Erythropoietin-mediated preservation of the white matter in rat spinal cord injury

Abstract We investigated the effect of a single administration of recombinant human erythropoietin (rhEPO) on the preservation of the ventral white matter of rats at 4 weeks after contusive spinal cord injury (SCI), a time at which functional recovery is significantly improved in comparison to the c...

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Veröffentlicht in:Neuroscience 2007-02, Vol.144 (3), p.865-877
Hauptverfasser: Vitellaro-Zuccarello, L, Mazzetti, S, Madaschi, L, Bosisio, P, Gorio, A, De Biasi, S
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container_issue 3
container_start_page 865
container_title Neuroscience
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creator Vitellaro-Zuccarello, L
Mazzetti, S
Madaschi, L
Bosisio, P
Gorio, A
De Biasi, S
description Abstract We investigated the effect of a single administration of recombinant human erythropoietin (rhEPO) on the preservation of the ventral white matter of rats at 4 weeks after contusive spinal cord injury (SCI), a time at which functional recovery is significantly improved in comparison to the controls [Gorio A, Necati Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Enver Vardar E, Cerami A, Brines M (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci U S A 99:9450–9455; Gorio A, Madaschi L, Di Stefano B, Carelli S, Di Giulio AM, De Biasi S, Coleman T, Cerami A, Brines M (2005) Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci U S A 102:16379–16384]. Specifically, we examined, by morphological and cytochemical methods combined with light, confocal and electron microscopy, i) myelin preservation, ii) activation of adult oligodendrocyte progenitors (OPCs) identified for the expression of NG2 transmembrane proteoglycan, iii) changes in the amount of the chondroitin sulfate proteoglycans neurocan, versican and phosphacan and of their glycosaminoglycan component labeled with Wisteria floribunda lectin, and iv) ventral horn density of the serotonergic plexus as a marker of descending motor control axons. Injured rats received either saline or a single dose of rhEPO within 30 min after SCI. The results showed that the significant improvement of functional outcome observed in rhEPO-treated rats was associated with a better preservation of myelin in the ventral white matter. Moreover, the significant increase of both the number of NG2-positive OPCs and the labeling for Nogo-A, a marker of differentiated oligodendrocytes, suggested that rhEPO treatment could result in the generation of new myelinating oligodendrocytes. Sparing of fiber tracts in the ventral white matter was confirmed by the increased density of the serotonergic plexus around motor neurons. As for chondroitin sulfate proteoglycans, only phosphacan, increased in saline-treated rats, returned to normal levels in rhEPO group, probably reflecting a better maintenance of glial-axolemmal relationships along nerve fibers. In conclusion, this investigation expands previous studies supporting the pleiotropic neuroprotective effect of rhEPO on secondary degenerative response and its therape
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Proc Natl Acad Sci U S A 99:9450–9455; Gorio A, Madaschi L, Di Stefano B, Carelli S, Di Giulio AM, De Biasi S, Coleman T, Cerami A, Brines M (2005) Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci U S A 102:16379–16384]. Specifically, we examined, by morphological and cytochemical methods combined with light, confocal and electron microscopy, i) myelin preservation, ii) activation of adult oligodendrocyte progenitors (OPCs) identified for the expression of NG2 transmembrane proteoglycan, iii) changes in the amount of the chondroitin sulfate proteoglycans neurocan, versican and phosphacan and of their glycosaminoglycan component labeled with Wisteria floribunda lectin, and iv) ventral horn density of the serotonergic plexus as a marker of descending motor control axons. Injured rats received either saline or a single dose of rhEPO within 30 min after SCI. The results showed that the significant improvement of functional outcome observed in rhEPO-treated rats was associated with a better preservation of myelin in the ventral white matter. Moreover, the significant increase of both the number of NG2-positive OPCs and the labeling for Nogo-A, a marker of differentiated oligodendrocytes, suggested that rhEPO treatment could result in the generation of new myelinating oligodendrocytes. Sparing of fiber tracts in the ventral white matter was confirmed by the increased density of the serotonergic plexus around motor neurons. As for chondroitin sulfate proteoglycans, only phosphacan, increased in saline-treated rats, returned to normal levels in rhEPO group, probably reflecting a better maintenance of glial-axolemmal relationships along nerve fibers. In conclusion, this investigation expands previous studies supporting the pleiotropic neuroprotective effect of rhEPO on secondary degenerative response and its therapeutic potential for the treatment of SCI and confirms that the preservation of the ventral white matter, which contains descending motor pathways, may be critical for limiting functional deficit.