hemoglobin concentration dynamics. J Spinal Cord Med 2021; 44:229-240. [PMID: 31211658 PMCID: PMC7952079 DOI: 10.1080/10790268.2019.1632060] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Context/objective: Examining hemoglobin (Hb) dynamics with regard to the potential of neurological remission in patients with traumatic spinal cord injury (TSCI).Design: Prospective Clinical Observational Study.Setting: BG Trauma Centre Ludwigshafen, Department of Paraplegiology, Rhineland-Palatinate, Germany.Methods: From 2011 to 2017 a total of 80 patients with acute spinal injury were enrolled and divided into three groups: initial neurological impairment either with (G1; n = 33) or without subsequent neurological remission (G0; n = 35) and vertebral fractures without initial neurological impairment as control group (C; n = 12). Blood samples were taken for 3 months at 11 time-points after injury. Analyses were performed using routine diagnostics.Outcome measures: Multiple logistic regression was used to determine the prognostic value of Hb regarding neurological remission respecting clinical covariates.Results: Data showed elevated mean Hb concentrations in G1 from the third day to 1 month compared to G0, Hb levels were significantly higher in G1 after 3 days (P = 0.03, G1 > G0). The final multiple logistic regression model based on this data predicting the presence of neurological remission resulted in an AUC (area under the curve) of 80.5% (CI: 67.8%-93.2%) in the ROC (receiver operating characteristic) analysis.Conclusion: Elevated Hb concentrations are associated with a higher likelihood of neurological remission. Elevated concentrations of Hb in G1 compared to G0 over time might be linked to both a better initial oxygen supply response and a decreased ECM (extracellular matrix) degradation highlighting the role of Hb as a valuable biomarker for neural regeneration after TSCI.
Collapse
Affiliation(s)
- Bahram Biglari
- Department of Paraplegiology, BG Trauma Centre Ludwigshafen, Ludwigshafen, Germany,Correspondence to: Bahram Biglari, Head of the Department, Department of Paraplegiology, BG Trauma Centre Ludwigshafen, Ludwig-Guttmann-Straße 13, Ludwigshafen am Rhein67071, Germany; Ph: +49/(0) 621 6810-2571.
| | - Raban Arved Heller
- Heidelberg Trauma Research Group, Department of Trauma and Reconstructive Surgery, Center for Orthopaedics, Trauma Surgery and SCI, Heidelberg University Hospital, Heidelberg, Germany
| | - Manuel Hörner
- Heidelberg Trauma Research Group, Department of Trauma and Reconstructive Surgery, Center for Orthopaedics, Trauma Surgery and SCI, Heidelberg University Hospital, Heidelberg, Germany
| | - Andre Sperl
- Heidelberg Trauma Research Group, Department of Trauma and Reconstructive Surgery, Center for Orthopaedics, Trauma Surgery and SCI, Heidelberg University Hospital, Heidelberg, Germany
| | - Tobias Bock
- Heidelberg Trauma Research Group, Department of Trauma and Reconstructive Surgery, Center for Orthopaedics, Trauma Surgery and SCI, Heidelberg University Hospital, Heidelberg, Germany
| | - Bruno Reible
- Heidelberg Trauma Research Group, Department of Trauma and Reconstructive Surgery, Center for Orthopaedics, Trauma Surgery and SCI, Heidelberg University Hospital, Heidelberg, Germany
| | - Patrick Haubruck
- Heidelberg Trauma Research Group, Department of Trauma and Reconstructive Surgery, Center for Orthopaedics, Trauma Surgery and SCI, Heidelberg University Hospital, Heidelberg, Germany
| | - Paul Alfred Grützner
- Department of Trauma Surgery and Orthopaedics, BG Trauma Centre Ludwigshafen, Ludwigshafen, Germany
| | - Arash Moghaddam
- Aschaffenburg Trauma and Orthopaedic Research Group, Center for Orthopaedics, Trauma Surgery and Sports Medicine, Hospital Aschaffenburg-Alzenau, Aschaffenburg, Germany
| |
Collapse
|
|
5
|
Cohrs G, Drucks B, Sürie JP, Vokuhl C, Synowitz M, Held-Feindt J, Knerlich-Lukoschus F. Expression profiles of pro-inflammatory and pro-apoptotic mediators in secondary tethered cord syndrome after myelomeningocele repair surgery. Childs Nerv Syst 2019; 35:315-328. [PMID: 30280214 DOI: 10.1007/s00381-018-3984-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 09/21/2018] [Indexed: 11/27/2022]
Abstract
PURPOSE The literature on histopathological and molecular changes that might underlie secondary tethered cord syndrome (TCS) after myelomeningocele (MMC) repair surgeries remains sparse. To address this problem, we analyzed specimens, which were obtained during untethering surgeries of patients who had a history of MMC repair surgery after birth. METHODS Specimens of 12 patients were analyzed in this study. Clinical characteristics were obtained retrospectively including pre-operative neurological and bowel/bladder-function, contractures and spasticity of lower extremities, leg and back pain, syringomyelia, and conus position on spinal MRI. Cellular marker expression profiles were established. Further, immunoreactivities (IR) of IL-1ß/IL-1R1, TNF-α/TNF-R1, and HIF-1α/-2α were analyzed qualitatively and semi-quantitatively by densitometry. Co-labeling with cellular markers was determined by multi-fluorescence-labeling. Cytokines were further analyzed on mRNA level. Immunostaining for cleaved PARP and TUNEL was performed to detect apoptotic cells. RESULTS Astrocytosis, appearance of monocytes, activated microglia, and apoptotic cells in TCS specimens were one substantial finding of these studies. Besides neurons, these cells co-stained with IL-1ß and TNF-α and their receptors, which were found on significantly elevated IR-level and partially mRNA-level in TCS specimens. Staining for HIF-1α/-2α confirmed induction of hypoxia-related factors in TCS specimens that were co-labeled with IL-1ß. Further, hints for apoptotic cell death became evident by TUNEL and PARP-positive cells in TCS neuroepithelia. CONCLUSIONS Our studies identified pro-inflammatory and pro-apoptotic mediators that, besides mechanical damaging and along with hypoxia, might promote TCS development. Besides optimizing surgical techniques, these factors should also be taken into account when searching for further options to improve TCS treatment.
Collapse
Affiliation(s)
- Gesa Cohrs
- Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, House 41, 24105, Kiel, Germany
| | - Bea Drucks
- Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, House 41, 24105, Kiel, Germany
| | - Jan-Philip Sürie
- Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, House 41, 24105, Kiel, Germany
| | - Christian Vokuhl
- Department of Pathology, University Hospital of Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, House 14, 24105, Kiel, Germany
| | - Michael Synowitz
- Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, House 41, 24105, Kiel, Germany
| | - Janka Held-Feindt
- Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, House 41, 24105, Kiel, Germany
| | - Friederike Knerlich-Lukoschus
- Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, House 41, 24105, Kiel, Germany.
