Division of Clinical Neurobiology, Department of Neurology, Medical University, Innsbruck, Austria.
Mov Disord. 2011 Feb 15;26(3):507-515. doi: 10.1002/mds.23474. Epub 2011 Jan 6.
Multiple system atrophy is a rapidly progressive neurodegenerative disorder with a markedly reduced life expectancy. Failure of symptomatic treatment raises an urgent need for disease-modifying strategies. We have investigated the neuroprotective potential of erythropoietin in (proteolipid protein)-α-synuclein transgenic mice exposed to 3-nitropropionic acid featuring multiple system atrophy-like pathology including oligodendroglial α-synuclein inclusions and selective neuronal degeneration. Mice were treated with erythropoietin starting before (early erythropoietin) and after (late erythropoietin) intoxication with 3-nitropropionic acid. Nonintoxicated animals receiving erythropoietin and intoxicated animals treated with saline served as control groups. Behavioral tests included pole test, open field activity, and motor behavior scale. Immunohistochemistry for tyrosine hydroxylase and dopamine and cyclic adenosine monophosphate-regulated phosphoprotein (DARPP-32) was analyzed stereologically. Animals receiving erythropoietin before and after 3-nitropropionic acid intoxication scored significantly lower on the motor behavior scale and they performed better in the pole test than controls with no significant difference between early and late erythropoietin administration. Similarly, rearing scores were worse in 3-nitropropionic acid-treated animals with no difference between the erythropoietin subgroups. Immunohistochemistry revealed significant attenuation of 3-nitropropionic acid-induced loss of tyrosine hydroxylase and DARPP-32 positive neurons in substantia nigra pars compacta and striatum, respectively, in both erythropoietin-treated groups without significant group difference in the substantia nigra. However, at striatal level, a significant difference between early and late erythropoietin administration was observed. In the combined (proteolipid protein)-α-synuclein 3-nitropropionic acid multiple system atrophy mouse model, erythropoietin appears to rescue dopaminergic and striatal gabaergic projection neurons. This effect is associated with improved motor function. Further studies are warranted to develop erythropoietin as a potential interventional therapy in multiple system atrophy.
多系统萎缩是一种进行性神经退行性疾病，预期寿命明显缩短。症状治疗的失败提出了迫切需要疾病修饰策略。我们研究了促红细胞生成素在（蛋白脂质蛋白）-α-突触核蛋白转基因小鼠暴露于 3-硝基丙酸中的神经保护潜力，3-硝基丙酸具有多系统萎缩样病理学特征，包括少突胶质细胞α-突触核蛋白包涵体和选择性神经元变性。在 3-硝基丙酸中毒之前（早期促红细胞生成素）和之后（晚期促红细胞生成素）开始用促红细胞生成素治疗小鼠。接受促红细胞生成素的非中毒动物和用生理盐水治疗的中毒动物作为对照组。行为测试包括棒测试、旷场活动和运动行为量表。立体学分析酪氨酸羟化酶和多巴胺及环腺苷单磷酸调节磷蛋白（DARPP-32）的免疫组织化学。在 3-硝基丙酸中毒前后接受促红细胞生成素的动物在运动行为量表上的评分明显较低，与对照组相比，它们在棒测试中的表现更好，早期和晚期促红细胞生成素给药之间没有显著差异。同样，3-硝基丙酸处理动物的饲养评分更差，促红细胞生成素亚组之间没有差异。免疫组织化学显示，在黑质致密部和纹状体中，酪氨酸羟化酶和 DARPP-32 阳性神经元的 3-硝基丙酸诱导丢失分别得到显著衰减，在两组促红细胞生成素治疗组中，黑质中没有显著的组间差异。然而，在纹状体水平上，观察到早期和晚期促红细胞生成素给药之间存在显著差异。在（蛋白脂质蛋白）-α-突触核蛋白 3-硝基丙酸多系统萎缩小鼠模型中，促红细胞生成素似乎可以挽救多巴胺能和纹状体 GABA 能投射神经元。这种作用与运动功能的改善有关。需要进一步研究以开发促红细胞生成素作为多系统萎缩的潜在干预治疗方法。
