Fumagalli Fabio, Madaschi Laura, Brenna Paola, Caffino Lucia, Marfia Giovanni, Di Giulio Anna Maria, Racagni Giorgio, Gorio Alfredo
Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
Eur J Pharmacol. 2008 Jan 6;578(1):19-27. doi: 10.1016/j.ejphar.2007.09.021. Epub 2007 Oct 2.
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.
脊髓急性损伤会导致神经元功能发生显著变化。在本研究中，我们探讨了神经营养因子在治疗此类急症的首选药物作用中的可能参与情况，即将糖皮质激素甲泼尼龙与促红细胞生成素进行比较，促红细胞生成素是一种细胞因子，最近显示其能显著缩短损伤后运动功能恢复所需的时间[Gorio, A., Gokmen, N., Erbayraktar, S., Yilmaz, O., Madaschi, L., Cichetti, C., Di Giulio, A.M., Vardar, E., Cerami, A., Brines, M., 2002. 重组人促红细胞生成素可对抗继发性损伤并显著促进实验性脊髓创伤后的神经功能恢复。《美国国家科学院院刊》99, 9450 - 9455]。我们发现，损伤后3小时，甲泼尼龙可降低创伤中心及脊髓尾段损伤增强的神经生长因子（NGF）mRNA水平，而促红细胞生成素则增强了NGF基因表达。损伤发生三天后，促红细胞生成素而非甲泼尼龙，在损伤部位尾侧和头侧均显著上调了NGF基因表达，基于神经营养因子的化学吸引特性，这一效应可能促进受损轴突向富含NGF的部位生长，并有助于增强再生过程。损伤7天后，甲泼尼龙和促红细胞生成素的作用差异消失，此时它们均增强了创伤中心的NGF mRNA水平。这些数据表明，甲泼尼龙和促红细胞生成素对神经营养因子NGF的激活模式不同，这严格取决于所检查的脊髓部位以及损伤后的时间。基于我们的研究结果，我们认为损伤后不久促红细胞生成素介导的NGF表达更高的增加，可能至少部分解释了与甲泼尼龙和生理盐水相比，促红细胞生成素能改善运动功能恢复的原因。
