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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.
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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
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Gholami M, Gilanpour H, Sadeghinezhad J, Asghari A. Facile fabrication of an erythropoietin-alginate/chitosan hydrogel and evaluation of its local therapeutic effects on spinal cord injury in rats. ACTA ACUST UNITED AC 2021; 29:255-265. [PMID: 34491566 DOI: 10.1007/s40199-021-00399-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 04/26/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND AND OBJECTIVE Spinal cord injury (SCI) is a major disabling disorder for which no effective treatment has yet been found. Regenerative incapability of neuronal cells as well as the secondary mechanisms of injury are the major reasons behind this clinical frustration. Thus, here we fabricated an erythropoietin-chitosan/alginate (EPO-CH/AL) hydrogel and investigated its local therapeutic effects on the apoptotic and inflammatory indices of SCI secondary injury. METHODS EPO-CH/AL hydrogels were fabricated by the ionic gelation method, and they were characterized using SEM and FTIR. In vitro drug release profile of EPO-CH/AL hydrogels was evaluated by UV-vis spectroscopy. Experimental SCI was inflicted in rats which were then treated with CH/AL hydrogels containing different doses of EPO (1000, 5000 and 10,000 IU/kg). The relative expression of Bax and Bcl2 (apoptosis index) and active and inactive forms of NF-κB (inflammation index) were assessed using western blot. Total serum levels of TNF-α were also assessed with ELISA, and histopathological and immunohistochemistry studies were carried out to check the overall changes in the injured tissues. RESULTS In vitro drug release test indicated that the EPO-CH/AL hydrogels had a sustained- and controlled-release profile for EPO under these conditions. All the fabricated hydrogels dramatically reduced the elevated inflammation and apoptosis indices of the SCI-inflicted rats (p ≤ 0.05). Nevertheless, only EPO-CH/AL hydrogel (1000 IU/kg EPO) significantly improved the tissue repair and histopathological appearance of the spinal cord at the sites of injury. CONCLUSION Based on our findings, EPO-CH/AL hydrogel (1000 IU/kg EPO) can effectively improve experimental SCI in rats via inhibiting apoptosis and inflammation. Further studies are warranted to elucidate the contributing role of the scaffold in the observed effects.
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Affiliation(s)
- Mahdi Gholami
- Department of Basic Science and Hygiene, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Hassan Gilanpour
- Department of Basic Science and Hygiene, Science and Research Branch, Islamic Azad University, Tehran, Iran.
| | - Javad Sadeghinezhad
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Ahmad Asghari
- Department of Clinical Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
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Rink S, Manthou ME, Arnold J, Grigo M, Dicken P, Abdulla DSY, Bendella H, Nohroudi K, Angelov DN. Motor, sensitive, and vegetative recovery in rats with compressive spinal-cord injury after combined treatment with erythropoietin and whole-body vibration. Restor Neurol Neurosci 2021; 39:85-100. [PMID: 33612500 DOI: 10.3233/rnn-201120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Physical therapy with whole body vibration (WBV) following compressive spinal cord injury (SCI) in rats restores density of perisomatic synapses, improves body weight support and leads to a better bladder function. The purpose of the study was to determine whether the combined treatment with WBV plus erythropoietin (EPO) would further improve motor, sensory and vegetative functions after SCI in rats. METHODS Severe compressive SCI at low thoracic level was followed by a single i.p. injection of 2,5μg (250 IU) human recombinant EPO. Physical therapy with WBV started on 14th day after injury and continued over a 12-week post injury period. Locomotor recovery, sensitivity tests and urinary bladder scores were analysed at 1, 3, 6, 9, and 12 weeks after SCI. The closing morphological measurements included lesion volume and numbers of axons in the preserved perilesional neural tissue bridges (PNTB). RESULTS Assessment of motor performance sensitivity and bladder function revealed no significant effects of EPO when compared to the control treatments. EPO treatment neither reduced the lesion volume, nor increased the number of axons in PNTB. CONCLUSIONS The combination of WBV + EPO exerts no positive effects on hind limbs motor performance and bladder function after compressive SCI in rats.
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Affiliation(s)
- Svenja Rink
- Department of Prosthetic Dentistry, School of Dental and Oral Medicine, University of Cologne, Cologne, Germany
| | - Maria Eleni Manthou
- Department of Histology and Embryology, School of Medicine, Faculty of Health Sciences, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Julia Arnold
- Department of Anatomy I, University of Cologne, Cologne, Germany
| | - Merle Grigo
- Department of Anatomy I, University of Cologne, Cologne, Germany
| | - Paulina Dicken
- Department of Anatomy I, University of Cologne, Cologne, Germany
| | - Diana Saad Yousif Abdulla
- Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Network Genomic Medicine, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Habib Bendella
- Department of Neurosurgery, University of Witten/Herdecke, Cologne Merheim Medical Center (CMMC), Cologne, Germany
| | - Klaus Nohroudi
- Department of Anatomy I, University of Cologne, Cologne, Germany
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Silva I, Alípio C, Pinto R, Mateus V. Potential anti-inflammatory effect of erythropoietin in non-clinical studies in vivo: A systematic review. Biomed Pharmacother 2021; 139:111558. [PMID: 33894624 DOI: 10.1016/j.biopha.2021.111558] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/19/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023] Open
Abstract
Erythropoietin (EPO) is a hypoxia-induced hormone produced in adult kidneys with erythropoietic and non-erythropoietic effects. In vivo studies represent an important role to comprehend the efficacy and safety in the early phase of repurposing drugs. The aim is to evaluate the potential anti-inflammatory effect of EPO observed in animal models of disease. Following PRISMA statements, electronic database Medline via PubMed platform was used to search articles with the research expression ((erythropoietin [MeSH Terms]) AND (inflammation [MeSH Terms]) AND (disease models, animal [MeSH Terms])). The inclusion criteria were original articles, studies where EPO was administered, studies where inflammation was studied and/or evaluated, non-clinical studies in vivo with rodents, and articles published in English. Thirty-six articles met the criteria for qualitative analysis. Exogenous EPO was used in models of sepsis, traumatic brain injury, and autoimmune neuritis, with an average of 3000 IU/Kg for single and multiple doses, using mice and rats. Biomarkers such as immune-related effectors, cytokines, reactive oxygen species, prostaglandins, and other biomarkers were assessed. EPO has been recognized as a multifunctional cytokine with anti-inflammatory properties, showing its significant effect both in acute and chronic models of inflammation. Further non-clinical studies are suggested for the enlightenment of anti-inflammatory mechanisms of EPO in lower doses, allowing us to understand the translational data for humans.
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Affiliation(s)
- Inês Silva
- H&TRC-Health and Technology Research Center, ESTeSL-Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal
| | - Carolina Alípio
- H&TRC-Health and Technology Research Center, ESTeSL-Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
| | - Rui Pinto
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal; JCS, Dr. Joaquim Chaves, Laboratório de Análises Clínicas, Miraflores, 1495-069 Algés, Portugal
| | - Vanessa Mateus
- H&TRC-Health and Technology Research Center, ESTeSL-Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal.
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The effect of combination therapy with erythropoietin and methylprednisolone in patients with traumatic cervical spinal cord injury: a pilot randomized controlled trial. Spinal Cord 2021; 59:347-353. [PMID: 33495576 DOI: 10.1038/s41393-020-00604-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 12/01/2020] [Accepted: 12/01/2020] [Indexed: 11/08/2022]
Abstract
STUDY DESIGN Pilot double-blinded randomized controlled trial. OBJECTIVES To investigate the additive effect of recombinant human erythropoietin (rhEPO) on functional outcome and disability in patients with traumatic cervical spinal cord injury (TCSCI). SETTINGS University-affiliated hospital in Mashhad, Iran. METHODS Patients with acute TCSCI admitted within 8 h after injury were randomly assigned to receive only methylprednisolone (M group) or rhEPO 500 IU/mL plus methylprednisolone (M + E group). All the patients underwent surgery within the next several days. Neurological function was assessed on admission, and at 6th and 12th months after the injury according to the sphincter function and American spinal cord injury association (ASIA) scale. RESULTS Overall, 54 patients (mean age: 39.7 ± 13.3 years) including 46 (85%) males were studied in two groups of 27. The likelihood of developing adverse neurological outcomes (ASIA impairment score of A compared to D or E) was not significantly different between the groups after 6 (OR = 0.39, 95% CI = 0.03-4.80, P = 0.46) and 12 months (OR = 0.83, 95% CI = 0.11-6.11, P = 0.86). The groups also showed no significant difference in 1-year mortality (OR = 0.83, 95% CI = 0.25-2.74, P = 0.76). CONCLUSIONS It is not clear whether combination therapy with erythropoietin compared to methylprednisolone alone improves neurological functions of patients with TCSCI. Our study provides interim data to guide future larger definitive trials.
