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      Synergistic actions of olomoucine and bone morphogenetic protein-4 in axonal repair after acute spinal cord contusion

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          Abstract

          To determine whether olomoucine acts synergistically with bone morphogenetic protein-4 in the treatment of spinal cord injury, we established a rat model of acute spinal cord contusion by impacting the spinal cord at the T 8 vertebra. We injected a suspension of astrocytes derived from glial-restricted precursor cells exposed to bone morphogenetic protein-4 (GDAs BMP) into the spinal cord around the site of the injury, and/or olomoucine intraperitoneally. Olomoucine effectively inhibited astrocyte proliferation and the formation of scar tissue at the injury site, but did not prevent proliferation of GDAs BMP or inhibit their effects in reducing the spinal cord lesion cavity. Furthermore, while GDAs BMP and olomoucine independently resulted in small improvements in locomotor function in injured rats, combined administration of both treatments had a significantly greater effect on the restoration of motor function. These data indicate that the combined use of olomoucine and GDAs BMP creates a better environment for nerve regeneration than the use of either treatment alone, and contributes to spinal cord repair after injury.

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          Most cited references47

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          Principles of CDK regulation.

          D Morgan (1995)
          As key regulators of the cell cycle, the cyclin-dependent kinases must be tightly regulated by extra- and intracellular signals. The activity of cyclin-dependent kinases is controlled by four highly conserved biochemical mechanisms, forming a web of regulatory pathways unmatched in its elegance and intricacy.
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            Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth.

            The inhibitory activity associated with myelin is a major obstacle for successful axon regeneration in the adult mammalian central nervous system (CNS). In addition to myelin-associated glycoprotein (MAG) and Nogo-A, available evidence suggests the existence of additional inhibitors in CNS myelin. We show here that a glycosylphosphatidylinositol (GPI)-anchored CNS myelin protein, oligodendrocyte-myelin glycoprotein (OMgp), is a potent inhibitor of neurite outgrowth in cultured neurons. Like Nogo-A, OMgp contributes significantly to the inhibitory activity associated with CNS myelin. To further elucidate the mechanisms that mediate this inhibitory activity of OMgp, we screened an expression library and identified the Nogo receptor (NgR) as a high-affinity OMgp-binding protein. Cleavage of NgR and other GPI-linked proteins from the cell surface renders axons of dorsal root ganglia insensitive to OMgp. Introduction of exogenous NgR confers OMgp responsiveness to otherwise insensitive neurons. Thus, OMgp is an important inhibitor of neurite outgrowth that acts through NgR and its associated receptor complex. Interfering with the OMgp/NgR pathway may allow lesioned axons to regenerate after injury in vivo.
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              Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve recovery after cervical spinal cord injury.

              Evidence that cell transplants can improve recovery outcomes in spinal cord injury (SCI) models substantiates treatment strategies involving cell replacement for humans with SCI. Most pre-clinical studies of cell replacement in SCI examine thoracic injury models. However, as most human injuries occur at the cervical level, it is critical to assess potential treatments in cervical injury models and examine their effectiveness using at-level histological and functional measures. To directly address cervical SCI, we used a C5 midline contusion injury model and assessed the efficacy of a candidate therapeutic for thoracic SCI in this cervical model. The contusion generates reproducible, bilateral movement and histological deficits, although a number of injury parameters such as acute severity of injury, affected gray-to-white matter ratio, extent of endogenous remyelination, and at-level locomotion deficits do not correspond with these parameters in thoracic SCI. On the basis of reported benefits in thoracic SCI, we transplanted human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells (OPCs) into this cervical model. hESC-derived OPC transplants attenuated lesion pathogenesis and improved recovery of forelimb function. Histological effects of transplantation included robust white and gray matter sparing at the injury epicenter and, in particular, preservation of motor neurons that correlated with movement recovery. These findings further our understanding of the histopathology and functional outcomes of cervical SCI, define potential therapeutic targets, and support the use of these cells as a treatment for cervical SCI.
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                Author and article information

                Journal
                Neural Regen Res
                Neural Regen Res
                NRR
                Neural Regeneration Research
                Medknow Publications & Media Pvt Ltd (India )
                1673-5374
                1876-7958
                15 October 2014
                : 9
                : 20
                : 1830-1838
                Affiliations
                [1 ]Capital Medical University School of Rehabilitation Medicine, Beijing, China
                [2 ]Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
                [3 ]Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China
                [4 ]Rehabilitation Center, Beijing Xiaotangshan Rehabilitation Hospital, Beijing, China
                [5 ]Department of General Surgery, China Rehabilitation Research Center, Beijing, China
                Author notes
                Corresponding author: Jianjun Li, Department of Spinal Cord Neurological Reconstruction, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing 100068, China, lcrrc9@ 123456gmail.com .

                Author contributions: Li JJ participated in study design, experimental supervision and financial support. Chen L and Wu L participated in study design, technical support, data acquisition, data analysis and paper drafting. Yang ML participated in study design. Gao F and Yuan L participated in experimental conduction. All authors approved the final version of the paper .

                Article
                NRR-9-1830
                10.4103/1673-5374.143431
                4239774
                76202b13-e78d-4a4b-9b34-912cfadab9de
                Copyright: © Neural Regeneration Research

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 August 2014
                Categories
                Technical Update

                nerve regeneration,spinal cord injury,olomoucine,glial-restricted precursor-derived astrocytes,glial scar,cavity,axonal regeneration,neural regeneration

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