- Deparment of Pediatric Neurosurgery, Asklepios klinik Sankt Augstin GmbH, Arnold-Janssen-Str. 29, 53757, Sankt Augustin, Germany.
| |
Collapse
|
|
6
|
de Barros AGC, Cristante AF, dos Santos GB, Natalino RJM, Ferreira RJR, de Barros-Filho TEP. Evaluation of the effects of erythropoietin and interleukin-6 in rats submitted to acute spinal cord injury. Clinics (Sao Paulo) 2019; 74:e674. [PMID: 31433044 PMCID: PMC6691840 DOI: 10.6061/clinics/2019/e674] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 03/19/2019] [Indexed: 12/02/2022] Open
Abstract
OBJECTIVE To evaluate the effects of interleukin-6 (IL-6) and erythropoietin (EPO) in experimental acute spinal cord injury (SCI) in rats. METHODS Using standardized equipment, namely, a New York University (NYU) Impactor, a SCI was produced in 50 Wistar rats using a 10-g weight drop from a 12.5-mm height. The rats were divided into the following 5 groups of 10 animals each: "Group EPO", treated with erythropoietin only; "Group EPO + IL-6", treated with both substances; "Group IL-6", receiving IL-6 administration only; "Group Placebo", receiving a placebo solution; and "Group Sham", submitted to an incomplete procedure (only laminectomy, without SCI). All drugs and the placebo solution were administered intraperitoneally for three weeks. The animals were followed up for 42 days. Functional motor recovery was monitored by the Basso, Beattie, and Bresnahan (BBB) scale on days 2, 7, 14, 21, 28, 35 and 42. Motor-evoked potential tests were performed on the 42nd day. Histological analysis was performed after euthanasia. RESULTS The group receiving EPO exhibited superior functional motor results on the BBB scale. IL-6 administration alone was not superior to the placebo treatment, and the IL-6 combination with EPO yielded worse results than did EPO alone. CONCLUSIONS Using EPO after acute SCI in rats yielded benefits in functional recovery. The combination of EPO and IL-6 showed benefits, but with inferior results compared to those of isolated EPO; moreover, isolated use of IL-6 resulted in no benefit.
Collapse
Affiliation(s)
| | - Alexandre Fogaça Cristante
- Instituto de Ortopedia e Traumatologia (IOT), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Corresponding author. E-mail:
| | - Gustavo Bispo dos Santos
- Instituto de Ortopedia e Traumatologia (IOT), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Renato José Mendonça Natalino
- Instituto de Ortopedia e Traumatologia (IOT), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Ricardo José Rodriguez Ferreira
- Instituto de Ortopedia e Traumatologia (IOT), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Tarcísio Eloy Pessoa de Barros-Filho
- Instituto de Ortopedia e Traumatologia (IOT), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| |
Collapse
|
|
7
|
Ren H, Chen X, Tian M, Zhou J, Ouyang H, Zhang Z. Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2018; 5:1800529. [PMID: 30479916 PMCID: PMC6247077 DOI: 10.1002/advs.201800529] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 06/06/2018] [Indexed: 05/29/2023]
Abstract
The balance of inflammation is critical to the repair of spinal cord injury (SCI), which is one of the most devastating traumas in human beings. Inflammatory cytokines, the direct mediators of local inflammation, have differential influences on the repair of the injured spinal cord. Some inflammatory cytokines are demonstrated beneficial to spinal cord repair in SCI models, while some detrimental. Various animal researches have revealed that local delivery of therapeutic agents efficiently regulates inflammatory cytokines and promotes repair from SCI. Quite a few clinical studies have also shown the promotion of repair from SCI through regulation of inflammatory cytokines. However, local delivery of a single agent affects only a part of the inflammatory cytokines that need to be regulated. Meanwhile, different individuals have differential profiles of inflammatory cytokines. Therefore, future studies may aim to develop personalized strategies of locally delivered therapeutic agent cocktails for effective and precise regulation of inflammation, and substantial functional recovery from SCI.
Collapse
Affiliation(s)
- Hao Ren
- The Third Affiliated Hospital of Guangzhou Medical UniversityNo. 63 Duobao RoadGuangzhou510150P. R. China
| | - Xuri Chen
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative MedicineSchool of Basic Medical ScienceZhejiang UniversityNo. 866 Yuhangtang RoadHangzhou310058P. R. China
| | - Mengya Tian
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative MedicineSchool of Basic Medical ScienceZhejiang UniversityNo. 866 Yuhangtang RoadHangzhou310058P. R. China
| | - Jing Zhou
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative MedicineSchool of Basic Medical ScienceZhejiang UniversityNo. 866 Yuhangtang RoadHangzhou310058P. R. China
| | - Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative MedicineSchool of Basic Medical ScienceZhejiang UniversityNo. 866 Yuhangtang RoadHangzhou310058P. R. China
| | - Zhiyong Zhang
- Translational Research Center for Regenerative Medicine and 3D Printing TechnologiesGuangzhou Medical UniversityNo. 63 Duobao RoadGuangzhou510150P. R. China
| |
Collapse
|
|
8
|
Cohrs G, Goerden S, Lucius R, Synowitz M, Mehdorn HM, Held-Feindt J, Knerlich-Lukoschus F. Spatial and Cellular Expression Patterns of Erythropoietin-Receptor and Erythropoietin during a 42-Day Post-Lesional Time Course after Graded Thoracic Spinal Cord Impact Lesions in the Rat. J Neurotrauma 2018; 35:593-607. [PMID: 28895456 DOI: 10.1089/neu.2017.4981] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Erythropoietin (Epo) exhibits promising neuroregenerative potential for spinal cord injury (SCI), and might be involved in other long-term sequelae, such as neuropathic pain development. The current studies investigated the time courses and spatial and cellular patterns of Epo and erythropoietin receptor (EpoR) expression along the spinal axis after graded SCI. Male Long Evans rats received 100 kdyn, 150 kdyn, and 200 kdyn thoracic (T9) contusions from an Infinite Horizon impactor. Sham controls received laminectomies. Anatomical and quantitative immunohistochemical analyses of the EpoR/Epo expression along the whole spinal axis were performed 7, 15, and 42 postoperative days (DPO) after the lesioning. Cellular expression was investigated by double- and triple-labeling for EpoR/Epo with cellular markers and proliferating cells in subgroups of 5-bromo-2-deoxyuridine pre-treated animals. Prolonged EpoR/Epo-expression was confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Quantified EpoR/Epo immunoreactivities in pain-related spinal cord regions and ventrolateral white matter (VLWM) were correlated with the mechanical sensitivity thresholds and locomotor function of the respective animals. EpoR and Epo were constitutively expressed in the ventral horn neurons and vascular and glial cells in the dorsal columns (DC) and the VLWM. After SCI, in addition to expression in the lesion core, EpoR/Epo immunoreactivities exhibited significant time- and lesion grade-dependent induction in the DC and VLWM along the spinal axis. EpoR and Epo immunoreactive cells were co-stained with markers for astroglial, neural precursor cell and vascular markers. In the VLWM, EpoR- and Epo-positive proliferating cells were co-stained with glial fibrillary acidic protein (GFAP) and nestin. The DC EpoR/Epo immunoreactivities exhibited linear relationships with the behavioral correlates of post-lesional chronic pain development at DPO 42. SCI leads to long-lasting multicellular EpoR/Epo induction beyond the lesion core in the spinal cord regions that are involved in central pain development and regenerative processes. Our studies provide a time frame to investigate the effects of Epo application on motor function or pain development, especially in the later time course after lesioning.
