Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, United States of America.
PLoS One. 2011;6(10):e27067. doi: 10.1371/journal.pone.0027067. Epub 2011 Oct 28.
Guillain-Barré syndrome (GBS) is a monophasic immune neuropathic disorder in which a significant proportion of patients have incomplete recovery. The patients with incomplete recovery almost always have some degree of failure of axon regeneration and target reinnervation. Anti-ganglioside antibodies (Abs) are the most commonly recognized autoimmune markers in all forms of GBS and specific Abs are associated with the slow/poor recovery. We recently demonstrated that specific anti-ganglioside Abs inhibit axonal regeneration and nerve repair in preclinical models by activation of small GTPase RhoA and its downstream effectors. The objective of this study was to determine whether erythropoietin (EPO), a pleiotropic cytokine with neuroprotective and neurotrophic properties, enhances nerve regeneration in preclinical cell culture and animal models of autoimmune neuropathy/nerve repair generated with monoclonal and patient derived Abs. Primary neuronal cultures and a standardized sciatic crush nerve model were used to assess the efficacy of EPO in reversing inhibitory effects of anti-ganglioside Abs on nerve repair. We found that EPO completely reversed the inhibitory effects of anti-ganglioside Abs on axon regeneration in cell culture models and significantly improved nerve regeneration/repair in an animal model. Moreover, EPO-induced proregenerative effects in nerve cells are through EPO receptors and Janus kinase 2/Signal transducer and activator of transcription 5 pathway and not via early direct modulation of small GTPase RhoA. These preclinical studies indicate that EPO is a viable candidate drug to develop further for neuroprotection and enhancing nerve repair in patients with GBS.
格林-巴利综合征（GBS）是一种单相免疫性神经病变疾病，其中相当一部分患者存在不完全恢复。不完全恢复的患者几乎总是存在一定程度的轴突再生和靶神经再支配失败。抗神经节苷脂抗体（Abs）是所有 GBS 形式中最常被识别的自身免疫标志物，特定的 Abs 与恢复缓慢/不良有关。我们最近证明，特定的抗神经节苷脂 Abs 通过激活小 GTPase RhoA 及其下游效应子，在临床前模型中抑制轴突再生和神经修复。本研究的目的是确定促红细胞生成素（EPO）是否能增强临床前细胞培养和使用单克隆和患者来源 Abs 产生的自身免疫性神经病/神经修复动物模型中的神经再生。原代神经元培养物和标准化坐骨神经挤压模型用于评估 EPO 逆转抗神经节苷脂 Abs 对神经修复抑制作用的功效。我们发现，EPO 完全逆转了抗神经节苷脂 Abs 对细胞培养模型中轴突再生的抑制作用，并显著改善了动物模型中的神经再生/修复。此外，EPO 诱导神经细胞的促再生作用是通过 EPO 受体和 Janus 激酶 2/信号转导和转录激活因子 5 通路，而不是通过早期直接调节小 GTPase RhoA。这些临床前研究表明，EPO 是一种可行的候选药物，可以进一步开发用于保护 GBS 患者的神经和增强神经修复。