</description><identifier>ISSN: 0306-4522</identifier><identifier>EISSN: 1873-7544</identifier><identifier>DOI: 10.1016/j.neuroscience.2006.10.023</identifier><identifier>PMID: 17141961</identifier><identifier>CODEN: NRSCDN</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Animals ; Antigens - drug effects ; Antigens - metabolism ; Axons - metabolism ; Axons - ultrastructure ; Biological and medical sciences ; Cell Membrane - drug effects ; Cell Membrane - metabolism ; chondroitin sulfate proteoglycans ; Chondroitin Sulfate Proteoglycans - drug effects ; Chondroitin Sulfate Proteoglycans - metabolism ; Erythropoietin - pharmacology ; Erythropoietin - therapeutic use ; Fundamental and applied biological sciences. Psychology ; Male ; Microscopy, Electron, Transmission ; Myelin Proteins - drug effects ; Myelin Proteins - metabolism ; Myelin Sheath - drug effects ; Myelin Sheath - metabolism ; Myelin Sheath - ultrastructure ; Nerve Fibers, Myelinated - drug effects ; Nerve Fibers, Myelinated - metabolism ; Nerve Fibers, Myelinated - pathology ; Nerve Regeneration - drug effects ; Nerve Regeneration - physiology ; Neural Pathways - drug effects ; Neural Pathways - metabolism ; Neurology ; Neuroprotective Agents - pharmacology ; Neuroprotective Agents - therapeutic use ; NG2 ; Nogo Proteins ; Nogo-A ; oligodendrocytes ; Oligodendroglia - drug effects ; Oligodendroglia - metabolism ; Oligodendroglia - ultrastructure ; precursor cells ; Proteoglycans - drug effects ; Proteoglycans - metabolism ; Rats ; Rats, Sprague-Dawley ; Recombinant Fusion Proteins - pharmacology ; Recombinant Fusion Proteins - therapeutic use ; serotonin ; Serotonin - metabolism ; Spinal Cord - drug effects ; Spinal Cord - metabolism ; Spinal Cord - physiopathology ; Spinal Cord Injuries - drug therapy ; Spinal Cord Injuries - metabolism ; Spinal Cord Injuries - physiopathology ; Stem Cells - drug effects ; Stem Cells - metabolism ; Stem Cells - ultrastructure ; Treatment Outcome ; Vertebrates: nervous system and sense organs ; Wallerian Degeneration - drug therapy ; Wallerian Degeneration - physiopathology ; Wallerian Degeneration - prevention &amp; control ; Wisteria floribunda</subject><ispartof>Neuroscience, 2007-02, Vol.144 (3), p.865-877</ispartof><rights>IBRO</rights><rights>2006 IBRO</rights><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c494t-5677103848c0dc33fc750785fb824c37e0c381bf481024b2d6373f1446b62d013</citedby><cites>FETCH-LOGICAL-c494t-5677103848c0dc33fc750785fb824c37e0c381bf481024b2d6373f1446b62d013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neuroscience.2006.10.023$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=18497945$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17141961$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vitellaro-Zuccarello, L</creatorcontrib><creatorcontrib>Mazzetti, S</creatorcontrib><creatorcontrib>Madaschi, L</creatorcontrib><creatorcontrib>Bosisio, P</creatorcontrib><creatorcontrib>Gorio, A</creatorcontrib><creatorcontrib>De Biasi, S</creatorcontrib><title>Erythropoietin-mediated preservation of the white matter in rat spinal cord injury</title><title>Neuroscience</title><addtitle>Neuroscience</addtitle><description>Abstract We investigated the effect of a single administration of recombinant human erythropoietin (rhEPO) on the preservation of the ventral white matter of rats at 4 weeks after contusive spinal cord injury (SCI), a time at which functional recovery is significantly improved in comparison to the controls [Gorio A, Necati Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Enver Vardar E, Cerami A, Brines M (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci U S A 99:9450–9455; Gorio A, Madaschi L, Di Stefano B, Carelli S, Di Giulio AM, De Biasi S, Coleman T, Cerami A, Brines M (2005) Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci U S A 102:16379–16384]. Specifically, we examined, by morphological and cytochemical methods combined with light, confocal and electron microscopy, i) myelin preservation, ii) activation of adult oligodendrocyte progenitors (OPCs) identified for the expression of NG2 transmembrane proteoglycan, iii) changes in the amount of the chondroitin sulfate proteoglycans neurocan, versican