Collapse
Affiliation(s)
- Gesa Cohrs
- 1 Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel , Kiel, Germany
| | - Stephan Goerden
- 1 Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel , Kiel, Germany
| | - Ralph Lucius
- 2 Anatomical Institute, Christian-Albrechts University Kiel , Kiel, Germany
| | - Michael Synowitz
- 1 Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel , Kiel, Germany
| | | | - Janka Held-Feindt
- 1 Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel , Kiel, Germany
| | | |
Collapse
|
|
9
|
Li J, Guo W, Xiong M, Zhang S, Han H, Chen J, Mao D, Yu H, Zeng Y. Erythropoietin facilitates the recruitment of bone marrow mesenchymal stem cells to sites of spinal cord injury. Exp Ther Med 2017; 13:1806-1812. [PMID: 28565771 PMCID: PMC5443180 DOI: 10.3892/etm.2017.4182] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 07/26/2016] [Indexed: 12/28/2022] Open
Abstract
Despite the successes of bone marrow mesenchymal stem cell (BMSC) transplantation for the treatment of spinal cord injuries, only a small fraction of grafted cells migrate to the target areas. Therefore, there remains a need for more efficient strategies of BMSC delivery. The present study was designed to explore this. Rat models of spinal cord injury (SCI) were established and exposed to phosphate buffered saline (control), BMSCs or BMSCs + erythropoietin (EPO). Basso, Beattie and Bresnahan (BBB) locomotor scale and grid walk tests were then utilized to estimate neurological rehabilitation. Additionally, the following assays were performed: Immunofluorescence localization of BMSCs to the site of SCI; the transwell migration assay to detect in vitro cellular migration; the terminal deoxynucleotidyl transferase dUTP nick end labeling assay to determine the apoptotic index of the lesion; and western blotting analysis to evaluate the expression of vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF) at the site of SCI. The BBB scores of the BMSC + EPO treated group were significantly increased compared with the BMSC treatment group (P<0.05). For example, BMSC + EPO treated rats had a significantly decreased number of hind limb slips compared with the BMSC treatment group (P<0.05). Furthermore, EPO significantly increased the migration capacity of BMSCs compared with the control group (P<0.001). In addition, the apoptotic index of the BMSC + EPO group was significantly decreased compared with the BMSC group (P<0.05). Green fluorescent protein-labeled BMSCs were detected at the site of SCI in the BMSC and BMSCs + EPO groups, with the signal being notably stronger in the latter. Moreover, the expression of VEGF and BDNF in the BMSCs + EPO group was significantly increased compared with the BMSC group (P<0.05). In conclusion, the results of the present study indicate that EPO can facilitate the recruitment of BMSCs to sites of SCI, increase expression of BDNF and VEGF, and accelerate recovery of neurological function following SCI.
Collapse
Affiliation(s)
- Jun Li
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Weichun Guo
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Min Xiong
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Shuangjie Zhang
- Department of Urology, Taihe Hospital of Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Heng Han
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Jie Chen
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Dan Mao
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Hualong Yu
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Yun Zeng
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| |
Collapse
|
|
10
|
Dynasore Improves Motor Function Recovery via Inhibition of Neuronal Apoptosis and Astrocytic Proliferation after Spinal Cord Injury in Rats. Mol Neurobiol 2016; 54:7471-7482. [PMID: 27822712 DOI: 10.1007/s12035-016-0252-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 10/23/2016] [Indexed: 01/02/2023]
Abstract
Spinal cord injury (SCI) is a common and devastating central nervous system insult which lacks efficient treatment. Our previous experimental findings indicated that dynamin-related protein 1 (Drp1) mediates mitochondrial fission during SCI, and inhibition of Drp1 plays a significant protective effect after SCI in rats. Dynasore inhibits GTPase activity at both the plasma membrane (dynamin 1, 2) and the mitochondria membrane (Drp1). The aim of the present study was to investigate the beneficial effects of dynasore on SCI and its underlying mechanism in a rat model. Sprague-Dawley rats were randomly assigned to sham, SCI, and 1, 10, and 30 mg dynasore groups. The rat model of SCI was established using an established Allen's model. Dynasore was administered via intraperitoneal injection immediately. Results of motor functional test indicated that dynasore ameliorated the motor dysfunction greatly at 3, 7, and 10 days after SCI in rats (P < 0.05). Results of western blot showed that dynasore has remarkably reduced the expressions of Drp1, dynamin 1, and dynamin 2 and, moreover, decreased the Bax, cytochrome C, and active Caspase-3 expressions, but increased the expressions of Bcl-2 at 3 days after SCI (P < 0.05). Notably, the upregulation of proliferating cell nuclear antigen (PCNA) and glial fibrillary acidic protein (GAFP) are inhibited by dynasore at 3 days after SCI (P < 0.05). Results of immunofluorescent double labeling showed that there were less apoptotic neurons and proliferative astrocytes in the dynasore groups compared with SCI group (P < 0.05). Finally, histological assessment via Nissl staining demonstrated that the dynasore groups exhibited a significantly greater number of surviving neurons compared with the SCI group (P < 0.05). This neuroprotective effect was dose-dependent (P < 0.05). To our knowledge, this is the first study to indicate that dynasore significantly enhances motor function which may be by inhibiting the activation of neuronal mitochondrial apoptotic pathway and astrocytic proliferation in rats after SCI.
Collapse
|
|
11
|
Yang L, Yan X, Xu Z, Tan W, Chen Z, Wu B. Delayed administration of recombinant human erythropoietin reduces apoptosis and inflammation and promotes myelin repair and functional recovery following spinal cord compressive injury in rats. Restor Neurol Neurosci 2016; 34:647-63. [PMID: 26444376 DOI: 10.3233/rnn-150498] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Liuzhu Yang
- Department of Orthopedics, Southern Medical University, Zhujiang Hospital, Guangzhou, Guangdong, China
- Department of Orthopedics, Hezhou city pepole’s hospital, Hezhou, Guangxi, China
| | - Xinping Yan
- Department of Orthopedics, Southern Medical University, Zhujiang Hospital, Guangzhou, Guangdong, China
| | - Zunying Xu
- Department of Orthopedics, Southern Medical University, Zhujiang Hospital, Guangzhou, Guangdong, China
| | - Wei Tan
- Department of Orthopedics, Southern Medical University, Zhujiang Hospital, Guangzhou, Guangdong, China
| | - Zhong Chen
- Department of Orthopedics, Southern Medical University, Zhujiang Hospital, Guangzhou, Guangdong, China
| | - Bo Wu
- Department of Orthopedics, Southern Medical University, Zhujiang Hospital, Guangzhou, Guangdong, China
| |
Collapse
|
|
12
|
Kowitzke B, Cohrs G, Leuschner I, Koch A, Synowitz M, Mehdorn HM, Held-Feindt J, Knerlich-Lukoschus F. Cellular Profiles and Molecular Mediators of Lesion Cascades in the Placode in Human Open Spinal Neural Tube Defects. J Neuropathol Exp Neurol 2016; 75:827-42. [PMID: 27354486 DOI: 10.1093/jnen/nlw057] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Indexed: 01/07/2023] Open
Abstract
Myelomeningoceles (mmc) are clinically challenging CNS malformations. Although improvement in their management has been achieved with respect to antenatal diagnosis, prevention, and fetal surgery, the cellular mechanisms of damage in the neural placode are poorly understood. We aimed to identify cellular and molecular factors in lesion amplifying cascades in mmc placodes. Seventeen mmc specimens obtained during reconstructive surgery that harbored sufficient neuroepithelial tissue were investigated. Normal adult and stillborn spinal cord tissue served as controls. Placodes exhibited similar cellular profiles with consistent neuronal marker expression, elevated GFAP-/vimentin immunoreactivity in all, and CD3/CD11b/CD68-immunolabeling in some cases. Increased expression of pro-inflammatory (tumor necrosis factor, interleukin-1β [Il-1β]/IL-1 receptor type 1 [IL-R1]) and neuroprotective erythropoietin/erythropoietin receptor (Epo/EpoR) cytokines was detected by immunohistochemistry, double-fluorescence labeling, and real-time RT-PCR. In all cases, there was a multi-cellular induction of IL-1β and IL1-R1. EpoR and Epo immunoreactivity was elevated in some cases with neuronal expression patterns. Epo was further co-expressed with HIF-1/-2α, which paralleled Epo induction in the corresponding placodes. These observations confirm the induction of cellular and molecular alterations in human mmc placodes that resemble the secondary lesion cascades induced by spinal cord injury. The pro-inflammatory and neuroprotective cytokine expression in mmc placodes may represent new targets for the treatment of open neural tube defects.
