Sättler M B, Merkler D, Maier K, Stadelmann C, Ehrenreich H, Bähr M, Diem R
Neurologische Universitätsklinik, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Cell Death Differ. 2004 Dec;11 Suppl 2:S181-92. doi: 10.1038/sj.cdd.4401504.
In multiple sclerosis (MS), long-term disability is primarily caused by axonal and neuronal damage. We demonstrated in a previous study that neuronal apoptosis occurs early during experimental autoimmune encephalomyelitis, a common animal model of MS. In the present study, we show that, in rats suffering from myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis, systemic application of erythropoietin (Epo) significantly increased survival and function of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. We identified three independent intracellular signaling pathways involved in Epo-induced neuroprotection in vivo: Protein levels of phospho-Akt, phospho-MAPK 1 and 2, and Bcl-2 were increased under Epo application. Using a combined treatment of Epo together with a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K) prevented upregulation of phospho-Akt and consecutive RGC rescue. We conclude that in MOG-EAE the PI3-K/Akt pathway has an important influence on RGC survival under systemic treatment with Epo.
在多发性硬化症（MS）中，长期残疾主要是由轴突和神经元损伤引起的。我们在先前的研究中证明，在实验性自身免疫性脑脊髓炎（一种常见的MS动物模型）早期会发生神经元凋亡。在本研究中，我们发现，在患有髓鞘少突胶质细胞糖蛋白（MOG）诱导的视神经炎的大鼠中，全身应用促红细胞生成素（Epo）可显著提高视网膜神经节细胞（RGCs）的存活率和功能，RGCs是构成视神经轴突的神经元。我们确定了体内Epo诱导神经保护作用涉及的三个独立的细胞内信号通路：应用Epo后，磷酸化Akt、磷酸化丝裂原活化蛋白激酶1和2以及Bcl-2的蛋白水平升高。使用Epo与磷脂酰肌醇3激酶（PI3-K）选择性抑制剂联合治疗可阻止磷酸化Akt的上调和随后的RGC挽救。我们得出结论，在MOG-EAE中，PI3-K/Akt通路在全身应用Epo治疗下对RGC存活具有重要影响。