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Thompson A, Farmer K, Rowe E, Hayley S. Erythropoietin modulates striatal antioxidant signalling to reduce neurodegeneration in a toxicant model of Parkinson's disease. Mol Cell Neurosci 2020; 109:103554. [DOI: 10.1016/j.mcn.2020.103554] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 12/13/2022] Open
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Abdullahi D, Ahmad Annuar A, Sanusi J. Improved spinal cord gray matter morphology induced by Spirulina platensis following spinal cord injury in rat models. Ultrastruct Pathol 2020; 44:359-371. [PMID: 32686973 DOI: 10.1080/01913123.2020.1792597] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Despite intense preclinical research focusing on developing potential strategies of mitigating spinal cord injury (SCI), SCI still results in permanent, debilitating symptoms for which there are currently no effective pharmacological interventions to improve the recovery of the fine ultrastructure of the spinal cord. Spirulina platensis is thought to have potential neuroprotective effects. We have previously demonstrated its protective potential on the lesioned corticospinal tracts and behavioral recovery. In this study, spirulina, known for its neuroprotective properties was used to further explore its protective effects on spinal cord gray matter ultrastructural. Twenty-four Sprague-Dawley rats were used and divided into sham group (laminectomy without SCI), control group (SCI without S. platensis), and S. platensis group (SCI + 180 mg/kg S. platensis). All animals were anesthetized via intramuscular injection. A partial crush injury was induced at the level of T12. The rats were humanely sacrificed for 28 days postinjury for ultrastructural study. There were significant mean differences with respect to pairwise comparisons between the ultrastructural grading score of neuronal perikarya of control and the S. platensis following injury at day 28, which correlates with the functional locomotor recovery at this timepoint in our previous study. The group supplemented with spirulina, thus, revealed a better improvement in the fine ultrastructure of the spinal cord gray matter when compared to the control group thereby suggesting neuroprotective potentials of spirulina in mitigating the effects of spinal cord injury and inducing functional recovery.
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Affiliation(s)
- Dauda Abdullahi
- Department of Anatomy, Faculty of Medicine, University of Malaya , Kuala Lumpur, Malaysia.,Department of Anatomy, College of Medical Sciences, Abubakar Tafawa Balewa University Bauchi , Bauchi, Nigeria
| | - Azlina Ahmad Annuar
- Department of Biomedical Science, Faculty of Medicine, University of Malaya , Kuala Lumpur, Malaysia
| | - Junedah Sanusi
- Department of Anatomy, Faculty of Medicine, University of Malaya , Kuala Lumpur, Malaysia
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Zhong L, Zhang H, Ding ZF, Li J, Lv JW, Pan ZJ, Xu DX, Yin ZS. Erythropoietin-Induced Autophagy Protects Against Spinal Cord Injury and Improves Neurological Function via the Extracellular-Regulated Protein Kinase Signaling Pathway. Mol Neurobiol 2020; 57:3993-4006. [PMID: 32647973 DOI: 10.1007/s12035-020-01997-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022]
Abstract
The objective of this study was to explore the neuroprotective molecular mechanisms of erythropoietin (EPO) in rats following spinal cord injury (SCI). First, a standard SCI model was established. After drug or saline treatment was administered, locomotor function was evaluated in rats using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. H&E, Nissl, and TUNEL staining were performed to assess the ratio of cavities, number of motor neurons, and apoptotic cells in the damaged area. The relative protein and mRNA expressions were examined using western blot and qRT-PCR analyses, and the inflammatory markers, axon special protein, and neuromuscular junctions (NMJs) were detected by immunofluorescence. Both doses of EPO notably improved locomotor function, but high-dose EPO was more effective than low-dose EPO. Moreover, EPO reduced the cavity ratio, cell apoptosis, and motor neuron loss in the damaged area, but enhanced the autophagy level and extracellular-regulated protein kinase (ERK) activity. Treatment with an ERK inhibitor significantly prevented the effect of EPO on SCI, and an activator mimicked the benefits of EPO. Further investigation revealed that EPO promoted SCI-induced autophagy via the ERK signaling pathway. EPO activates autophagy to promote locomotor function recovery in rats with SCI via the ERK signaling pathway.
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Affiliation(s)
- Lin Zhong
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, #218 Jixi Road, Hefei, 230022, China.,Department of Orthopedics, The Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Hui Zhang
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, #218 Jixi Road, Hefei, 230022, China
| | - Zheng-Fei Ding
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, #218 Jixi Road, Hefei, 230022, China
| | - Jian Li
- Department of Toxicology, School of Public Health, Anhui Medical University, #81 Mei Shan Road, Hefei, 230032, China.,Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China
| | - Jin-Wei Lv
- Department of Toxicology, School of Public Health, Anhui Medical University, #81 Mei Shan Road, Hefei, 230032, China.,Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China
| | - Zheng-Jun Pan
- Department of Orthopedics, The Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - De-Xiang Xu
- Department of Toxicology, School of Public Health, Anhui Medical University, #81 Mei Shan Road, Hefei, 230032, China. .,Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China.
| | - Zong-Sheng Yin
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, #218 Jixi Road, Hefei, 230022, China.
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Tanaka T, Murata H, Miyazaki R, Yoshizumi T, Sato M, Ohtake M, Tateishi K, Kim P, Yamamoto T. Human recombinant erythropoietin improves motor function in rats with spinal cord compression-induced cervical myelopathy. PLoS One 2019; 14:e0214351. [PMID: 31821342 PMCID: PMC6903714 DOI: 10.1371/journal.pone.0214351] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 11/12/2019] [Indexed: 01/11/2023] Open
Abstract
Objective Erythropoietin (EPO) is a clinically available hematopoietic cytokine. EPO has shown beneficial effects in the context of spinal cord injury and other neurological conditions. The aim of this study was to evaluate the effect of EPO on a rat model of spinal cord compression-induced cervical myelopathy and to explore the possibility of its use as a pharmacological treatment. Methods To develop the compression-induced cervical myelopathy model, an expandable polymer was implanted under the C5-C6 laminae of rats. EPO administration was started 8 weeks after implantation of a polymer. Motor function of rotarod performance and grip strength was measured after surgery, and motor neurons were evaluated with H-E, NeuN and choline acetyltransferase staining. Apoptotic cell death was assessed with TUNEL and Caspase-3 staining. The 5HT, GAP-43 and synaptophysin were evaluated to investigate the protection and plasticity of axons. Amyloid beta precursor protein (APP) was assessed to evaluate axonal injury. To assess transfer of EPO into spinal cord tissue, the EPO levels in spinal cord tissue were measured with an ELISA for each group after subcutaneous injection of EPO. Results High-dose EPO maintained motor function in the compression groups. EPO significantly prevented the loss of motor neurons and significantly decreased neuronal apoptotic cells. Expression of 5HT and synaptophysin was significantly preserved in the EPO group. APP expression was partly reduced in the EPO group. The EPO levels in spinal cord tissue were significantly higher in the high-dose EPO group than other groups. Conclusion EPO improved motor function in rats with compression-induced cervical myelopathy. EPO suppressed neuronal cell apoptosis, protected motor neurons, and induced axonal protection and plasticity. The neuroprotective effects were produced following transfer of EPO into the spinal cord tissue. These findings suggest that EPO has high potential as a treatment for degenerative cervical myelopathy.
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Affiliation(s)
- Takahiro Tanaka
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Hidetoshi Murata
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- * E-mail:
| | - Ryohei Miyazaki
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Tetsuya Yoshizumi
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Mitsuru Sato
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Makoto Ohtake
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Kensuke Tateishi
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Phyo Kim
- Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan
| | - Tetsuya Yamamoto
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
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Abdullahi D, Ahmad Annuar A, Sanusi J. Neuroprotective potential of Spirulina platensis on lesioned spinal cord corticospinal tract under experimental conditions in rat models. Ultrastruct Pathol 2019; 43:273-289. [PMID: 31779507 DOI: 10.1080/01913123.2019.1695693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Spinal cord injury (SCI) results from penetrating or compressive traumatic injury to the spine in humans or by the surgical compression of the spinal cord in experimental animals. In this study, the neuroprotective potential of Spirulina platensis was investigated on ultrastructural and functional recovery of the spinal cord following surgical-induced injury. Twenty-four Sprague-Dawley rats were divided into three groups; sham group, control (trauma) group, and experimental (S. platensis) group (180 mg/kg) of eight rats each. For each group, the rats were then subdivided into two groups to allow measurement at two different timepoints (day 14 and 28) for the microscopic analysis. Rats in the control and experimental S. platensis groups were subjected to partial crush injury at the level of T12 with Inox number 2 modified forceps by compressing on the spinal cord for 30 s. Pairwise comparisons of ultrastructural grading mean scores difference between the control and experimental S. platensis groups reveals that there were significant differences on the axonal ultrastructure, myelin sheath and BBB Score on Day 28; these correlate with the functional locomotor recovery at this timepoint. The results suggest that supplementation with S. platensis induces functional recovery and effective preservation of the spinal cord ultrastructure after SCI. These findings will open new potential avenue for further research into the mechanism of S. platensis-mediated spinal cord repair.
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Affiliation(s)
- Dauda Abdullahi
- Department of Anatomy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.,Department of Human Anatomy, College of Medical Sciences, Abubakar Tafawa Balewa University Bauchi, Bauchi, Nigeria
| | - Azlina Ahmad Annuar
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Junedah Sanusi
- Department of Anatomy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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11
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Leung YY. Management and prevention of third molar surgery-related trigeminal nerve injury: time for a rethink. J Korean Assoc Oral Maxillofac Surg 2019; 45:233-240. [PMID: 31728330 PMCID: PMC6838349 DOI: 10.5125/jkaoms.2019.45.5.233] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 09/19/2019] [Indexed: 12/26/2022] Open
Abstract
Trigeminal nerve injury as a consequence of lower third molar surgery is a notorious complication and may affect the patient in long term. Inferior alveolar nerve (IAN) and lingual nerve (LN) injury result in different degree of neurosensory deficit and also other neurological symptoms. The long term effects may include persistent sensory loss, chronic pain and depression. It is crucial to understand the pathophysiology of the nerve injury from lower third molar surgery. Surgery remains the most promising treatment in moderate-to-severe nerve injuries. There are limitations in the current treatment methods and full recovery is not commonly achievable. It is better to prevent nerve injury than to treat with unpredictable results. Coronectomy has been proved to be effective in reducing IAN injury and carries minimal long-term morbidity. New technologies, like the roles of erythropoietin and stem cell therapy, are being investigated for neuroprotection and neural regeneration. Breakthroughs in basic and translational research are required to improve the clinical outcomes of the current treatment modalities of third molar surgery-related nerve injury.