Collapse
Affiliation(s)
- Bea Kowitzke
- Department of Neurosurgery (BK, GC, MS, HMM, JH-F, FK-L)Department of Pathology (IL), University Hospital of Schleswig-Holstein Campus Kiel, Kiel, Germany;Department of Neuropathology (AK), Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
| | - Gesa Cohrs
- Department of Neurosurgery (BK, GC, MS, HMM, JH-F, FK-L)Department of Pathology (IL), University Hospital of Schleswig-Holstein Campus Kiel, Kiel, Germany;Department of Neuropathology (AK), Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
| | - Ivo Leuschner
- Department of Neurosurgery (BK, GC, MS, HMM, JH-F, FK-L)Department of Pathology (IL), University Hospital of Schleswig-Holstein Campus Kiel, Kiel, Germany;Department of Neuropathology (AK), Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
| | - Arend Koch
- Department of Neurosurgery (BK, GC, MS, HMM, JH-F, FK-L)Department of Pathology (IL), University Hospital of Schleswig-Holstein Campus Kiel, Kiel, Germany;Department of Neuropathology (AK), Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
| | - Michael Synowitz
- Department of Neurosurgery (BK, GC, MS, HMM, JH-F, FK-L)Department of Pathology (IL), University Hospital of Schleswig-Holstein Campus Kiel, Kiel, Germany;Department of Neuropathology (AK), Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
| | - Hubertus Maximilian Mehdorn
- Department of Neurosurgery (BK, GC, MS, HMM, JH-F, FK-L)Department of Pathology (IL), University Hospital of Schleswig-Holstein Campus Kiel, Kiel, Germany;Department of Neuropathology (AK), Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
| | - Janka Held-Feindt
- Department of Neurosurgery (BK, GC, MS, HMM, JH-F, FK-L)Department of Pathology (IL), University Hospital of Schleswig-Holstein Campus Kiel, Kiel, Germany;Department of Neuropathology (AK), Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
| | - Friederike Knerlich-Lukoschus
- Department of Neurosurgery (BK, GC, MS, HMM, JH-F, FK-L)Department of Pathology (IL), University Hospital of Schleswig-Holstein Campus Kiel, Kiel, Germany;Department of Neuropathology (AK), Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
| |
Collapse
|
|
13
|
Effects of tacrolimus and erythropoietin in experimental spinal cord lesion in rats: functional and histological evaluation. Spinal Cord 2015; 54:439-44. [PMID: 26481712 PMCID: PMC5399139 DOI: 10.1038/sc.2015.172] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/25/2015] [Accepted: 09/03/2015] [Indexed: 11/08/2022]
Abstract
STUDY DESIGN Experimental study with rats. OBJECTIVE To evaluate functional and histological effects of tacrolimus (FK 506) and erythropoietin (EPO) after experimental spinal cord contusion injury (SCI). SETTING Brazil. METHODS Wistar rats (n=60) were submitted to SCI with the NYU Impactor system. The control group received saline; the EPO group received EPO; the group EPO+FK 506 received EPO associated with tacrolimus and the group FK 506 received tacrolimus only. The Sham group underwent SCI, but did not receive any drug. Locomotor function was evaluated after SCI by BBB (Basso, Beattie and Bresnahan) weekly and by the motor-evoked potential test in 42 days. The spinal cord was histologically evaluated. RESULTS There was a significant difference between treated and the control groups from the seventh day on for BBB scores, with no difference between the groups EPO and EPO+FK 506 by the end of the study. There were significant differences between groups for necrosis and bleeding, but not for hiperemia, degeneration and cellular infiltrate. Axon neuron count was different between all groups (P=0.001), between EPO+FK 506 and FK 506 (P=0.011) and between EPO+FK 506 and Sham (P=0.002). Amplitude was significantly different between all groups except between control and sham. For latency, there was no difference. CONCLUSIONS This study did not reveal significant differences in the recovery of locomotor function, or in the histological and electrophysiological analysis in animals treated with EPO and tacrolimus after thoracic SCI.
Collapse
|
|
14
|
Li J, Guo W, Xiong M, Han H, Chen J, Mao D, Tang B, Yu H, Zeng Y. Effect of SDF-1/CXCR4 axis on the migration of transplanted bone mesenchymal stem cells mobilized by erythropoietin toward lesion sites following spinal cord injury. Int J Mol Med 2015; 36:1205-14. [PMID: 26398409 PMCID: PMC4601746 DOI: 10.3892/ijmm.2015.2344] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 07/15/2015] [Indexed: 12/13/2022] Open
Abstract
Accumulating evidence has indicated that the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a crucial role in the recruitment of bone marrow-derived mesenchymal stem cells (BMSCs) into lesion sites in animal models. The aim of this study was to investigate the effects of the SDF-1/CXCR4 axis on the migration of transplanted BMSCs mobilized by erythropoietin (EPO) toward the lesion site following spinal cord injury (SCI). A model of SCI was established in rats using the modified Allen's test. In the EPO group, EPO was administered at a distance of 2 mm cranially and then 2 mm caudally from the site of injury. In the BMSC group, 10 μl of BMSC suspension was administered in the same manner. In the BMSC + EPO group, both BMSCs and EPO were administered as described above. In the BMSC + EPO + AMD3100 group, in addition to the injection of BMSCs and EPO, AMD3100 (a chemokine receptor antagonist) was administered. The Basso-Beattie-Bresnahan (BBB) Locomotor Rating Scale and a grid walk test were used to estimate the neurological recovery following SCI. Enzyme-linked immunosorbent assay (ELISA) was performed to assess the tumor necrosis factor-α (TNF-α) and SDF-1 expression levels. An immunofluorescence assay was performed to identify the distribution of the BMSCs in the injured spinal cord. A Transwell migration assay was performed to examine BMSC migration. A terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay was performed to detect the apoptotic index (AI). Western blot analysis was performed to measure the expression levels of erythropoietin receptor (EPOR) and CXCR4. Significant improvements in locomotor function were detected in the BMSC + EPO group compared with the BMSC group (P<0.05). GFP-labeled BMSCs were observed and were located at the lesion sites. Additionally, EPO significantly decreased the TNF-α levels and increased the SDF-1 levels in the injured spinal cord (P<0.05). The AI in the BMSC + EPO group was significantly lower compared with that in the other groups (P<0.05). Furthermore, EPO significantly upregulated the protein expression of CXCR4 in the BMSCs and promoted the migration of the BMSCs, whereas these effects were markedly inhibited when the BMSCs were co-transplanted with AMD3100. The findings of the present study confirm that EPO mobilizes BMSCs to the lesion site following SCI and enhances the anti-apoptotic effects of the BMSCs by upregulating the expression of SDF-1/CXCR4 axis.
