非动脉炎性前部缺血性视神经病变啮齿动物模型中的视神经炎症和脱髓鞘。
Optic nerve inflammation and demyelination in a rodent model of nonarteritic anterior ischemic optic neuropathy.
机构信息
Department of Ophthalmology and Visual Sciences, University of Maryland-Baltimore, Baltimore, Maryland.
出版信息
Invest Ophthalmol Vis Sci. 2013 Dec 5;54(13):7952-61. doi: 10.1167/iovs.13-12064.
PURPOSE
Optic nerve (ON) ischemia associated with nonarteric anterior ischemic optic neuropathy (NAION) results in axon and myelin damage. Myelin damage activates the intraneural Ras homolog A (RhoA), contributing to axonal regeneration failure. We hypothesized that increasing extrinsic macrophage activity after ON infarct would scavenge degenerate myelin and improve postischemic ON recovery. We used the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) to upregulate ON macrophage activity, and evaluated GM-CSF's effects after ON ischemia in the NAION rodent model (rAION).
METHODS
Following rAION induction, GM-CSF was administered via intraventricular injection. Retinal ganglion cell (RGC) stereologic analysis was performed 1 month postinduction. The retinae and optic nerve laminae of vehicle- and GM-CSF-treated animals were examined immunohistochemically and ultrastructurally using transmission electron microscopy (TEM). RhoA activity was analyzed using a rhotekin affinity immunoanalysis and densitometry. Isolated ONs were analyzed functionally ex vivo by compound action potential (CAP) analysis.
RESULTS
Rodent NAION produces ON postinfarct demyelination and myelin damage, functionally demonstrable by CAP analysis and ultrastructurally by TEM. Granulocyte-macrophage colony-stimulating factor increased intraneural inflammation, activating and recruiting endogenous microglia, with only a moderate amount of exogenous macrophage recruitment. Treatment with GM-CSF reduced postinfarct intraneural RhoA activity, but did not neuroprotect RGCs after rAION.
CONCLUSIONS
Sudden ON ischemia results in previously unrecognized axonal demyelination, which may have a clinically important role in NAION-related functional defects and recovery. Granulocyte-macrophage colony-stimulating factor is not neuroprotective when administered directly to the optic nerve following ON ischemia, and does not improve axonal regeneration. It dramatically increases ON-microglial activation and recruitment.
目的
与非动脉性前部缺血性视神经病变（NAION）相关的视神经（ON）缺血导致轴突和髓鞘损伤。髓鞘损伤激活神经内 Ras 同源物 A（RhoA），导致轴突再生失败。我们假设，在 ON 梗死后增加外源性巨噬细胞活性将清除变性髓鞘并改善缺血后 ON 的恢复。我们使用细胞因子粒细胞-巨噬细胞集落刺激因子（GM-CSF）来上调 ON 巨噬细胞活性，并在 NAION 啮齿动物模型（rAION）中评估 ON 缺血后 GM-CSF 的作用。
方法
rAION 诱导后，通过脑室注射给予 GM-CSF。诱导后 1 个月进行视网膜神经节细胞（RGC）立体学分析。使用透射电子显微镜（TEM）对 vehicle 和 GM-CSF 处理动物的视网膜和视神经层进行免疫组织化学和超微结构检查。使用 rhotekin 亲和免疫分析和密度测定法分析 RhoA 活性。通过复合动作电位（CAP）分析离体研究 ON 的功能。
结果
啮齿动物 NAION 导致 ON 梗死后脱髓鞘和髓鞘损伤，CAP 分析和 TEM 超微结构均证明了这一点。粒细胞-巨噬细胞集落刺激因子增加了神经内炎症，激活并募集了内源性小胶质细胞，仅引起少量外源性巨噬细胞募集。GM-CSF 治疗降低了梗死后神经内的 RhoA 活性，但 rAION 后并未保护 RGC。
结论
突然的 ON 缺血导致以前未被认识的轴突脱髓鞘，这在与 NAION 相关的功能缺陷和恢复中可能具有重要的临床意义。粒细胞-巨噬细胞集落刺激因子在 ON 缺血后直接施用于视神经时没有神经保护作用，也不能改善轴突再生。它极大地增加了 ON 小胶质细胞的激活和募集。
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