Erythropoietin-mediated preservation of the white matter in rat spinal cord injury.
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 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.
Vitellaro-Zuccarello
L
L
Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Via Celoria 26, I-20133 Milano, Italy. laura.vitellaro@unimi.it
Mazzetti
S
S
Madaschi
L
L
Bosisio
P
P
Gorio
A
A
De Biasi
S
S
D000818:Animals; D000941:Antigens / Q000187:drug effects / Q000378:metabolism; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000187:drug effects / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D046529:Microscopy, Electron, Transmission; D009185:Myelin Proteins / Q000187:drug effects / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000070798:Nogo Proteins; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011509:Proteoglycans / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012701:Serotonin / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016896:Treatment Outcome; D014855:Wallerian Degeneration / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D011508:Chondroitin Sulfate Proteoglycans; D004921:Erythropoietin; D009185:Myelin Proteins; D018696:Neuroprotective Agents; D000070798:Nogo Proteins; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins; D012701:Serotonin; D000099216:Chondroitin Sulfate Proteoglycan 4; C000603199:RTN4 protein, human; C000603197:Rtn4 protein, rat