Collapse
Affiliation(s)
- Jun Li
- Department of Orthopaedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Weichun Guo
- Department of Orthopaedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Min Xiong
- Department of Orthopaedics, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Heng Han
- Department of Orthopaedics, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Jie Chen
- Department of Orthopaedics, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Dan Mao
- Department of Orthopaedics, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Bing Tang
- Department of Orthopaedics, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Hualong Yu
- Department of Orthopaedics, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Yun Zeng
- Department of Orthopaedics, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| |
Collapse
|
|
15
|
Peng WS, Qi C, Zhang H, Gao ML, Wang H, Ren F, Li XQ. Distribution of paired immunoglobulin-like receptor B in the nervous system related to regeneration difficulties after unilateral lumbar spinal cord injury. Neural Regen Res 2015; 10:1139-46. [PMID: 26330840 PMCID: PMC4541248 DOI: 10.4103/1673-5374.160111] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2015] [Indexed: 12/21/2022] Open
Abstract
Paired immunoglobulin-like receptor B (PirB) is a functional receptor of myelin-associated inhibitors for axonal regeneration and synaptic plasticity in the central nervous system, and thus suppresses nerve regeneration. The regulatory effect of PirB on injured nerves has received a lot of attention. To better understand nerve regeneration inability after spinal cord injury, this study aimed to investigate the distribution of PirB (via immunofluorescence) in the central nervous system and peripheral nervous system 10 days after injury. Immunoreactivity for PirB increased in the dorsal root ganglia, sciatic nerves, and spinal cord segments. In the dorsal root ganglia and sciatic nerves, PirB was mainly distributed along neuronal and axonal membranes. PirB was found to exhibit a diffuse, intricate distribution in the dorsal and ventral regions. Immunoreactivity for PirB was enhanced in some cortical neurons located in the bilateral precentral gyri. Overall, the findings suggest a pattern of PirB immunoreactivity in the nervous system after unilateral spinal transection injury, and also indicate that PirB may suppress repair after injury.
Collapse
Affiliation(s)
- Wan-Shu Peng
- Department of Pathophysiology, Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Chao Qi
- Department of Pathophysiology, Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Hong Zhang
- Department of Pathophysiology, Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Mei-Ling Gao
- Department of Pathophysiology, Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Hong Wang
- Department of Pathophysiology, Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Fei Ren
- Department of Pathophysiology, Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Xia-Qing Li
- Department of Pathophysiology, Shanxi Medical University, Taiyuan, Shanxi Province, China
| |
Collapse
|
|
16
|
Erythropoietin activates the phosporylated cAMP [adenosine 3′5′ cyclic monophosphate] response element-binding protein pathway and attenuates delayed paraplegia after ischemia-reperfusion injury. J Thorac Cardiovasc Surg 2015; 149:920-4. [DOI: 10.1016/j.jtcvs.2014.11.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 10/20/2014] [Accepted: 11/04/2014] [Indexed: 11/30/2022]
|
|
17
|
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: 43] [Impact Index Per Article: 4.3] [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.
Collapse
|
|
18
|
Yılmaz MB, Tönge M, Emmez H, Kaymaz F, Kaymaz M. Neuroprotective effects of quetiapine on neuronal apoptosis following experimental transient focal cerebral ischemia in rats. J Korean Neurosurg Soc 2013; 54:1-7. [PMID: 24044072 PMCID: PMC3772279 DOI: 10.3340/jkns.2013.54.1.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 04/28/2013] [Accepted: 07/17/2013] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE This study was undertaken in the belief that the atypical antipsychotic drug quetiapine could prevent apoptosis in the penumbra region following ischemia, taking into account findings that show 5-hydroxytryptamine-2 receptor blockers can prevent apoptosis. METHODS We created 5 groups, each containing 6 animals. Nothing was done on the K-I group used for comparisons with the other groups to make sure adequate ischemia had been achieved. The K-II group was sacrificed on the 1st day after transient focal cerebral ischemia and the K-III group on the 3rd day. The D-I group was administered quetiapine following ischemia and sacrificed on the 1st day while the D-II group was administered quetiapine every day following the ischemia and sacrificed on the 3rd day. The samples were stained with the immunochemical TUNEL method and the number of apoptotic cells were counted. RESULTS There was a significant difference between the first and third day control groups (K-II/K-III : p=0.004) and this indicates that apoptotic cell death increases with time. This increase was not encountered in the drug groups (D-I/D-II : p=1.00). Statistical analysis of immunohistochemical data revealed that quetiapine decreased the apoptotic cell death that normally increased with time. CONCLUSION Quetiapine is already in clinical use and is a safe drug, in contrast to many substances that are used to prevent ischemia and are not normally used clinically. Our results and the literature data indicate that quetiapine could help both as a neuronal protector and to resolve neuropsychiatric problems caused by the ischemia in cerebral ischemia cases.
Collapse
Affiliation(s)
- Muhammet Bahadır Yılmaz
- Department of Neurosurgery, Ministry of Health, Training and Research Hospital, Kayseri, Turkey
| | | | | | | | | |
Collapse
|
|
19
|
Cervical spinal erythropoietin induces phrenic motor facilitation via extracellular signal-regulated protein kinase and Akt signaling. J Neurosci 2012; 32:5973-83. [PMID: 22539857 DOI: 10.1523/jneurosci.3873-11.2012] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Erythropoietin (EPO) is typically known for its role in erythropoiesis but is also a potent neurotrophic/neuroprotective factor for spinal motor neurons. Another trophic factor regulated by hypoxia-inducible factor-1, vascular endothelial growth factor (VEGF), signals via ERK and Akt activation to elicit long-lasting phrenic motor facilitation (pMF). Because EPO also signals via ERK and Akt activation, we tested the hypothesis that EPO elicits similar pMF. Using retrograde labeling and immunohistochemical techniques, we demonstrate in adult, male, Sprague Dawley rats that EPO and its receptor, EPO-R, are expressed in identified phrenic motor neurons. Intrathecal EPO at C4 elicits long-lasting pMF; integrated phrenic nerve burst amplitude increased >90 min after injection (63 ± 12% baseline 90 min after injection; p < 0.001). EPO increased phosphorylation (and presumed activation) of ERK (1.6-fold vs controls; p < 0.05) in phrenic motor neurons; EPO also increased pAkt (1.6-fold vs controls; p < 0.05). EPO-induced pMF was abolished by the MEK/ERK inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene] and the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one], demonstrating that ERK MAP kinases and Akt are both required for EPO-induced pMF. Pretreatment with U0126 and LY294002 decreased both pERK and pAkt in phrenic motor neurons (p < 0.05), indicating a complex interaction between these kinases. We conclude that EPO elicits spinal plasticity in respiratory motor control. Because EPO expression is hypoxia sensitive, it may play a role in respiratory plasticity in conditions of prolonged or recurrent low oxygen.