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Affiliation(s)
- Yiu Yan Leung
- Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Hong Kong, Hong Kong
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Ho MT, Teal CJ, Shoichet MS. A hyaluronan/methylcellulose-based hydrogel for local cell and biomolecule delivery to the central nervous system. Brain Res Bull 2019; 148:46-54. [PMID: 30898580 DOI: 10.1016/j.brainresbull.2019.03.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/01/2019] [Accepted: 03/12/2019] [Indexed: 02/03/2023]
Abstract
Regenerative medicine strategies rely on exogenous cell transplantation and/or endogenous cell stimulation. Biomaterials can help to increase the regenerative potential of cells and biomolecules by controlling transplanted cell fate and provide a local, sustained release of biomolecules. In this review, we describe the use of a hyaluronan/methylcellulose (HAMC)-based hydrogel as a delivery vehicle to the brain, spinal cord, and retina to promote cellular survival and tissue repair. We discuss various controlled release strategies to prolong the delivery of factors for neuroprotection. The versatility of this hydrogel for a diversity of applications highlights its potential to enhance cell- and biomolecule-based treatment strategies.
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Affiliation(s)
- Margaret T Ho
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, Canada
| | - Carter J Teal
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, Canada
| | - Molly S Shoichet
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada; Department of Chemistry, University of Toronto, Toronto, Canada.
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13
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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.
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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
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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.
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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
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15
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Suner HI, Kurt G, Yildirim Z, Bulduk EB, Borcek AO, Demirci H, Kartal B, Kaplanoglu GT. Investigation of the Effect of Alemtuzumab in an Experimental Spinal Cord Trauma Model in Rats. World Neurosurg 2018; 121:e723-e730. [PMID: 30292667 DOI: 10.1016/j.wneu.2018.09.197] [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: 08/12/2018] [Revised: 09/24/2018] [Accepted: 09/25/2018] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Spinal cord injuries generate the most negative response to medical treatment among all general body injuries. This important morbidity is thought to be caused by a complex secondary damage mechanism. In the present study, we examined the neuroprotective effects of alemtuzumab in a spinal cord trauma model. METHODS We divided 24 Long-Evans male rats into 4 groups (n = 6 per group). Laminectomy was performed at T5-T8 in all groups. Trauma was applied using the Yasargil temporary aneurysm clip for 60 seconds at these spinal cord levels in all groups, except for group 1. Next, 1 mg/kg of alemtuzumab was administered to each rat in groups 3 and 4. A functional evaluation was performed on days 1, 3, and 5 in groups 1, 2, and 4, and the rats were then sacrificed. The rats in group 3 were sacrificed on the third postoperative day to observe the early effects of alemtuzumab. The biochemical examination findings of malondialdehyde and glutathione in plasma and tissue samples and histopathological findings of the spinal cord were evaluated and compared by statistical analysis. RESULTS The inflammatory findings in the trauma group were not seen in either group treated with alemtuzumab. The clinical motor examination and inclined plane test results were also significantly better in these groups. CONCLUSION Our results have shown that alemtuzumab might prevent spinal cord injury after trauma and is a histopathologically and biochemically strong anti-inflammatory, antioxidant, and neuroprotective agent.
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Affiliation(s)
- Halil Ibrahim Suner
- Department of Neurosurgery, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Gokhan Kurt
- Department of Neurosurgery, Faculty of Medicine, Gazi University, Ankara, Turkey
| | | | - Erkut Baha Bulduk
- Department of Neurosurgery, Eskisehir Government Hospital, Eskisehir, Turkey
| | - Alp Ozgun Borcek
- Department of Neurosurgery, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Harun Demirci
- Department of Neurosurgery, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Bahar Kartal
- Department of Histology and Embryology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Gulnur Take Kaplanoglu
- Department of Histology and Embryology, Faculty of Medicine, Gazi University, Ankara, Turkey
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16
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Level-Specific Differences in Systemic Expression of Pro- and Anti-Inflammatory Cytokines and Chemokines after Spinal Cord Injury. Int J Mol Sci 2018; 19:ijms19082167. [PMID: 30044384 PMCID: PMC6122077 DOI: 10.3390/ijms19082167] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 07/23/2018] [Accepted: 07/23/2018] [Indexed: 11/17/2022] Open
Abstract
While over half of all spinal cord injuries (SCIs) occur in the cervical region, the majority of preclinical studies have focused on models of thoracic injury. However, these two levels are anatomically distinct—with the cervical region possessing a greater vascular supply, grey-white matter ratio and sympathetic outflow relative to the thoracic region. As such, there exists a significant knowledge gap in the secondary pathology at these levels following SCI. In this study, we characterized the systemic plasma markers of inflammation over time (1, 3, 7, 14, 56 days post-SCI) after moderate-severe, clip-compression cervical and thoracic SCI in a rat model. Using high-throughput ELISA panels, we observed a clear level-specific difference in plasma levels of VEGF, leptin, IP10, IL18, GCSF, and fractalkine. Overall, cervical SCI had reduced expression of both pro- and anti-inflammatory proteins relative to thoracic SCI, likely due to sympathetic dysregulation associated with higher level SCIs. However, contrary to the literature, we did not observe level-dependent splenic atrophy with our incomplete SCI model. This is the first study to compare the systemic plasma-level changes following cervical and thoracic SCI using level-matched and time-matched controls. The results of this study provide the first evidence in support of level-targeted intervention and also challenge the phenomenon of high SCI-induced splenic atrophy in incomplete SCI models.
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17
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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.
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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
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18
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Zhang H, Fang X, Huang D, Luo Q, Zheng M, Wang K, Cao L, Yin Z. Erythropoietin signaling increases neurogenesis and oligodendrogenesis of endogenous neural stem cells following spinal cord injury both in vivo and in vitro. Mol Med Rep 2017; 17:264-272. [PMID: 29115443 PMCID: PMC5780136 DOI: 10.3892/mmr.2017.7873] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 10/13/2017] [Indexed: 12/17/2022] Open
Abstract
Erythropoietin (Epo) promotes functional recovery following spinal cord injury (SCI); however, the exact underlying mechanisms are yet to be determined. Although endogenous neural stem cells (NSCs) in the adult spinal cord are a therapeutic target in SCI models, the effect of Epo on this NSC population remains unknown. The present study investigated the effects of Epo on endogenous NSCs in the adult spinal cord both in vitro and in vivo. For the in vivo analyses, normal rats (Normal) and SCI contusion model rats (SCI) received either recombinant human Epo or saline treatment for 7 days (5,000 U/kg), and spinal cords were subsequently analyzed at 2, 8, and 14 days. For in vitro analyses, NSCs harvested from adult rat spinal cords were exposed to Epo (10 U/ml). A significant increase in β-tubulin+ new neurons (P<0.01) was observed at all three time points and O4+ new oligodendrocytes (P<0.05) at days 8 and 14 in the SCI+Epo group compared with the SCI+Saline group. This was concomitant with a prolonged activation of Epo signaling; however, no effect on NSCs proliferation was observed. Similar results were also obtained in vitro. Motor functional recovery was also noted at days 8 and 14 only in the Epo-treated SCI rats. Although the expression of Epo and EpoR significantly increased in Normal+Epo rats compared with Normal+Saline rats (P<0.05), the cell numbers and phenotype were comparable between the two groups. To the best of the author's knowledge, this is the first study to demonstrate that Epo signaling promotes both neurogenesis and oligodendrogenesis following SCI and that these may represent the underlying mechanisms for the functional recovery and therapeutic effects of Epo following SCI.
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Affiliation(s)
- Hui Zhang
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xiao Fang
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Dake Huang
- School of Basic Medical Science, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Qingli Luo
- School of Basic Medical Science, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Meijuan Zheng
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Kangkang Wang
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Le Cao
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Zongsheng Yin
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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19
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Faccendini A, Vigani B, Rossi S, Sandri G, Bonferoni MC, Caramella CM, Ferrari F. Nanofiber Scaffolds as Drug Delivery Systems to Bridge Spinal Cord Injury. Pharmaceuticals (Basel) 2017; 10:ph10030063. [PMID: 28678209 PMCID: PMC5620607 DOI: 10.3390/ph10030063] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 06/13/2017] [Accepted: 07/01/2017] [Indexed: 12/21/2022] Open
Abstract
The complex pathophysiology of spinal cord injury (SCI) may explain the current lack of an effective therapeutic approach for the regeneration of damaged neuronal cells and the recovery of motor functions. A primary mechanical injury in the spinal cord triggers a cascade of secondary events, which are involved in SCI instauration and progression. The aim of the present review is to provide an overview of the therapeutic neuro-protective and neuro-regenerative approaches, which involve the use of nanofibers as local drug delivery systems. Drugs released by nanofibers aim at preventing the cascade of secondary damage (neuro-protection), whereas nanofibrous structures are intended to re-establish neuronal connectivity through axonal sprouting (neuro-regeneration) promotion, in order to achieve a rapid functional recovery of spinal cord.
