Cytokine therapy-mediated neuroprotection in a Friedreich's ataxia mouse model.
Cytokine therapy-mediated neuroprotection in a Friedreich's ataxia mouse model.
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DOI：
10.1002/ana.24846
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发表时间：
2017-02
影响因子：
11.2
通讯作者：
Wilkins A
中科院分区：
文献类型：
--
作者：
Kemp KC;Cerminara N;Hares K;Redondo J;Cook AJ;Haynes HR;Burton BR;Pook M;Apps R;Scolding NJ;Wilkins A
弗里德赖希共济失调是一种毁灭性的神经系统疾病，目前缺乏任何有效的治疗方法。我们研究了细胞因子、粒细胞集落刺激因子（G-CSF）和干细胞因子（SCF）在弗里德赖希共济失调人源化小鼠模型中的神经保护作用。小鼠每月接受细胞因子的皮下输注，同时还使用广泛的行为运动性能测试在每月的时间点进行评估。治疗6个月后，进行感觉和运动神经传导的神经生理学评估。随后，处死小鼠进行背根神经节、脊髓和小脑的信使RNA、蛋白质和组织学分析。细胞因子给药导致与弗里德赖希共济失调相关的生化、神经病理、神经生理和行为缺陷的显著逆转。G-CSF和SCF均对共济失调蛋白水平（疾病发病机制中的主要分子缺陷）和共济失调蛋白表达的调节因子具有显著影响。观察到运动协调和自发活动的持续改善，即使在神经症状发作后也是如此。治疗还恢复了感觉神经复合电位的持续时间。周围神经传导的改善与细胞因子诱导的共济失调蛋白表达的增加呈正相关，提供了共济失调蛋白增加与神经生理功能之间的联系。疾病相关病理学的消除也很明显，炎症/神经胶质增生减少，组织损伤区域的神经干细胞数量增加。这些实验表明，细胞因子已经在临床上用于其他条件提供了一种新的，快速翻译，疾病改善，神经保护治疗弗里德赖希共济失调的前景。神经学年鉴2017;81：212-226
Friedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuroprotective effects of the cytokines, granulocyte‐colony stimulating factor (G‐CSF) and stem cell factor (SCF) in a humanized murine model of Friedreich's ataxia. Mice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioral motor performance tests. After 6 months of treatment, neurophysiological evaluation of both sensory and motor nerve conduction was performed. Subsequently, mice were sacrificed for messenger RNA, protein, and histological analysis of the dorsal root ganglia, spinal cord, and cerebellum. Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological, and behavioural deficits associated with Friedreich's ataxia. Both G‐CSF and SCF had pronounced effects on frataxin levels (the primary molecular defect in the pathogenesis of the disease) and a regulators of frataxin expression. Sustained improvements in motor coordination and locomotor activity were observed, even after onset of neurological symptoms. Treatment also restored the duration of sensory nerve compound potentials. Improvements in peripheral nerve conduction positively correlated with cytokine‐induced increases in frataxin expression, providing a link between increases in frataxin and neurophysiological function. Abrogation of disease‐related pathology was also evident, with reductions in inflammation/gliosis and increased neural stem cell numbers in areas of tissue injury. These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease‐modifying, and neuroprotective treatment for Friedreich's ataxia. Ann Neurol 2017;81:212–226