Collapse
|
|
20
|
Zhang X, Li QY, Xiao BG. Anti-inflammatory effect of erythropoietin therapy on experimental autoimmune encephalomyelitis. Int J Neurosci 2012; 122:255-62. [PMID: 22176555 DOI: 10.3109/00207454.2011.648761] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Previous studies report that erythropoietin (EPO) has a neuroprotective role in some neurodegenerative diseases, but the mechanisms are not completely elucidated. The aim of this study was to investigate whether EPO exerts neuroprotective role in experimental autoimmune encephalomyelitis (EAE) via the routes of anti-inflammation. We established an EAE mice model treated intraperitoneally with EPO at the dose of 5,000 IU/kg on schedule, and recorded the clinical score and weight fluctuation. The infiltration of inflammatory cells in the spinal cord of EAE mice was observed with hemotoxylin and eosin (HE) staining, and the levels of IL-10, IFN-γ, IL-17, and MHC-II in central nervous system (CNS)-infiltrating cells and peripheral mononuclear cells were detected by flow cytometry or ELISA. EPO therapy ameliorates clinical signs of EAE mice, inhibits the body weight loss, and decreases the infiltration of inflammatory cells in spinal cords. IL-17 and IFN-γ are reduced, while IL-10 is not increased significantly, in both CNS-infiltrating cells and peripheral mononuclear cells of EPO-treated EAE mice, as compared with EAE control group. EPO also reduces the expression of MHC-II on peripheral antigen presentation cells. Our results indicate that EPO exerts a beneficial role in EAE by inhibiting the levels of IL-17 and IFN-γ in peripheral splenic cells and CNS-infiltrating cells.
Collapse
Affiliation(s)
- Xiang Zhang
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | | | | |
Collapse
|
|
21
|
Zhao J, Li G, Zhang Y, Su X, Hang C. The potential role of JAK2/STAT3 pathway on the anti-apoptotic effect of recombinant human erythropoietin (rhEPO) after experimental traumatic brain injury of rats. Cytokine 2011; 56:343-50. [PMID: 21843949 DOI: 10.1016/j.cyto.2011.07.018] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2011] [Revised: 07/09/2011] [Accepted: 07/15/2011] [Indexed: 12/11/2022]
Abstract
Previous studies indicate that administration of recombinant human erythropoietin (rhEPO) protects cortical neurons following traumatic brain injury (TBI). The mechanisms of rhEPO's neuroprotection are complex and interacting, including anti-apoptosis. Here we aim to demonstrate the role of janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway on the anti-apoptotic effect of rhEPO in Feeney free falling TBI model. Activation of JAK2/STAT3 in pericontusional cortex was analyzed among rats in Sham, TBI, TBI+rhEPO, TBI+rhEPO+AG490 groups (rhEPO: 5000 U/kg day; JAK2 inhibitor AG490: 5 mg/kg day, intraperitoneal) through Western blotting, electrophoretic mobility shift assay. Bcl-2 and Bcl-xl expression (Q-PCR, Western blotting) and cell apoptosis (TUNEL) in pericontusional cortex were also detected in each group. As a result, we found that TBI could activate JAK2 and STAT3, and increase cell apoptosis in pericontusional cortex. RhEPO enhanced the expression of p-JAK2 and p-STAT3, up-regulated the mRNA and protein levels of Bcl-2 and Bcl-xl, followed by increased cell survival. Moreover, AG490 attenuated rhEPO's neuroprotection by down-regulating rhEPO-induced activation of JAK2/STAT3, and inhibiting Bcl-2 and Bcl-xl. These results suggest the essential role of JAK2/STAT3 pathway on the anti-apoptotic benefit of post-TBI rhEPO treatment.
Collapse
Affiliation(s)
- Jinbing Zhao
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Jiangsu Province, Nanjing 210002, PR China
| | | | | | | | | |
Collapse
|
|
22
|
Kwon BK, Okon E, Hillyer J, Mann C, Baptiste D, Weaver LC, Fehlings MG, Tetzlaff W. A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury. J Neurotrauma 2011; 28:1545-88. [PMID: 20146558 PMCID: PMC3143410 DOI: 10.1089/neu.2009.1149] [Citation(s) in RCA: 186] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
An increasing number of therapies for spinal cord injury (SCI) are emerging from the laboratory and seeking translation into human clinical trials. Many of these are administered as soon as possible after injury with the hope of attenuating secondary damage and maximizing the extent of spared neurologic tissue. In this article, we systematically review the available pre-clinical research on such neuroprotective therapies that are administered in a non-invasive manner for acute SCI. Specifically, we review treatments that have a relatively high potential for translation due to the fact that they are already used in human clinical applications, or are available in a form that could be administered to humans. These include: erythropoietin, NSAIDs, anti-CD11d antibodies, minocycline, progesterone, estrogen, magnesium, riluzole, polyethylene glycol, atorvastatin, inosine, and pioglitazone. The literature was systematically reviewed to examine studies in which an in-vivo animal model was utilized to assess the efficacy of the therapy in a traumatic SCI paradigm. Using these criteria, 122 studies were identified and reviewed in detail. Wide variations exist in the animal species, injury models, and experimental designs reported in the pre-clinical literature on the therapies reviewed. The review highlights the extent of investigation that has occurred in these specific therapies, and points out gaps in our knowledge that would be potentially valuable prior to human translation.
Collapse
Affiliation(s)
- Brian K Kwon
- University of British Columbia, Combined Neurosurgical and Orthopaedic Spine Program, Department of Orthopaedics, Vancouver, British Columbia, Canada.
| | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Erythropoietin: recent developments in the treatment of spinal cord injury. Neurol Res Int 2011; 2011:453179. [PMID: 21766022 PMCID: PMC3135044 DOI: 10.1155/2011/453179] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Accepted: 05/09/2011] [Indexed: 01/10/2023] Open
Abstract
Erythropoietin (EPO), originally identified for its critical function in regulating production and survival of erythrocytes, is a member of the type 1 cytokine superfamily. Recent studies have shown that EPO has cytoprotective effects in a wide variety of cells and tissues. Here is presented the analysis of EPO effects on spinal cord injury (SCI), considering both animal experiments concerning to mechanisms of neurodegeneration in SCI and EPO as a neuroprotective agent, and some evidences coming from ongoing clinical trials. The evidences underling that EPO could be a promising therapeutic agent in a variety of neurological insults, including trauma, are mounting. In particular, it is highlighted that administration of EPO or other recently generated EPO analogues such as asialo-EPO and carbamylated-EPO demonstrate interesting preclinical and clinical characteristics, rendering the evaluation of these tissue-protective agents imperative in human clinical trials. Moreover the demonstration of rhEPO and its analogues' broad neuroprotective effects in animal models of cord lesion and in human trial like stroke, should encourage scientists and clinicians to design clinical trials assessing the efficacy of these pharmacological compounds on SCI.
Collapse
|
|
24
|
Rabchevsky AG, Patel SP, Springer JE. Pharmacological interventions for spinal cord injury: where do we stand? How might we step forward? Pharmacol Ther 2011; 132:15-29. [PMID: 21605594 DOI: 10.1016/j.pharmthera.2011.05.001] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Accepted: 04/28/2011] [Indexed: 12/15/2022]
Abstract
Despite numerous studies reporting some measures of efficacy in the animal literature, there are currently no effective therapies for the treatment of traumatic spinal cord injuries (SCI) in humans. The purpose of this review is to delineate key pathophysiological processes that contribute to neurological deficits after SCI, as well as to describe examples of pharmacological approaches that are currently being tested in clinical trials, or nearing clinical translation, for the therapeutic management of SCI. In particular, we will describe the mechanistic rationale to promote neuroprotection and/or functional recovery based on theoretical, yet targeted pathological events. Finally, we will consider the clinical relevancy for emerging evidence that pharmacologically targeting mitochondrial dysfunction following injury may hold the greatest potential for increasing tissue sparing and, consequently, the extent of functional recovery following traumatic SCI.