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Affiliation(s)
- Angela Faccendini
- Department of Drug Sciences, University of Pavia, Viale Taramelli, 12, 27100 Pavia, Italy.
| | - Barbara Vigani
- Department of Drug Sciences, University of Pavia, Viale Taramelli, 12, 27100 Pavia, Italy.
| | - Silvia Rossi
- Department of Drug Sciences, University of Pavia, Viale Taramelli, 12, 27100 Pavia, Italy.
| | - Giuseppina Sandri
- Department of Drug Sciences, University of Pavia, Viale Taramelli, 12, 27100 Pavia, Italy.
| | | | | | - Franca Ferrari
- Department of Drug Sciences, University of Pavia, Viale Taramelli, 12, 27100 Pavia, Italy.
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20
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Geary MB, Li H, Zingman A, Ketz J, Zuscik M, De Mesy Bentley KL, Noble M, Elfar JC. Erythropoietin accelerates functional recovery after moderate sciatic nerve crush injury. Muscle Nerve 2017; 56:143-151. [PMID: 28168703 DOI: 10.1002/mus.25459] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 10/29/2016] [Accepted: 11/02/2016] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Erythropoietin (EPO) has been identified as a neuroregenerative agent. We hypothesize that it may accelerate recovery after crush injury and may vary with crush severity. METHODS Mice were randomized to mild, moderate, or severe crush of the sciatic nerve and were treated with EPO or vehicle control after injury. The sciatic function index (SFI) was monitored over the first week. Microstructural changes were analyzed by immunofluorescence for neurofilament (NF) and myelin (P0 ), and electron microscopy was used to assess ultrastructural changes. RESULTS In moderate crush injuries, EPO significantly improved SFI at 7 days post-injury, an effect not observed with other severity levels. Increases in the ratio of P0 to NF were observed after EPO treatment in moderate crush injuries. Electron microscopy demonstrated endothelial cell hypertrophy in the EPO group. CONCLUSIONS EPO accelerates recovery in moderately crushed nerves, which may be through effects on myelination and vascularization. Injury severity may influence the efficacy of EPO. Muscle Nerve 56: 143-151, 2017.
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Affiliation(s)
- Michael B Geary
- Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York, 14642, USA
| | - Haiyan Li
- Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York, 14642, USA
| | - Alissa Zingman
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, New York, USA
| | - John Ketz
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, New York, USA
| | - Michael Zuscik
- Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York, 14642, USA
| | - Karen L De Mesy Bentley
- Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York, 14642, USA.,Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Mark Noble
- Department of Biomedical Genetics, Stem Cell Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - John C Elfar
- Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York, 14642, USA.,Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, New York, USA
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21
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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
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22
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Cariou A, Deye N, Vivien B, Richard O, Pichon N, Bourg A, Huet L, Buleon C, Frey J, Asfar P, Legriel S, Narcisse S, Mathonnet A, Cravoisy A, Dequin PF, Wiel E, Razazi K, Daubin C, Kimmoun A, Lamhaut L, Marx JS, de la Garanderie DP, Ecollan P, Combes A, Spaulding C, Barat F, Ben Boutieb M, Coste J, Chiche JD, Pène F, Mira JP, Treluyer JM, Hermine O, Carli P. Early High-Dose Erythropoietin Therapy After Out-of-Hospital Cardiac Arrest: A Multicenter, Randomized Controlled Trial. J Am Coll Cardiol 2016; 68:40-9. [PMID: 27364049 DOI: 10.1016/j.jacc.2016.04.040] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 03/17/2016] [Accepted: 04/05/2016] [Indexed: 12/29/2022]
Abstract
BACKGROUND Preliminary data suggested a clinical benefit in treating out-of-hospital cardiac arrest (OHCA) patients with a high dose of erythropoietin (Epo) analogs. OBJECTIVES The authors aimed to evaluate the efficacy of epoetin alfa treatment on the outcome of OHCA patients in a phase 3 trial. METHODS The authors performed a multicenter, single-blind, randomized controlled trial. Patients still comatose after a witnessed OHCA of presumed cardiac origin were eligible. In the intervention group, patients received 5 intravenous injections spaced 12 h apart during the first 48 h (40,000 units each, resulting in a maximal dose of 200,000 total units), started as soon as possible after resuscitation. In the control group, patients received standard care without Epo. The main endpoint was the proportion of patients in each group reaching level 1 on the Cerebral Performance Category (CPC) scale (survival with no or minor neurological sequelae) at day 60. Secondary endpoints included all-cause mortality rate, distribution of patients in CPC levels at different time points, and side effects. RESULTS In total, 476 patients were included in the primary analysis. Baseline characteristics were similar in the 2 groups. At day 60, 32.4% of patients (76 of 234) in the intervention group reached a CPC 1 level, as compared with 32.1% of patients (78 of 242) in the control group (odds ratio: 1.01; 95% confidence interval: 0.68 to 1.48). The mortality rate and proportion of patients in each CPC level did not differ at any time points. Serious adverse events were more frequent in Epo-treated patients as compared with controls (22.6% vs. 14.9%; p = 0.03), particularly thrombotic complications (12.4% vs. 5.8%; p = 0.01). CONCLUSIONS In patients resuscitated from an OHCA of presumed cardiac cause, early administration of erythropoietin plus standard therapy did not confer a benefit, and was associated with a higher complication rate. (High Dose of Erythropoietin Analogue After Cardiac Arrest [Epo-ACR-02]; NCT00999583).
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Affiliation(s)
- Alain Cariou
- Medical Intensive Care Unit, Cochin Hospital (APHP), Paris, France; Paris Descartes University, Paris, France; INSERM U970 (team 4), Parisian Cardiovascular Research Center, Paris Descartes University, Paris, France.
| | - Nicolas Deye
- Medical Intensive Care Unit, Lariboisière Hospital (APHP) and INSERM U942, Paris, France
| | - Benoît Vivien
- Paris Descartes University, Paris, France; SAMU 75, Necker Hospital (AP-HP), Paris, France
| | - Olivier Richard
- SAMU 78, Centre Hospitalier de Versailles, Versailles, France
| | | | | | - Loïc Huet
- SAMU 94, Henri Mondor Hospital (APHP), Créteil, France
| | - Clément Buleon
- CHU de Caen, Pôle Réanimations, Anesthésie, SAMU, Caen, Caen, France
| | | | - Pierre Asfar
- Réanimation Médicale et de Médecine Hyperbare, CHU d'Angers, Angers, France
| | - Stéphane Legriel
- Medical ICU, Centre Hospitalier de Versailles, Versailles, France
| | | | - Armelle Mathonnet
- Medical-Surgical Intensive Care Unit, Hôpital de La Source, Centre Hospitalier Regional d'Orléans, Orléans, France
| | | | | | - Eric Wiel
- Emergency Department and SAMU 59, Lille University Hospital, Lille, France
| | - Keyvan Razazi
- Medical ICU, Hôpital Henri Mondor (APHP), Créteil, France
| | - Cédric Daubin
- CHU de Caen, Department of Medical Intensive Care, Caen, France
| | - Antoine Kimmoun
- Service de Réanimation Médicale Brabois, CHU de Nancy, Vandœuvres-les-Nancy, France
| | - Lionel Lamhaut
- INSERM U970 (team 4), Parisian Cardiovascular Research Center, Paris Descartes University, Paris, France; SAMU 75, Necker Hospital (AP-HP), Paris, France; Intensive Care Unit, Necker University Hospital (APHP), Paris, France
| | | | - Didier Payen de la Garanderie
- SMUR & Surgical Intensive Care, Lariboisière University Hospital (APHP) and Paris 7 University Denis Diderot, Paris, France
| | | | - Alain Combes
- Medical Intensive Care Unit, INSERM, UMRS-1166, Université Pierre et Marie Curie, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié-Salpêtrière (APHP), Paris, France
| | - Christian Spaulding
- Paris Descartes University, Paris, France; INSERM U970 (team 4), Parisian Cardiovascular Research Center, Paris Descartes University, Paris, France; Cardiology Department, Cochin University Hospital (APHP), Paris, France
| | - Florence Barat
- Clinical Trial Unit, Central Pharmacy, APHP, Paris, France
| | - Myriam Ben Boutieb
- Biostatistics and Epidemiology Unit, Hôtel-Dieu Hospital (APHP, Paris, France
| | - Joël Coste
- Paris Descartes University, Paris, France; Biostatistics and Epidemiology Unit, Hôtel-Dieu Hospital (APHP, Paris, France
| | - Jean-Daniel Chiche
- Medical Intensive Care Unit, Cochin Hospital (APHP), Paris, France; Paris Descartes University, Paris, France
| | - Frédéric Pène
- Medical Intensive Care Unit, Cochin Hospital (APHP), Paris, France; Paris Descartes University, Paris, France
| | - Jean-Paul Mira
- Medical Intensive Care Unit, Cochin Hospital (APHP), Paris, France; Paris Descartes University, Paris, France
| | - Jean-Marc Treluyer
- Paris Descartes University, Paris, France; Clinical Research Unit, Paris Centre and Paris Descartes University, Paris, France
| | - Olivier Hermine
- Paris Descartes University, Paris, France; Hematology Department, Necker Hospital (APHP), Imagine institute, INSERM U1123 CNRS erl 8654, Labex des Globules Rouges Grex, Paris, France
| | - Pierre Carli
- Paris Descartes University, Paris, France; SAMU 75, Necker Hospital (AP-HP), Paris, France
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Kermani HR, Nakhaee N, Fatahian R, Najar AG. Effect of Aspirin on Spinal Cord Injury: An Experimental Study. IRANIAN JOURNAL OF MEDICAL SCIENCES 2016; 41:217-22. [PMID: 27217606 PMCID: PMC4876300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Aspirin is an anti-inflammatory drug, peroxyl radical scavenger, and antioxidant agent that inhibits phospholipases, nitric oxide synthetases, and cyclooxygenase enzymes. The existing literature contains no studies on the effects of various doses of aspirin on spinal cord injury (SCI). Therefore, we sought to investigate the putative effects of aspirin on experimental SCI. The weight-drop injury model was used to produce SCI in 100 albino Wistar rats. The animals were allocated to five groups: a control group, where the rats did not undergo any surgical or medical intervention except for anesthesia; a sham-treated group, where laminectomy was performed without SCI and no further therapy was administered; and three other groups, where the rats with SCI received low-dose aspirin [20 mg/kg], high-dose aspirin [80 mg/kg], and a vehicle, respectively. Half of the rats were sacrificed 24 hours later, and their spinal cords were excised for biochemical studies. The other rats were subjected to Basso, Beattie, and Bresnahan (BBB) locomotor rating scale scoring once a week for 6 consecutive weeks. Aspirin decreased lipid peroxidation following SCI as the mean (± standard error) catalase level was significantly higher in the high-dose aspirin group (46.10±12.01) than in the sham-treated group (16.07±2.42) and the vehicle-treated group (15.31±3.20) (P<0.05; P<0.05, respectively). Both of the groups treated with high-dose and low-dose aspirin demonstrated a higher mean BBB score than did the control group (P<0.001) and the sham-treated group (P<0.001). Our data provide evidence in support of the potential effects of aspirin in biochemical and neurobehavioral recovery after SCI.
