Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Mol Med. 2012 May 9;18(1):697-706. doi: 10.2119/molmed.2012.00050.
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 central nervous system. We recently showed that a modified repetitive hypoxic preconditioning (RHP) 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 3 and 10 wks of sustained intraocular hypertension in an adult mouse model of inducible, open-angle glaucoma, with or without RHP before intraocular pressure 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 the 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 antiapoptotic, prosurvival mechanisms at both somatic and axonal levels, reflects a novel form of inducible neuronal plasticity that may provide innovative therapeutic targets for preventing and treating glaucoma and other neurodegenerative diseases.
与所有细胞一样，神经元通过表型的短暂改变来适应应激，这种表观遗传反应构成了中枢神经系统急性缺血损伤预适应的基础。我们最近表明，改良的重复低氧预处理（RHP）方案可显著将急性视网膜缺血损伤的缺血耐受窗口从数天延长至数月。本研究旨在确定这种独特的持久神经保护表型是否也能抵抗青光眼性神经退行性变。在成年诱导性开角型青光眼小鼠模型中，在眼内压升高之前进行 RHP 预处理或不进行预处理，评估持续眼内高压 3 周和 10 周后视网膜神经节细胞在体细胞和轴突水平上的死亡情况。在实验性青光眼 3 周后，用 brn3 阳性神经节细胞体的丧失以及几个凋亡终点的增加来评估，用 RHP 预处理的小鼠明显且强烈地减轻了这种情况。在用 RHP 预处理 10 周后，通过 brn3 和 SMI32 免疫染色也证实了 RHP 对体细胞的保护。此外，在后层状视神经中轴突密度的定量分析也证明了 RHP 治疗的小鼠具有很强的保留作用，神经丝免疫染色也显示，在 10 周的实验性青光眼后，在视网膜和视神经中，预处理诱导的轴突完整性/存活得到了改善。这种独特的、表型改变的延长期，是通过在体细胞和轴突水平上激活潜在的抗凋亡、促进生存的机制在视网膜神经节细胞中建立的，反映了一种新的诱导性神经元可塑性形式，可能为预防和治疗青光眼和其他神经退行性疾病提供创新的治疗靶点。