Collapse
Affiliation(s)
- Alexander G Rabchevsky
- Spinal Cord & Brain injury Research Center, Lexington, University of Kentucky, KY 40536-0509, USA.
| | | | | |
Collapse
|
|
25
|
Stöver T, Lenarz T. Biomaterials in cochlear implants. GMS CURRENT TOPICS IN OTORHINOLARYNGOLOGY, HEAD AND NECK SURGERY 2011; 8:Doc10. [PMID: 22073103 PMCID: PMC3199815 DOI: 10.3205/cto000062] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The cochlear implant (CI) represents, for almost 25 years now, the gold standard in the treatment of children born deaf and for postlingually deafened adults. These devices thus constitute the greatest success story in the field of ‘neurobionic’ prostheses. Their (now routine) fitting in adults, and especially in young children and even babies, places exacting demands on these implants, particularly with regard to the biocompatibility of a CI’s surface components. Furthermore, certain parts of the implant face considerable mechanical challenges, such as the need for the electrode array to be flexible and resistant to breakage, and for the implant casing to be able to withstand external forces. As these implants are in the immediate vicinity of the middle-ear mucosa and of the junction to the perilymph of the cochlea, the risk exists – at least in principle – that bacteria may spread along the electrode array into the cochlea. The wide-ranging requirements made of the CI in terms of biocompatibility and the electrode mechanism mean that there is still further scope – despite the fact that CIs are already technically highly sophisticated – for ongoing improvements to the properties of these implants and their constituent materials, thus enhancing the effectiveness of these devices. This paper will therefore discuss fundamental material aspects of CIs as well as the potential for their future development.
Collapse
Affiliation(s)
- Timo Stöver
- Department of Otolaryngology, Goethe University Frankfurt, Frankfurt a.M., Germany
| | | |
Collapse
|
|
26
|
Kwon BK, Okon EB, Tsai E, Beattie MS, Bresnahan JC, Magnuson DK, Reier PJ, McTigue DM, Popovich PG, Blight AR, Oudega M, Guest JD, Weaver LC, Fehlings MG, Tetzlaff W. A grading system to evaluate objectively the strength of pre-clinical data of acute neuroprotective therapies for clinical translation in spinal cord injury. J Neurotrauma 2010; 28:1525-43. [PMID: 20507235 DOI: 10.1089/neu.2010.1296] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The past three decades have seen an explosion of research interest in spinal cord injury (SCI) and the development of hundreds of potential therapies that have demonstrated some promise in pre-clinical experimental animal models. A growing number of these treatments are seeking to be translated into human clinical trials. Conducting such a clinical trial, however, is extremely costly, not only for the time and money required to execute it, but also for the limited resources that will then no longer be available to evaluate other promising therapies. The decision about what therapies have sufficient pre-clinical evidence of efficacy to justify testing in humans is therefore of utmost importance. Here, we have developed a scoring system for objectively grading the body of pre-clinical literature on neuroprotective treatments for acute SCI. The components of the system include an evaluation of a number of factors that are thought to be important in considering the "robustness" of a therapy's efficacy, including the animal species and injury models that have been used to test it, the time window of efficacy, the types of functional improvements effected by it, and whether efficacy has been independently replicated. The selection of these factors was based on the results of a questionnaire that was performed within the SCI research community. A modified Delphi consensus-building exercise was then conducted with experts in pre-clinical SCI research to refine the criteria and decide upon how to score them. Finally, the grading system was applied to a series of potential neuroprotective treatments for acute SCI. This represents a systematic approach to developing an objective method of evaluating the extent to which the pre-clinical literature supports the translation of a particular experimental treatment into human trials.
Collapse
Affiliation(s)
- Brian K Kwon
- Combined Neurosurgical and Orthopaedic Spine Program, Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
|
|
28
|
Yoo JY, Won YJ, Lee JH, Kim JU, Sung IY, Hwang SJ, Kim MJ, Hong HN. Neuroprotective effects of erythropoietin posttreatment against kainate-induced excitotoxicity in mixed spinal cultures. J Neurosci Res 2009; 87:150-63. [PMID: 18711747 DOI: 10.1002/jnr.21832] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Although the neuroprotective effects of erythropoietin (EPO) preconditioning are well known, the potential of postapplied EPO to protect neurons against excitotoxic injury has not been clearly established. Here we show that kainate (KA)-induced excitotoxicity, which plays a key role in secondary spinal cord injury, decreased neuron survival, inhibited neurite extension, and significantly reduced the expression of erythropoietin receptors (EpoR) in cultured spinal neurons. Posttreatment with EPO for 48 hr protected neurons against KA-induced injury, opposing KA-induced apoptosis and promoting regrowth of motoneuron neurites. These neuroprotective effects were paralleled by a restoration of EpoR expression. The importance of the EpoR signaling pathway was demonstrated using an EpoR blocking antibody, which neutralized the neuroprotective action of EPO posttreatment and prevented EPO-induced increases in EpoR expression. We also found that up-regulated EpoR stimulated the Janus kinase 2 (JAK2) pathway, which is known to facilitate neuronal growth and neurite regeneration. Although EPO posttreatment modestly attenuated KA-induced reactive gliosis in mixed neuron-glial cultures, blocking EpoR activity did not alter glial fibrillary acidic protein expression or astrocyte proliferation. In conclusion, 48 hr treatment with EPO following KA exposure induced EpoR-dependent protection against excitotoxic injury, demonstrating that preconditioning is not a prerequisite for neuroprotection by EPO. The neuroprotective effects of EPO posttreatment were mediated by an EpoR-dependent signaling pathway that possibly involves JAK2. The neuroprotective effect of EPO posttreatment against KA excitotoxicity appears to reflect direct effects on neurons and not indirect effects mediated by astrocytes.
Collapse
Affiliation(s)
- Jong Yoon Yoo
- Department of Rehabilitation Medicine, University of Ulsan College of Medicine, Songpa-gu, Seoul, South Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Yamasaki K, Setoguchi T, Takenouchi T, Yone K, Komiya S. Stem cell factor prevents neuronal cell apoptosis after acute spinal cord injury. Spine (Phila Pa 1976) 2009; 34:323-7. [PMID: 19182706 DOI: 10.1097/brs.0b013e318193a1de] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A rat spinal cord injury (SCI) model and immunohistochemistry were used to examine the levels of expression of stem cell factor and c-kit. In addition, we examined whether intraperitoneal administration of stem cell factor could prevent neural cells apoptosis after acute SCI. OBJECTIVE To evaluate the antiapoptotic effect of stem cell factor after SCI. SUMMARY OF BACKGROUND DATA It is well known that the mode of delayed neuronal and glial cell death after SCI is apoptosis. Inhibition of apoptosis might thus promote neurologic improvement after SCI. Stem cell factor and its receptor c-kit exhibit pleiotropic effects in early hematopoiesis, and are also known to prevent hematopoietic progenitor cell apoptosis. Stem cell factor has recently been reported to be a survival factor for neural stem cells in vitro. We examined the levels of expression of stem cell factor and c-kit in normal and injured rat spinal cord. In addition, we examined whether stem cell factor prevents neural cell apoptosis after acute SCI. METHODS We examined the expression of stem cell factor and c-kit in spinal cord after injury by quantitative RT-PCR and immunohistochemistry. Antiapoptotic effects of stem cell factor were examined using rats with SCI that received stem cell factor intraperitoneally, and were examined immunohistochemically with anticleaved PARP antibody and antiactive caspase-3 antibody between 1 and 3 days after injury. RESULTS Upregulation of stem cell factor and c-kit expression occured after SCI. We also found that neurons express stem cell factor, and neurons and oligodendrocytes express c-kit after SCI. In addition, intraperitoneal administration of stem cell factor prevented spinal neural cells apoptosis after injury. CONCLUSION These findings suggest the possibility that stem cell factor, a hematopoietic cytokine, could be useful as an agent for treatment of SCI.