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Affiliation(s)
- Hamed Reihani Kermani
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran,Correspondence: Hamed Reihani Kermani, MD; No 5 Alley, Hezaroyekshab Street, Zip Code: 7618653771, Kerman, Iran Tel/Fax: +98 34 32457861
| | - Nouzar Nakhaee
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Reza Fatahian
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Ahmad Gholamhosseinian Najar
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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Therapies negating neuroinflammation after brain trauma. Brain Res 2015; 1640:36-56. [PMID: 26740405 DOI: 10.1016/j.brainres.2015.12.024] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 12/07/2015] [Accepted: 12/14/2015] [Indexed: 12/11/2022]
Abstract
Traumatic brain injury (TBI) elicits a complex secondary injury response, with neuroinflammation as a crucial central component. Long thought to be solely a deleterious factor, the neuroinflammatory response has recently been shown to be far more intricate, with both beneficial and detrimental consequences depending on the timing, magnitude and specific immune composition of the response post-injury. Despite extensive preclinical and clinical research into mechanisms of secondary injury after TBI, no effective neuroprotective therapy has been identified, with potential candidates repeatedly proving disappointing in the clinic. The neuroinflammatory response offers a promising avenue for therapeutic targeting, aiming to quell the deleterious consequences without influencing its function in providing a neurotrophic environment supportive of repair. The present review firstly describes the findings of recent clinical trials that aimed to modulate inflammation as a means of neuroprotection. Secondly, we discuss promising multifunctional and single-target anti-inflammatory candidates either currently in trial, or with ample experimental evidence supporting clinical application. This article is part of a Special Issue entitled SI:Brain injury and recovery.
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Wu MF, Zhang SQ, Gu R, Liu JB, Li Y, Zhu QS. Transplantation of erythropoietin gene-modified neural stem cells improves the repair of injured spinal cord. Neural Regen Res 2015; 10:1483-90. [PMID: 26604911 PMCID: PMC4625516 DOI: 10.4103/1673-5374.165521] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The protective effects of erythropoietin on spinal cord injury have not been well described. Here, the eukaryotic expression plasmid pcDNA3.1 human erythropoietin was transfected into rat neural stem cells cultured in vitro. A rat model of spinal cord injury was established using a free falling object. In the human erythropoietin-neural stem cells group, transfected neural stem cells were injected into the rat subarachnoid cavity, while the neural stem cells group was injected with non-transfected neural stem cells. Dulbecco's modified Eagle's medium/F12 medium was injected into the rats in the spinal cord injury group as a control. At 1–4 weeks post injury, the motor function in the rat lower limbs was best in the human erythropoietin-neural stem cells group, followed by the neural stem cells group, and lastly the spinal cord injury group. At 72 hours, compared with the spinal cord injury group, the apoptotic index and Caspase-3 gene and protein expressions were apparently decreased, and the bcl-2 gene and protein expressions were noticeably increased, in the tissues surrounding the injured region in the human erythropoietin-neural stem cells group. At 4 weeks, the cavities were clearly smaller and the motor and somatosensory evoked potential latencies were remarkably shorter in the human erythropoietin-neural stem cells group and neural stem cells group than those in the spinal cord injury group. These differences were particularly obvious in the human erythropoietin-neural stem cells group. More CM-Dil-positive cells and horseradish peroxidase-positive nerve fibers and larger amplitude motor and somatosensory evoked potentials were found in the human erythropoietin-neural stem cells group and neural stem cells group than in the spinal cord injury group. Again, these differences were particularly obvious in the human erythropoietin-neural stem cells group. These data indicate that transplantation of erythropoietin gene-modified neural stem cells into the subarachnoid cavity to help repair spinal cord injury and promote the recovery of spinal cord function better than neural stem cell transplantation alone. These findings may lead to significant improvements in the clinical treatment of spinal cord injuries.
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Affiliation(s)
- Min-Fei Wu
- Department of Orthopedics, the Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Shu-Quan Zhang
- Department of Orthopedics, Tianjin Nankai Hospital, Tianjin, China
| | - Rui Gu
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jia-Bei Liu
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Ye Li
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Qing-San Zhu
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
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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.
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Kertmen H, Gürer B, Yilmaz ER, Kanat MA, Arikok AT, Ergüder BI, Hasturk AE, Ergil J, Sekerci Z. Antioxidant and antiapoptotic effects of darbepoetin-α against traumatic brain injury in rats. Arch Med Sci 2015; 11:1119-28. [PMID: 26528358 PMCID: PMC4624756 DOI: 10.5114/aoms.2015.54869] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 08/14/2013] [Accepted: 10/04/2013] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION In this study, we tried to determine whether darbepoetin-α would protect the brain from oxidative stress and apoptosis in a rat traumatic brain injury model. MATERIAL AND METHODS The animals were randomized into four groups; group 1 (sham), group 2 (trauma), group 3 (darbepoetin α), group 4 (methylprednisolone). In the sham group only the skin incision was performed. In all the other groups, a moderate traumatic brain injury modelwas applied. RESULTS Following trauma both glutathione peroxidase, superoxide dismutase levels decreased (p < 0.001 for both); darbepoetin-α increased the activity of both antioxidant enzymes (p = 0.001 and p < 0.001 respectively). Trauma caused significant elevation in the nitric oxide synthetase and xanthine oxidase levels (p < 0.001 for both). Administration of darbepoetin-α significantly decreased the levels of nitric oxide synthetase and xanthine oxidase (p < 0.001 for both). Also, trauma caused significant elevation in the nitric oxide levels (p < 0.001); darbepoetin-α administration caused statistically significant reduction in the nitric oxide levels (p < 0.001). On the other hand, malondialdehyde levels were increased following trauma (p < 0.001), and darbepoetin α significantly reduced the malondialdehyde levels (p < 0.001). Due to the elevated apoptotic activity following the injury, caspase-3 activity increased significantly. Darbepoetin-α treatment significantly inhibited apoptosis by lowering the caspase-3 activity (p < 0.001). In the darbepoetin group, histopathological score was lower than the trauma group (p = 0.016). CONCLUSIONS In this study, darbepoetin-α was shown to be at least as effective as methylprednisolone in protecting brain from oxidative stress, lipid peroxidation and apoptosis.
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Affiliation(s)
- Hayri Kertmen
- Ministry of Health, Diskapi Yildirim Beyazit Education and Research Hospital, Neurosurgery Clinic, Ankara, Turkey
| | - Bora Gürer
- Ministry of Health, Diskapi Yildirim Beyazit Education and Research Hospital, Neurosurgery Clinic, Ankara, Turkey
| | - Erdal Resit Yilmaz
- Ministry of Health, Diskapi Yildirim Beyazit Education and Research Hospital, Neurosurgery Clinic, Ankara, Turkey
| | - Mehmet Ali Kanat
- Ministry of Health, Refik Saydam National Public Health Agency, Ankara, Turkey
| | - Ata Türker Arikok
- Department of Pathology, Ministry of Health, Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey
| | | | - Askin Esen Hasturk
- Department of Neurosurgery, Ministry of Health, Oncology Training and Research Hospital, Ankara, Turkey
| | - Julide Ergil
- Department of Anesthesiology, Ministry of Health, Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey
| | - Zeki Sekerci
- Ministry of Health, Diskapi Yildirim Beyazit Education and Research Hospital, Neurosurgery Clinic, Ankara, Turkey
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Kabu S, Gao Y, Kwon BK, Labhasetwar V. Drug delivery, cell-based therapies, and tissue engineering approaches for spinal cord injury. J Control Release 2015; 219:141-154. [PMID: 26343846 DOI: 10.1016/j.jconrel.2015.08.060] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 08/23/2015] [Accepted: 08/31/2015] [Indexed: 12/28/2022]
Abstract
Spinal cord injury (SCI) results in devastating neurological and pathological consequences, causing major dysfunction to the motor, sensory, and autonomic systems. The primary traumatic injury to the spinal cord triggers a cascade of acute and chronic degenerative events, leading to further secondary injury. Many therapeutic strategies have been developed to potentially intervene in these progressive neurodegenerative events and minimize secondary damage to the spinal cord. Additionally, significant efforts have been directed toward regenerative therapies that may facilitate neuronal repair and establish connectivity across the injury site. Despite the promise that these approaches have shown in preclinical animal models of SCI, challenges with respect to successful clinical translation still remain. The factors that could have contributed to failure include important biologic and physiologic differences between the preclinical models and the human condition, study designs that do not mirror clinical reality, discrepancies in dosing and the timing of therapeutic interventions, and dose-limiting toxicity. With a better understanding of the pathobiology of events following acute SCI, developing integrated approaches aimed at preventing secondary damage and also facilitating neuroregenerative recovery is possible and hopefully will lead to effective treatments for this devastating injury. The focus of this review is to highlight the progress that has been made in drug therapies and delivery systems, and also cell-based and tissue engineering approaches for SCI.
