Mol. Med.：正性应激有助于预防青光眼

2012年4月3日，《每日科学》报道，华盛顿大学圣路易斯医学院的研究人员通过小鼠研究，已设计出一种预防青光眼视神经损伤的治疗方法。相关研究论文在线发表在Molecular Medicine上，首次表明预处理诱导的耐受性可以预防神经退行性疾病。

研究通过使小鼠反复暴露在类似于高海拔地区的低氧状态中，增加了视神经细胞的损伤耐受性。间断性低氧环境应激诱导了一种耐受性的保护反应，这些反应使视神经细胞及其他神经细胞具有更低的损伤易感性。

通常认为应激是一种消极现象，但也有其他研究表明应激的积极性，象运动和低氧环境一样，预处理细胞能诱导出细胞更强的损伤与疾病耐受性。

以前一直认为中枢神经系统的耐受性只持续几天时间，但去年发现一种预处理操作可将耐受效应从几天扩展到几个月。即在2周时间内，将小鼠几次暴露于缺氧或低氧浓度情况下，即可触发一种延期的耐受性，在预处理结束后，大脑至少8周内不受中风损伤。那么，这种损伤耐受性的延期是否也能预防以神经元缓慢、进展性丢失为特征的神经退行性疾病？

为了寻求答案，科学家们对青光眼动物模型展开了研究。根据青光眼缓慢、进展性地杀死视网膜神经节细胞，而将其划分为神经退行性疾病，它是引起失明的主要原因，与眼压增加相关，唯一的治疗药物是降眼压药物，还没有保护视网膜和视神经免受损伤的治疗方法。视网膜神经节细胞体分布于眼睛视网膜内，它们的分枝与轴突集合成束，形成视神经，现在还不知道青光眼中损伤开始于细胞体还是轴突，但是随着越来越多的视网膜神经节细胞死亡，患者就会丧失周边视力，最后变成盲人。

该新研究发现，青光眼诱导手术前接受预处理的小鼠只丧失了3%视网膜神经节细胞体。科学家们现在正在研究预处理激活或抑制了哪些基因，希望确定出细胞抗损伤的基因活性变化。同时，也在开展临床试验，来观察应激诱导的耐受性是否能减少急性损伤后的大脑损伤，如中风、蛛网膜下腔出血或创伤。另外，希望这项新发现会加速耐受潜在有效性在帕金森病、阿尔海茨默症及其他神经退行性病动物模型中的研究。（生物谷bioon.com）

doi:10.2119/molmed.2012.00050
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Glaucoma-Induced Degeneration of Retinal Ganglion Cells Prevented by Hypoxic Preconditioning: A Model of "Glaucoma Tolerance"

Zhu Y, Zhang L, Schmidt JF, Gidday JM

Like all cells, neurons adapt to stress by transient alterations in phenotype, an epigenetic response that forms the basis for preconditioning against acute ischemic injury in the CNS. We recently showed that a modified repetitive hypoxic preconditioning regimen significantly extends the window of ischemic tolerance to acute retinal ischemic injury from days to months. The present study was undertaken to determine if this uniquely protracted neuroprotective phenotype would also confer resistance to glaucomatous neurodegeneration. Retinal ganglion cell death at somatic and axonal levels was assessed after both three and ten weeks of sustained intraocular hypertension in an adult mouse model of inducible, open-angle glaucoma, with or without repetitive hypoxic preconditioning (RHP) prior to IOP elevation. Loss of brn3-positive ganglion cell soma after 3 wks of experimental glaucoma, along with increases in several apoptotic endpoints, were all significantly and robustly attenuated in mice subjected to RHP. Soma protection by RHP was also confirmed after 10 wks of intraocular hypertension by brn3 and SMI32 immunostaining. In addition, quantification of axon density in postlaminar optic nerve documented robust preservation in RHP-treated mice, and neurofilament immunostaining also revealed preconditioning-induced improvements in axon integrity/survival in both retina and optic nerve after 10 wks of experimental glaucoma. This uniquely protracted period of phenotypic change, established in retinal ganglion cells by the activation of latent anti-apoptotic, pro-survival mechanisms at both somatic and axonal levels, reflects a novel form of inducible neuronal plasticity that may provide novel therapeutic targets for preventing and treating glaucoma and other neurodegenerative diseases.