Hines-Beard Jessica, Bond Wesley S, Backstrom Jon R, Rex Tonia S
Vanderbilt Eye Institute, Vanderbilt University, 11435 MRB IV, 2213 Garland Avenue, Nashville, TN, 37232, USA.
Vanderbilt Brain Institute, Vanderbilt University, 11435 MRB IV, 2213 Garland Avenue, Nashville, TN, 37232, USA.
J Neuroinflammation. 2016 Feb 15;13:39. doi: 10.1186/s12974-016-0499-5.
Glaucoma is a complex neurodegeneration and a leading cause of blindness worldwide. Current therapeutic strategies, which are all directed towards lowering the intraocular pressure (IOP), do not stop progression of the disease. We have demonstrated that recombinant adeno-associated virus (rAAV) gene delivery of a form of erythropoietin with attenuated erythropoietic activity (EpoR76E) can preserve retinal ganglion cells, their axons, and vision without decreasing IOP. The goal of this study was to determine if modulation of neuroinflammation or oxidative stress played a role in the neuroprotective activity of EPO.R76E.
Five-month-old DBA/2J mice were treated with either rAAV.EpoR76E or a control vector and collected at 8 months of age. Neuroprotection was assessed by quantification of axon transport and visual evoked potentials. Microglia number and morphology and cytokine and chemokine levels were quantified. Message levels of oxidative stress-related proteins were assessed.
Axon transport and visual evoked potentials were preserved in rAAV.EpoR76E-treated mice. The number of microglia was decreased in retinas from 8-month-old rAAV.EpoR76E-treated mice, but proliferation was unaffected. The blood-retina barrier was also unaffected by treatment. Levels of some pro-inflammatory cytokines were decreased in retinas from rAAV.EpoR76E-treated mice including IL-1, IL-12, IL-13, IL-17, CCL4, and CCL5. TNFα messenger RNA (mRNA) was increased in retinas from 8-month-old mice compared to 3-month-old controls regardless of treatment. Expression of several antioxidant proteins was increased in retinas of rAAV.EpoR76E-treated 8-month-old mice.
Treatment with rAAV.EpoR76E preserves vision in the DBA/2J model of glaucoma at least in part by decreasing infiltration of peripheral immune cells, modulating microglial reactivity, and decreasing oxidative stress.
青光眼是一种复杂的神经退行性疾病，是全球失明的主要原因。目前所有旨在降低眼压（IOP）的治疗策略都无法阻止疾病的进展。我们已经证明，通过重组腺相关病毒（rAAV）递送具有减弱的促红细胞生成活性的促红细胞生成素形式（EpoR76E）可以保护视网膜神经节细胞、其轴突和视力，而不会降低眼压。本研究的目的是确定神经炎症或氧化应激的调节是否在EPO.R76E的神经保护活性中起作用。
对5月龄的DBA/2J小鼠用rAAV.EpoR76E或对照载体进行治疗，并在8月龄时收集。通过定量轴突运输和视觉诱发电位来评估神经保护作用。对小胶质细胞数量和形态以及细胞因子和趋化因子水平进行定量。评估氧化应激相关蛋白的信使水平。
rAAV.EpoR76E治疗的小鼠中轴突运输和视觉诱发电位得到保留。在8月龄rAAV.EpoR76E治疗的小鼠视网膜中，小胶质细胞数量减少，但增殖未受影响。血视网膜屏障也不受治疗影响。rAAV.EpoR76E治疗的小鼠视网膜中一些促炎细胞因子水平降低，包括IL-1、IL-12、IL-13、IL-17、CCL4和CCL5。无论治疗如何，与3月龄对照相比，8月龄小鼠视网膜中TNFα信使核糖核酸（mRNA）增加。在rAAV.EpoR76E治疗的8月龄小鼠视网膜中，几种抗氧化蛋白的表达增加。
rAAV.EpoR76E治疗至少部分通过减少外周免疫细胞浸润、调节小胶质细胞反应性和降低氧化应激来保护DBA/2J青光眼模型的视力。
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