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Affiliation(s)
- Shushi Kabu
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Yue Gao
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Brian K Kwon
- Department of Orthopaedics, International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC, Canada V5Z 1M9
| | - Vinod Labhasetwar
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
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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: 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.
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30
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Freitag MT, Márton G, Pajer K, Hartmann J, Walder N, Rossmann M, Parzer P, Redl H, Nógrádi A, Stieltjes B. Monitoring of Short-Term Erythropoietin Therapy in Rats with Acute Spinal Cord Injury Using Manganese-Enhanced Magnetic Resonance Imaging. J Neuroimaging 2014; 25:582-9. [DOI: 10.1111/jon.12202] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 07/29/2014] [Accepted: 09/13/2014] [Indexed: 11/28/2022] Open
Affiliation(s)
- Martin Thomas Freitag
- Quantitative Imaging-Based Disease Characterization; Department of Radiology; German Cancer Research Center; Heidelberg Germany
| | - Gábor Márton
- Laboratory of Neural Regeneration; Department of Anatomy; Histology, and Embryology; Faculty of Medicine; University of Szeged; Hungary
| | - Krisztián Pajer
- Laboratory of Neural Regeneration; Department of Anatomy; Histology, and Embryology; Faculty of Medicine; University of Szeged; Hungary
| | - Jens Hartmann
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology; Research Center of the AUVA; Vienna Austria
| | - Nadja Walder
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology; Research Center of the AUVA; Vienna Austria
| | - Markus Rossmann
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology; Research Center of the AUVA; Vienna Austria
| | - Peter Parzer
- Section Disorders of Personality Development; Department of Child and Adolescent Psychiatry; Center for Psychosocial Medicine; University of Heidelberg; Germany
| | - Heinz Redl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology; Research Center of the AUVA; Vienna Austria
| | - Antal Nógrádi
- Laboratory of Neural Regeneration; Department of Anatomy; Histology, and Embryology; Faculty of Medicine; University of Szeged; Hungary
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology; Research Center of the AUVA; Vienna Austria
| | - Bram Stieltjes
- Quantitative Imaging-Based Disease Characterization; Department of Radiology; German Cancer Research Center; Heidelberg Germany
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Abstract
Spinal cord injury results in significant mortality and morbidity, lifestyle changes, and difficult rehabilitation. Treatment of spinal cord injury is challenging because the spinal cord is both complex to treat acutely and difficult to regenerate. Nanomaterials can be used to provide effective treatments; their unique properties can facilitate drug delivery to the injury site, enact as neuroprotective agents, or provide platforms to stimulate regrowth of damaged tissues. We review recent uses of nanomaterials including nanowires, micelles, nanoparticles, liposomes, and carbon-based nanomaterials for neuroprotection in the acute phase. We also review the design and neural regenerative application of electrospun scaffolds, conduits, and self-assembling peptide scaffolds.
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Affiliation(s)
- Jacqueline Y. Tyler
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907
| | - Xiao-Ming Xu
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute and Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Ji-Xin Cheng
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907
- Department of Chemistry, Purdue University, West Lafayette, IN 47907
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Luk CT, Shi SY, Choi D, Cai EP, Schroer SA, Woo M. In vivo knockdown of adipocyte erythropoietin receptor does not alter glucose or energy homeostasis. Endocrinology 2013; 154:3652-9. [PMID: 23885016 DOI: 10.1210/en.2013-1113] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The growing prevalence of obesity and diabetes necessitate a better understanding of the role of adipocyte biology in metabolism. Increasingly, erythropoietin (EPO) has been shown to have extraerythropoietic and cytoprotective roles. Exogenous administration has recently been shown to have beneficial effects on obesity and diabetes in mouse models and EPO can modulate adipogenesis and insulin signaling in 3T3-L1 adipocytes. However, its physiological role in adipocytes has not been identified. Using male and female mice with adipose tissue-specific knockdown of the EPO receptor, we determine that adipocyte EPO signaling is not essential for the maintenance of energy homeostasis or glucose metabolism. Adipose tissue-specific disruption of EPO receptor did not alter adipose tissue expansion, adipocyte morphology, insulin resistance, inflammation, or angiogenesis in vivo. In contrast to the pharmacological effects of EPO, we demonstrate that EPO signaling at physiological levels is not essential for adipose tissue regulation of metabolism.
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MESH Headings
- Adipose Tissue, Brown/blood supply
- Adipose Tissue, Brown/cytology
- Adipose Tissue, Brown/immunology
- Adipose Tissue, Brown/metabolism
- Adipose Tissue, White/blood supply
- Adipose Tissue, White/cytology
- Adipose Tissue, White/metabolism
- Adipose Tissue, White/pathology
- Adiposity
- Adult
- Animals
- Cells, Cultured
- Diabetes Mellitus, Type 2/immunology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Diet, High-Fat/adverse effects
- Energy Metabolism
- Female
- Gene Expression Regulation
- Glucose/metabolism
- Humans
- Insulin Resistance
- Male
- Mice
- Mice, Knockout
- Middle Aged
- Neovascularization, Physiologic
- Obesity/etiology
- Obesity/immunology
- Obesity/metabolism
- Obesity/pathology
- Receptors, Erythropoietin/genetics
- Receptors, Erythropoietin/metabolism
- Specific Pathogen-Free Organisms
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Affiliation(s)
- Cynthia T Luk
- MD, PhD, Toronto General Research Institute, 101 College Street, MaRS Centre/TMDT, Room 10-363, Toronto, Ontario, Canada M5G 1L7.
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Savigni DL, O'Hare Doig RL, Szymanski CR, Bartlett CA, Lozić I, Smith NM, Fitzgerald M. Three Ca2+ channel inhibitors in combination limit chronic secondary degeneration following neurotrauma. Neuropharmacology 2013; 75:380-90. [PMID: 23958451 DOI: 10.1016/j.neuropharm.2013.07.034] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Revised: 07/24/2013] [Accepted: 07/30/2013] [Indexed: 01/29/2023]
Abstract
Following neurotrauma, cells beyond the initial trauma site undergo secondary degeneration, with excess Ca2+ a likely trigger for loss of neurons, compact myelin and function. Treatment using inhibitors of specific Ca2+ channels has shown promise in preclinical studies, but clinical trials have been disappointing and combinatorial approaches are needed. We assessed efficacy of multiple combinations of three Ca2+ channel inhibitors at reducing secondary degeneration following partial optic nerve transection in rat. We used lomerizine to inhibit voltage gated Ca2+ channels; oxidised adenosine-triphosphate (oxATP) to inhibit purinergic P2X7 receptors and/or 2-[7-(1H-imidazol-1-yl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydro quinoxalin-1-yl]acetic acid (INQ) to inhibit Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Only the three Ca2+ channel inhibitors delivered in combination significantly preserved visual function, as assessed using the optokinetic nystagmus visual reflex, at 3 months after injury. Preservation of retinal ganglion cells was partial and is unlikely to have accounted for differential effects on function. A range of the Ca2+ channel inhibitor combinations prevented swelling of optic nerve vulnerable to secondary degeneration. Each of the treatments involving lomerizine significantly increased the proportion of axons with normal compact myelin. Nevertheless, limiting decompaction of myelin was not sufficient for preservation of function in our model. Multiple combinations of Ca2+ channel inhibitors reduced formation of atypical node/paranode complexes; outcomes were not associated with preservation of visual function. However, prevention of lengthening of the paranodal gap that was only achieved by treatment with the three Ca2+ channel inhibitors in combination was an important additional effect that likely contributed to the associated preservation of the optokinetic reflex using this combinatorial treatment strategy.
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Affiliation(s)
- Donna L Savigni
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia
| | - Ryan L O'Hare Doig
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia
| | - Charis R Szymanski
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia
| | - Carole A Bartlett
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia
| | - Ivan Lozić
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia
| | - Nicole M Smith
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia
| | - Melinda Fitzgerald
- Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia.