and phosphacan and of their glycosaminoglycan component labeled with Wisteria floribunda lectin, and iv) ventral horn density of the serotonergic plexus as a marker of descending motor control axons. Injured rats received either saline or a single dose of rhEPO within 30 min after SCI. The results showed that the significant improvement of functional outcome observed in rhEPO-treated rats was associated with a better preservation of myelin in the ventral white matter. Moreover, the significant increase of both the number of NG2-positive OPCs and the labeling for Nogo-A, a marker of differentiated oligodendrocytes, suggested that rhEPO treatment could result in the generation of new myelinating oligodendrocytes. Sparing of fiber tracts in the ventral white matter was confirmed by the increased density of the serotonergic plexus around motor neurons. As for chondroitin sulfate proteoglycans, only phosphacan, increased in saline-treated rats, returned to normal levels in rhEPO group, probably reflecting a better maintenance of glial-axolemmal relationships along nerve fibers. 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Psychology</subject><subject>Male</subject><subject>Microscopy, Electron, Transmission</subject><subject>Myelin Proteins - drug effects</subject><subject>Myelin Proteins - metabolism</subject><subject>Myelin Sheath - drug effects</subject><subject>Myelin Sheath - metabolism</subject><subject>Myelin Sheath - ultrastructure</subject><subject>Nerve Fibers, Myelinated - drug effects</subject><subject>Nerve Fibers, Myelinated - metabolism</subject><subject>Nerve Fibers, Myelinated - pathology</subject><subject>Nerve Regeneration - drug effects</subject><subject>Nerve Regeneration - physiology</subject><subject>Neural Pathways - drug effects</subject><subject>Neural Pathways - metabolism</subject><subject>Neurology</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Neuroprotective Agents - therapeutic use</subject><subject>NG2</subject><subject>Nogo Proteins</subject><subject>Nogo-A</subject><subject>oligodendrocytes</subject><subject>Oligodendroglia - drug effects</subject><subject>Oligodendroglia - metabolism</subject><subject>Oligodendroglia - ultrastructure</subject><subject>precursor cells</subject><subject>Proteoglycans - drug effects</subject><subject>Proteoglycans - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Recombinant Fusion Proteins - pharmacology</subject><subject>Recombinant Fusion Proteins - therapeutic use</subject><subject>serotonin</subject><subject>Serotonin - metabolism</subject><subject>Spinal Cord - drug effects</subject><subject>Spinal Cord - metabolism</subject><subject>Spinal Cord - physiopathology</subject><subject>Spinal Cord Injuries - drug therapy</subject><subject>Spinal Cord Injuries - metabolism</subject><subject>Spinal Cord Injuries - physiopathology</subject><subject>Stem Cells - drug effects</subject><subject>Stem Cells - metabolism</subject><subject>Stem Cells - ultrastructure</subject><subject>Treatment Outcome</subject><subject>Vertebrates: nervous system and sense organs</subject><subject>Wallerian Degeneration - drug therapy</subject><subject>Wallerian Degeneration - physiopathology</subject><subject>Wallerian Degeneration - prevention &amp; control</subject><subject>Wisteria floribunda</subject><issn>0306-4522</issn><issn>1873-7544</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkluP1CAUgInRuOPqXzDERN86QqFAfTDZrOsl2cTEyzOh9DRD7UAFumb-vTTTZI0vygsJ5zucw8dB6AUle0qoeD3uPSwxJOvAW9jXhIgS2JOaPUA7qiSrZMP5Q7QjjIiKN3V9gZ6kNJKyGs4eowsqKaetoDv05Sae8iGGOTjIzldH6J3J0OM5QoJ4Z7ILHocB5wPgXweXAR9NzhCx8ziajNPsvJmwDbEvR-MST0_Ro8FMCZ5t-yX6_v7m2_XH6vbzh0_XV7eV5S3PVSOkpIQprizpLWODlQ2Rqhk6VXPLJBDLFO0GriipeVf3gkk2UM5FJ-qeUHaJXp3vnWP4uUDK-uiShWkyHsKStFBMNbRt_wnStjQiW1HAN2fQFrspwqDn6I4mnjQlelWvR_2ner2qX2NFfUl-vlVZumLxPnVzXYCXG2CSNdMQjbcu3XOKt7LlTeHenTko8u4cRL2V610Em3Uf3P_18_ava-zkvCuVf8AJ0hiWWD6uvF6nWhP9dR2WdVaIKG5lS9hvfwq9Kw</recordid><startdate>20070209</startdate><enddate>20070209</enddate><creator>Vitellaro-Zuccarello, L</creator><creator>Mazzetti, S</creator><creator>Madaschi, L</creator><creator>Bosisio, P</creator><creator>Gorio, A</creator><creator>De Biasi, S</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>20070209</creationdate><title>Erythropoietin-mediated preservation of the white matter in rat spinal cord injury</title><author>Vitellaro-Zuccarello, L ; Mazzetti, S ; Madaschi, L ; Bosisio, P ; Gorio, A ; De Biasi, S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c494t-5677103848c0dc33fc750785fb824c37e0c381bf481024b2d6373f1446b62d013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Antigens - drug effects</topic><topic>Antigens - metabolism</topic><topic>Axons - metabolism</topic><topic>Axons - ultrastructure</topic><topic>Biological and medical sciences</topic><topic>Cell Membrane - drug effects</topic><topic>Cell Membrane - metabolism</topic><topic>chondroitin sulfate proteoglycans</topic><topic>Chondroitin Sulfate Proteoglycans - drug effects</topic><topic>Chondroitin Sulfate Proteoglycans - metabolism</topic><topic>Erythropoietin - pharmacology</topic><topic>Erythropoietin - therapeutic use</topic><topic>Fundamental and applied biological sciences. 