Single exposure to erythropoietin modulates Nerve Growth Factor expression in the spinal cord following traumatic injury: comparison with methylprednisolone.
Acute lesions of the spinal cord lead to dramatic changes in neuronal function. In the present study, we examined the possible involvement of neurotrophic factors in the action of the drug of choice for the treatment of such an emergency, i.e. the glucocorticoid methylprednisolone is compared to erythropoietin, a cytokine recently shown to markedly shorten the time necessary for motor recovery following injury [Gorio, A., Gokmen, N., Erbayraktar, S., Yilmaz, O., Madaschi, L., Cichetti, C., Di Giulio, A.M., 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. 99, 9450-9455]. We found that methylprednisolone reduces the lesion-enhanced Nerve Growth Factor (NGF) mRNA levels 3 h after injury in the trauma epicenter and caudal section of the cord whereas erythropoietin reinforced the NGF gene expression. Three days after the occurrence of the lesion, erythropoietin, but not methylprednisolone, significantly up-regulated the NGF gene expression both caudally and rostrally to the lesion site, an effect that, based on the chemo-attractant properties of neurotrophin, might facilitate the growth of injured axons toward NGF-rich sites and contribute to the enhancement of the regenerative process. The differences between the effects of methylprednisolone and erythropoietin dissipate 7 days after the lesion when they both enhance NGF mRNA levels at the epicenter. These data show that methylprednisolone and erythropoietin display a different pattern of activation of the neurotrophin NGF which is strictly dependent on the portion of the cord examined and the time elapsed from the injury. Based on our results, we suggest that the higher increase of NGF expression mediated by erythropoietin soon after the injury might explain, at least in part, the improved recovery of motor functions produced by erythropoietin compared to methylprednisolone and saline.
Fumagalli
Fabio
F
Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
Madaschi
Laura
L
Brenna
Paola
P
Caffino
Lucia
L
Marfia
Giovanni
G
Di Giulio
Anna Maria
AM
Racagni
Giorgio
G
Gorio
Alfredo
A
D000818:Animals; D004921:Erythropoietin / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D008775:Methylprednisolone / Q000494:pharmacology*; D020932:Nerve Growth Factor / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors
D005938:Glucocorticoids; D012333:RNA, Messenger; D004921:Erythropoietin; D020932:Nerve Growth Factor; D008775:Methylprednisolone