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Minocycline treatment inhibits lipid peroxidation, preserves spinal cord ultrastructure, and improves functional outcome after traumatic spinal cord injury in the rat. Spine (Phila Pa 1976) 2013; 38:1253-9. [PMID: 23370685 DOI: 10.1097/brs.0b013e3182895587] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A prospective, randomized experimental research. OBJECTIVE To evaluate the short- and long-term neuroprotective effects of minocycline on the secondary injury process of an experimental traumatic spinal cord injury (SCI) model. SUMMARY OF BACKGROUND DATA Traumatic SCI is a devastating problem of health that results in high morbidity and mortality rates. The loss of function after SCI results from both the primary mechanical insult and the subsequent, multifaceted secondary response. METHODS A total of 80 adult male Spraque-Dawley rats (breeded by the Baskent University Animal Research Center) were randomly divided into 4 groups. A T10 contusion injury was produced by using modified Allen technique in all groups except the control group. No medication was administered to the rats in the trauma group. Minocycline was administered intraperitoneally and intravenously to the treatment groups. Short-term and/or long-term neuroprotective effects of minocycline on the lipid peroxidation (malondialdehyde, glutathione), apoptosis (terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate-biotin nick end labeling), ultrastructure of spinal cord (tissue electron microscopy), and behavioral assessments (Basso-Beattie-Bresnahan) were evaluated. RESULTS As compared with the trauma group, tissue malondialdehyde and glutathione levels demonstrated that minocycline significantly diminishes lipid peroxidation. Electromicroscopic study showed that minocycline preserves the ultrastructure of spinal cord tissue in the early post-traumatic period. Minocycline treatment significantly reduced the number of terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate-biotin nick end labeling positive cells both 1 day and 28 days after SCI. Behavioral assessments showed significant improvement in the hind limb functions of minocycline receiving rats starting 7 days after the SCI. Any statistically significant difference was not found between intraperitoneal or intravenous routes for minocycline injection. CONCLUSION Minocycline is neuroprotective and contributes to functional improvement after traumatic SCI by eliminating the destructive process of secondary injury. Having both satisfying anti-inflammatory and antiapoptotic effects in experimental models, it promises to be of therapeutic use in human SCI.
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Erythropoietin treatment is associated with an augmented immune response to the influenza vaccine in hematologic patients. Exp Hematol 2013; 41:167-71. [DOI: 10.1016/j.exphem.2012.10.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Revised: 09/07/2012] [Accepted: 10/17/2012] [Indexed: 01/08/2023]
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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.
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Effects of darbepoetin-α in spinal cord ischemia-reperfusion injury in the rabbit. Acta Neurochir (Wien) 2012; 154:1037-43; discussion 1043-4. [PMID: 22354718 DOI: 10.1007/s00701-012-1298-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2011] [Accepted: 01/30/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND Darbepoetin-alpha (DA) is a novel erythropoiesis-stimulating agent developed for treating anemia. In animal models, recombinant human erythropoietin has been reported to be beneficial for neuroprotection. In this study, we determined whether DA would protect the spinal cord against ischemia-reperfusion injury in a rabbit model. METHODS Forty rabbits were randomized into five groups of eight animals each: group 1 (sham), group 2 (ischemia), group 3 (vehicle), group 4 (30 mg/kg methylprednisolone), group 5 (30 μg/kg DA). Only laparotomy was performed in the sham group. In all the other groups, the spinal cord ischemia model was created by a 20-min occlusion of the aorta just caudal to renal artery with an aneurysm clip. The drugs were administered immediately after the clamp was removed. The animals were killed 24 h later. Spinal cord segments between L2 and L5 were harvested for analysis. Neurological evaluation was performed with the Tarlov scoring system just before the animals were killed. Level of tissue malondialdehyde was analyzed as a marker of lipid peroxidation and tissue caspase-3 activity as a marker of apoptosis. Also, histopathological evaluation of the tissues was performed. RESULTS Both malondialdehyde and caspase-3 levels were significantly decreased by DA administration. Histopathological evaluation of the tissues also demonstrated decrease in neuronal degeneration and infiltration parameters after DA administration. In the DA group, neurological outcome scores were statistically significantly better compared with the ischemia and the vehicle groups. CONCLUSIONS Although further studies considering different dose regimens and time intervals are required, DA was shown to be at least as effective as methylprednisolone in spinal cord ischemia/reperfusion model.
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Hematopoietic Growth Factor Family for Stroke Drug Development. Transl Stroke Res 2012. [DOI: 10.1007/978-1-4419-9530-8_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Simon F, Scheuerle A, Gröger M, Vcelar B, McCook O, Möller P, Georgieff M, Calzia E, Radermacher P, Schelzig H. Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury. Intensive Care Med 2011; 37:1525-33. [PMID: 21779851 DOI: 10.1007/s00134-011-2303-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2010] [Accepted: 03/08/2011] [Indexed: 12/13/2022]
Abstract
PURPOSE Recombinant human erythropoietin (rhEPO) attenuated ischemia/reperfusion (I/R) injury-induced spinal cord damage. Since carbamylated EPO derivatives are stated to be devoid of rhEPO side effects, we tested the hypothesis that a newly developed carbamylated EPO-FC fusion protein (cEPO-FC) would compare favorably with rhEPO. METHODS Anesthetized and mechanically ventilated pigs randomly received cEPO-FC (50 μg kg(-1)), rhEPO (5,000 IU kg(-1)) or vehicle (n = 9 per group) 30 min prior to 30 min of aortic occlusion and over the 4 h of reperfusion. During aortic occlusion, mean arterial pressure (MAP) was maintained at 80-120% of baseline values by esmolol, nitroglycerin, and adenosine-5'-triphosphate (ATP). During reperfusion, noradrenaline was titrated to keep MAP at pre-ischemic levels. Spinal cord function was assessed by motor evoked potentials (MEP) and lower limb reflexes. Tissue damage was evaluated using hematoxylin and eosin, Nissl, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Plasma levels of interleukin-6, tumor necrosis factor-α, and 8-isoprostanes were measured as markers of systemic inflammation and oxidative stress. RESULTS While only cEPO-FC restored MEP amplitude to values close to pre-occlusion levels, both cEPO-FC and rhEPO comparably restored lower limb reflexes and reduced the percentage of damaged neurons. Infiltration of mononuclear inflammatory cells was moderate without intergroup difference; positive TUNEL staining was barely detectable in any group. I/R injury increased blood cytokine levels without intergroup difference, whereas both cEPO-FC and rhEPO significantly lowered 8-isoprostane levels. CONCLUSIONS In a porcine model of aortic balloon occlusion-induced spinal cord I/R injury, cEPO-FC and rhEPO comparably protected against ischemic spinal cord dysfunction and neuronal damage. This effect coincided with attenuated oxidative stress.
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Affiliation(s)
- Florian Simon
- Abteilung für Thorax- und Gefässchirurgie, Universitätsklinikum, Ulm, Germany
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Kale A, Börcek AÖ, Emmez H, Yildirim Z, Durdağ E, Lortlar N, Kurt G, Doğulu F, Kılıç N. Neuroprotective effects of gabapentin on spinal cord ischemia-reperfusion injury in rabbits. J Neurosurg Spine 2011; 15:228-37. [DOI: 10.3171/2011.4.spine10583] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Object
Extensive research has been focused on neuroprotection after spinal cord trauma to alleviate the effects of secondary injury. This study aims to investigate the neuroprotective effects of gabapentin in an experimental spinal cord ischemia reperfusion injury.
Methods
Thirty-two adult male New Zealand white rabbits received spinal cord ischemic injury using the aortic occlusion model. Animals were divided into 4 groups (sham, control, low-dose, and high-dose treatment groups; 8 rabbits in each group). High (200 mg/kg) and low (30 mg/kg) doses of gabapentin were administered to the animals in the treatment groups after spinal cord ischemic injury. Neurological status of the animals, ultrastructural findings in injured tissue samples, and levels of tissue injury markers in these 2 groups were compared with findings in the animals that did not receive the ischemic procedure (sham-operated group) and those that received normal saline after administration of ischemia.
Results
Regarding levels of tissue injury marker levels after ischemic injury, animals in the gabapentin-treated groups demonstrated better results than animals in the other groups. The ultrastructural findings and caspase-3 activity were similar. The treatment groups demonstrated better results than the other groups.
Conclusions
Gabapentin demonstrated significant neuroprotection after early phases of ischemic injury. Further studies with different experimental settings including neurological outcome are required to achieve conclusive results.
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Affiliation(s)
| | | | | | - Zuhal Yildirim
- 3Biochemistry, Gazi University, Faculty of Medicine, Ankara, Turkey
| | | | | | | | | | - Nedret Kılıç
- 3Biochemistry, Gazi University, Faculty of Medicine, Ankara, Turkey
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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.
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Affiliation(s)
- Brian K Kwon
- University of British Columbia, Combined Neurosurgical and Orthopaedic Spine Program, Department of Orthopaedics, Vancouver, British Columbia, Canada.
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Murua A, Orive G, Hernández RM, Pedraz JL. Emerging technologies in the delivery of erythropoietin for therapeutics. Med Res Rev 2011; 31:284-309. [PMID: 19967731 DOI: 10.1002/med.20184] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Deciphering the function of proteins and their roles in signaling pathways is one of the main goals of biomedical research, especially from the perspective of uncovering pathways that may ultimately be exploited for therapeutic benefit. Over the last half century, a greatly expanded understanding of the biology of the glycoprotein hormone erythropoietin (Epo) has emerged from regulator of the circulating erythrocyte mass to a widely used therapeutic agent. Originally viewed as the renal hormone responsible for erythropoiesis, recent in vivo studies in animal models and clinical trials demonstrate that many other tissues locally produce Epo independent of its effects on red blood cell mass. Thus, not only its hematopoietic activity but also the recently discovered nonerythropoietic actions in addition to new drug delivery systems are being thoroughly investigated in order to fulfill the specific Epo release requirements for each therapeutic approach. The present review focuses on updating the information previously provided by similar reviews and recent experimental approaches are presented to describe the advances in Epo drug delivery achieved in the last few years and future perspectives.