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Proc Natl Acad Sci U S A 99:9450–9455; Gorio A, Madaschi L, Di Stefano B, Carelli S, Di Giulio AM, De Biasi S, Coleman T, Cerami A, Brines M (2005) Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci U S A 102:16379–16384]. Specifically, we examined, by morphological and cytochemical methods combined with light, confocal and electron microscopy, i) myelin preservation, ii) activation of adult oligodendrocyte progenitors (OPCs) identified for the expression of NG2 transmembrane proteoglycan, iii) changes in the amount of the chondroitin sulfate proteoglycans neurocan, versican and phosphacan and of their glycosaminoglycan component labeled with Wisteria floribunda lectin, and iv) ventral horn density of the serotonergic plexus as a marker of descending motor control axons. Injured rats received either saline or a single dose of rhEPO within 30 min after SCI. The results showed that the significant improvement of functional outcome observed in rhEPO-treated rats was associated with a better preservation of myelin in the ventral white matter. Moreover, the significant increase of both the number of NG2-positive OPCs and the labeling for Nogo-A, a marker of differentiated oligodendrocytes, suggested that rhEPO treatment could result in the generation of new myelinating oligodendrocytes. Sparing of fiber tracts in the ventral white matter was confirmed by the increased density of the serotonergic plexus around motor neurons. As for chondroitin sulfate proteoglycans, only phosphacan, increased in saline-treated rats, returned to normal levels in rhEPO group, probably reflecting a better maintenance of glial-axolemmal relationships along nerve fibers. In conclusion, this investigation expands previous studies supporting the pleiotropic neuroprotective effect of rhEPO on secondary degenerative response and its therapeutic potential for the treatment of SCI and confirms that the preservation of the ventral white matter, which contains descending motor pathways, may be critical for limiting functional deficit.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>17141961</pmid><doi>10.1016/j.neuroscience.2006.10.023</doi><tpages>13</tpages></addata></record>
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1873-7544
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subjects Animals
Antigens - drug effects
Antigens - metabolism
Axons - metabolism
Axons - ultrastructure
Biological and medical sciences
Cell Membrane - drug effects
Cell Membrane - metabolism
chondroitin sulfate proteoglycans
Chondroitin Sulfate Proteoglycans - drug effects
Chondroitin Sulfate Proteoglycans - metabolism
Erythropoietin - pharmacology
Erythropoietin - therapeutic use
Fundamental and applied biological sciences. Psychology
Male
Microscopy, Electron, Transmission
Myelin Proteins - drug effects
Myelin Proteins - metabolism
Myelin Sheath - drug effects
Myelin Sheath - metabolism
Myelin Sheath - ultrastructure
Nerve Fibers, Myelinated - drug effects
Nerve Fibers, Myelinated - metabolism
Nerve Fibers, Myelinated - pathology
Nerve Regeneration - drug effects
Nerve Regeneration - physiology
Neural Pathways - drug effects
Neural Pathways - metabolism
Neurology
Neuroprotective Agents - pharmacology
Neuroprotective Agents - therapeutic use
NG2
Nogo Proteins
Nogo-A
oligodendrocytes
Oligodendroglia - drug effects
Oligodendroglia - metabolism
Oligodendroglia - ultrastructure
precursor cells
Proteoglycans - drug effects
Proteoglycans - metabolism
Rats
Rats, Sprague-Dawley
Recombinant Fusion Proteins - pharmacology
Recombinant Fusion Proteins - therapeutic use
serotonin
Serotonin - metabolism
Spinal Cord - drug effects
Spinal Cord - metabolism
Spinal Cord - physiopathology
Spinal Cord Injuries - drug therapy
Spinal Cord Injuries - metabolism
Spinal Cord Injuries - physiopathology
Stem Cells - drug effects
Stem Cells - metabolism
Stem Cells - ultrastructure
Treatment Outcome
Vertebrates: nervous system and sense organs
Wallerian Degeneration - drug therapy
Wallerian Degeneration - physiopathology
Wallerian Degeneration - prevention & control
Wisteria floribunda
title Erythropoietin-mediated preservation of the white matter in rat spinal cord injury
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