Collapse
Affiliation(s)
- Kouhei Yamasaki
- Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | | | | | | | | |
Collapse
|
|
30
|
The efficacy of erythropoietin on acute spinal cord injury. An experimental study on a rat model. Arch Orthop Trauma Surg 2009; 129:189-94. [PMID: 18309506 DOI: 10.1007/s00402-008-0594-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2007] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The accumulated knowledge of erythropoietin (EPO) interaction in neural injury has led to potentially novel therapeutic strategies. Previous experimental studies of recombinant human EPO (rhEPO) administration have shown favorable results after central and peripheral neural injury. In the present study we used the aneurysmal clip model to evaluate the efficacy of two different regimes of rhEPO administration on the functional outcome after severe acute spinal cord injury (ASCI). MATERIALS AND METHODS Thirty rats were operated on with posterior laminectomy at thoracic 10th vertebra. Spinal cord trauma produced by extradural placement of the aneurysm clip, for 1 min. Animals were divided into three groups; the first group received a low total EPO dose (EPO-L), (2 doses of 1,000 IU each s.c.). The second group was administered the high total EPO dose (EPO-H), (14 doses of 1,000 IU each s.c.), and the third was the Control group, which received normal saline in the same time fashion with EPO-H group. Follow-up was for 6 weeks. Estimation of the functional progress of each rat was calculated using the locomotor rating scale of Basso et al, with a range from 0 to 21. RESULTS After surgery the animals suffered paraplegia with urinary disturbances. Rats that received EPO demonstrated statistically significant functional improvement compared to the Control group, throughout study interval. On the last follow-up at 6 weeks the EPO-L rats achieved a mean score 17.3 +/- 1.15, the EPO-H 14.7 +/- 1.82, and the control group 8.2 +/- 0.78. Comparison between the two EPO groups reveals superior final outcome of the group treated with lower total dose. CONCLUSION Our study supports current knowledge, that EPO administration has a positive effect on functional recovery after experimental ASCI. These data reflect the positive impact of EPO on the pathophysiologic cascade of secondary neural damage. However, we observed a dose-related effect on functional recovery. Interestingly, large doses do not seem to favor the neurological recovery as lower doses do.
Collapse
|
|
31
|
Erythropoietin in 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 2008; 18:314-23. [PMID: 19030901 DOI: 10.1007/s00586-008-0829-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2008] [Revised: 08/15/2008] [Accepted: 11/04/2008] [Indexed: 12/18/2022]
Abstract
Spinal cord injury (SCI) is a devastating condition for individual patients and costly for health care systems requiring significant long-term expenditures. Cytokine erythropoietin (EPO) is a glycoprotein mediating cytoprotection in a variety of tissues, including spinal cord, through activation of multiple signaling pathways. It has been reported that EPO exerts its beneficial effects by apoptosis blockage, reduction of inflammation, and restoration of vascular integrity. Neuronal regeneration has been also suggested. In the present review, the pathophysiology of SCI and the properties of endogenous or exogenously administered EPO are briefly described. Moreover, an attempt to present the current traumatic, ischemic and inflammatory animal models that mimic SCI is made. Currently, a clearly effective pharmacological treatment is lacking. It is highlighted that administration of EPO or other recently generated EPO analogues such as asialo-EPO and carbamylated-EPO demonstrate exceptional preclinical characteristics, rendering the evaluation of these tissue-protective agents imperative in human clinical trials.
Collapse
|
|
32
|
Berkingali N, Warnecke A, Gomes P, Paasche G, Tack J, Lenarz T, Stöver T. Neurite outgrowth on cultured spiral ganglion neurons induced by erythropoietin. Hear Res 2008; 243:121-6. [PMID: 18672044 DOI: 10.1016/j.heares.2008.07.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2007] [Revised: 06/27/2008] [Accepted: 07/02/2008] [Indexed: 11/27/2022]
Abstract
The morphological correlate of deafness is the loss of hair cells with subsequent degeneration of spiral ganglion neurons (SGN). Neurotrophic factors have a neuroprotective effect, and especially brain-derived neurotrophic factor (BDNF) has been demonstrated to protect SGN in vitro and after ototoxic trauma in vivo. Erythropoietin (EPO) attenuates hair cell loss in rat cochlea explants that were treated with gentamycin. Recently, it has also been shown that EPO reduces the apoptose rate in hippocampal neurons. Therefore, the aim of the study was to examine the effects of EPO on SGN in vitro. Spiral ganglion cells were isolated from neonatal rats and cultured for 48 h in serum-free medium supplemented with EPO and/or BDNF. Results showed that survival rates of SGN were not significantly improved when cultivated with EPO alone. Also, EPO did not further increase BDNF-induced survival of SGN. However, significant elongation of neurites was determined when SGN were cultivated with EPO alone. Even though a less than additive effect was observed, combined treatment with BDNF and EPO led to a significant elongation of neurites when compared to individual treatment with BDNF or EPO. It can be concluded that EPO induces neurite outgrowth rather than promoting survival. Thus, EPO presents as an interesting candidate to enhance and modulate the regenerative effect of BDNF on SGN.
Collapse
Affiliation(s)
- Nurdanat Berkingali
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Hannover, Hannover, Germany
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Mann C, Lee JH, Liu J, Stammers AM, Sohn HM, Tetzlaff W, Kwon BK. Delayed treatment of spinal cord injury with erythropoietin or darbepoetin—A lack of neuroprotective efficacy in a contusion model of cord injury. Exp Neurol 2008; 211:34-40. [DOI: 10.1016/j.expneurol.2007.12.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2007] [Revised: 12/09/2007] [Accepted: 12/11/2007] [Indexed: 11/26/2022]
|
|
34
|
Noguchi CT, Asavaritikrai P, Teng R, Jia Y. Role of erythropoietin in the brain. Crit Rev Oncol Hematol 2007; 64:159-71. [PMID: 17482474 PMCID: PMC2083122 DOI: 10.1016/j.critrevonc.2007.03.001] [Citation(s) in RCA: 180] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2006] [Revised: 01/12/2007] [Accepted: 03/14/2007] [Indexed: 11/21/2022] Open
Abstract
Multi-tissue erythropoietin receptor (EPO-R) expression provides for erythropoietin (EPO) activity beyond its known regulation of red blood cell production. This review highlights the role of EPO and EPO-R in brain development and neuroprotection. EPO-R brain expression includes neural progenitor cells (NPC), neurons, glial cells and endothelial cells. EPO is produced in brain in a hypoxia sensitive manner, stimulates NPC proliferation and differentiation, and neuron survival, and contributes to ischemic preconditioning. Mice lacking EPO or EPO-R exhibit increased neural cell apoptosis during development before embryonic death due to severe anemia. EPO administration provides neural protection in animal models of brain ischemia and trauma, reducing the extent of injury and damage. Intrinsic EPO production in brain and EPO stimulation of endothelial cells contribute to neuroprotection and these are of particular importance since only low levels of EPO appear to cross the blood-brain barrier when administered at high dose intravenously. The therapeutic potential of EPO for brain ischemia/trauma and neurodegenerative diseases has shown promise in early clinical trial and awaits further validation.
Collapse
Affiliation(s)
- Constance Tom Noguchi
- Molecular Medicine Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-1822, USA.
| | | | | | | |
Collapse
|