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Affiliation(s)
- Ainhoa Murua
- Laboratory of Pharmacy and Pharmaceutical Technology, Networking Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, SLFPB-EHU, Faculty of Pharmacy, University of the Basque Country, 01006, Vitoria-Gasteiz, Spain
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Moore EM, Bellomo R, Nichol AD. Erythropoietin as a novel brain and kidney protective agent. Anaesth Intensive Care 2011; 39:356-72. [PMID: 21675055 DOI: 10.1177/0310057x1103900306] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Erythropoietin is a 30.4 kDa glycoprotein produced by the kidney, which is mostly known for its physiological function in regulating red blood cell production in the bone marrow Accumulating evidence, however suggests that erythropoietin has additional organ protective effects, which may specifically be useful in protecting the brain and kidneys from injury. Experimental evidence suggests that these protective mechanisms are multi-factorial in nature and may include inhibition of apoptotic cell death, stimulation of cellular regeneration, inhibition of deleterious pathways and promotion of recovery. In this article we review the physiology of erythropoietin, assess previous work that supports the role of erythropoietin as a general tissue protective agent and explain the mechanisms by which it may achieve this tissue protective effect. We then focus on specific laboratory and clinical data that suggest that erythropoietin has a strong brain protective and kidney protective effect. In addition, we comment on the implications of these studies for clinicians at the bedside and for researchers designing controlled trials to further elucidate the true clinical utility of erythropoietin as a neuroprotective and nephroprotective agent. Finally, we describe EPO-TBI, a double-blinded multi-centre randomised controlled trial involving the authors that is being conducted to investigate the organ protective effects of erythropoietin on the brain, and also assesses its effect on the kidneys.
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Affiliation(s)
- E M Moore
- Department of Epidemiology and Preventive Medicine, Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia
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44
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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.
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45
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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: 68] [Impact Index Per Article: 4.9] [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.
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Affiliation(s)
- Alexander G Rabchevsky
- Spinal Cord & Brain injury Research Center, Lexington, University of Kentucky, KY 40536-0509, USA.
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Lombardero M, Kovacs K, Scheithauer BW. Erythropoietin: a hormone with multiple functions. Pathobiology 2011; 78:41-53. [PMID: 21474975 DOI: 10.1159/000322975] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2010] [Accepted: 11/22/2010] [Indexed: 12/17/2022] Open
Abstract
Erythropoietin (EPO), the main hemopoietic hormone synthesized by the kidney as well as by the liver in fetal life, is implicated in mammalian erythropoiesis. Production and secretion of EPO and the expression of its receptor (EPO-R) are regulated by tissue oxygenation. EPO and EPO-R, expressed in several tissues, exert pleiotropic activities and have different effects on nonhemopoietic cells. EPO is a cytokine with antiapoptotic activity and plays a potential neuroprotective and cardioprotective role against ischemia. EPO is also involved in angiogenesis, neurogenesis, and the immune response. EPO can prevent metabolic alterations, neuronal and vascular degeneration, and inflammatory cell activation. Consequently, EPO may be of therapeutic use for a variety of disorders. Many tumors express EPO and/or EPO-R, but the action of EPO on tumor cells remains controversial. It has been suggested that EPO promotes the proliferation and survival of cancer cells expressing EPO-R. On the other hand, other reports have concluded that EPO-R plays no role in tumor progression. This review provides a detailed insight into the nonhemopoietic role of EPO and its mechanism(s) of action which may lead to a better understanding of its potential therapeutic value in diverse clinical settings.
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Affiliation(s)
- Matilde Lombardero
- Department of Anatomy and Animal Production, Faculty of Veterinary Sciences, University of Santiago de Compostela, Lugo, Spain.
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47
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Ning B, Zhang A, Song H, Gong W, Ding Y, Guo S, Zhao Y, Jiang J, Jia T. Recombinant human erythropoietin prevents motor neuron apoptosis in a rat model of cervical sub-acute spinal cord compression. Neurosci Lett 2010; 490:57-62. [PMID: 21167907 DOI: 10.1016/j.neulet.2010.12.025] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 12/08/2010] [Accepted: 12/09/2010] [Indexed: 11/24/2022]
Abstract
The objective of the study was to investigate the effects of recombinant human erythropoietin (rhEPO) in a rat model of cervical sub-acute spinal cord compression. 80 Wistar rats were randomly divided into 4 groups. Rats in the sham group (Group A, n=5) underwent surgical procedures without cervical spinal cord compression; while rats in other groups were subjected to the spinal compression process. In the control group (Group B, n=25), rats received an i.v. injection of 1 mL saline at day 7 post-surgery. Rats in the low-dose group (Group C, n=25) and the high-dose group (Group D, n=25) were treated with rhEPO at 500 units/kg body-weight and 5000 units/kg, respectively, via intravenous injection at day 7 post surgery. Limb motor function was scored by Basso-Beattie-Bresnahan (BBB) standards at 3, 7, 14, 21 and 28 days post-surgery. The distribution and quantities of EPO and its receptor (EPO-R) in the compressed segment of the spinal cord were detected by immunohistochemistry. Motor neuron apoptosis in the spinal cord was evaluated using TUNEL staining and flow cytometry at the indicated time points. Finally, IL-8, TNF-α, IL-6, and IL-1β levels in the compressed cervical spinal cord were determined by ELISA within the lesion epicenter at each time point post-surgery. The data suggest that expression of EPO-R was significantly increased following sub-acute cervical spinal cord compression; Groups C and D exhibited better BBB scores at all observed time points compared with the control group (p<0.01). Using TUNEL staining and FCM, we observed that rhEPO profoundly inhibited motor neuron apoptosis in the spinal cord at day 21 (p<0.01). Additionally, treatment with rhEPO halted the elevation of inflammatory cytokines. rhEPO administration decreased motor neuron apoptosis in the cervical spinal cord, improved motor functions and reduced the inflammatory response in a sub-acute cervical spinal cord compression model. Moreover, sustained treatment with low doses of rhEPO revealed a positive therapeutic effect.
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Affiliation(s)
- Bin Ning
- Shandong University, Shandong, China; Department of Orthopedic, Jinan Central Hospital of Shandong University, Shandong, China
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Erythropoetin as a novel agent with pleiotropic effects against acute lung injury. Eur J Clin Pharmacol 2010; 67:1-9. [PMID: 21069520 DOI: 10.1007/s00228-010-0938-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2010] [Accepted: 09/28/2010] [Indexed: 12/14/2022]
Abstract
Current pharmacotherapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is not optimal, and the biological and physiological complexity of these severe lung injury syndromes requires consideration of combined-agent treatments or agents with pleiotropic action. In this regard, exogenous erythropoietin (EPO) represents a possible candidate since a number of preclinical studies have revealed beneficial effects of EPO administration in various experimental models of ALI. Taken together, this treatment strategy is not a single mediator approach, but it rather provides protection by modulating multiple levels of early signaling pathways involved in apoptosis, inflammation, and peroxidation, potentially restoring overall homeostasis. Furthermore, EPO appears to confer vascular protection by promoting angiogenesis. However, only preliminary studies exist and more experimental and clinical studies are necessary to clarify the efficacy and potentially cytoprotective mechanisms of EPO action. In addition to the attempts to optimize the dose and timing of EPO administration, it would be of great value to minimize any potential toxicity, which is essential for EPO to fulfill its role as a potential candidate for the treatment of ALI in routine clinical practice. The present article reviews recent advances that have elucidated biological and biochemical activities of EPO that may be potentially applicable for ALI/ARDS management.
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Emmez H, Börcek AÖ, Kaymaz M, Kaymaz F, Durdağ E, Civi S, Gülbahar O, Aykol S, Paşaoğlu A. Neuroprotective effects of gabapentin in experimental spinal cord injury. World Neurosurg 2010; 73:729-34. [PMID: 20934165 DOI: 10.1016/j.wneu.2010.04.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2009] [Accepted: 04/07/2010] [Indexed: 11/27/2022]
Abstract
BACKGROUND Extensive research has focused on neuroprotection after spinal cord trauma to alleviate the effects of secondary injury. This study aims to investigate the neuroprotective effects of gabapentin in experimental spinal cord injury. METHODS Thirty-six adult, male Wistar rats received spinal cord injury using the clip compression method. Animals were divided into five groups. High (200 mg/kg) and low doses (30 mg/kg) of gabapentin were administered to the animals in the treatment groups after spinal cord trauma and ultrastructural findings and lipid peroxidation levels of these two groups were compared with the animals that received only laminectomy, only trauma, and trauma and 30 mg/kg methylprednisolone. RESULTS Regarding tissue lipid peroxidation levels after trauma, animals in gabapentin groups demonstrated better results than the trauma group. However, these results were no better than the methylprednisolone group. The results regarding the ultrastructural findings were similar. Treatment groups demonstrated better ultrastructural findings than the trauma group. In addition, the results of the high dose gabapentin group were significantly better than the low dose gabapentin group. CONCLUSIONS Gabapentin demonstrated similar neuroprotective effects as methylprednisolone in early phase of spinal cord injury. Further studies with different experimental settings including neurological outcome are required to achieve conclusive results.
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Affiliation(s)
- Hakan Emmez
- Department of Neurosurgery, Gazi University Faculty of Medicine, Ankara, Turkey
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50
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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.
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Affiliation(s)
- Brian K Kwon
- Combined Neurosurgical and Orthopaedic Spine Program, Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada.
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