Centre for Brain Repair, University of Cambridge, Cambridge, UK.
Neurobiol Dis. 2012 Jan;45(1):243-52. doi: 10.1016/j.nbd.2011.08.008. Epub 2011 Aug 10.
Glaucoma, a leading cause of blindness, is a neurodegenerative disease characterized by progressive loss of retinal ganglion cell axons in the optic nerve and their cell bodies in the retina. Reactive retinal glial changes have been observed in glaucoma but the role of such glial changes in the pathogenesis of the condition remains unclear. In the present study we found that retinal ganglion cells in an experimental animal model of glaucoma have an increased axon regenerative potential. Regeneration of adult rat retinal ganglion cell axons after optic nerve crush was significantly increased in vivo when combined with intraocular pressure-induced experimental glaucoma. This enhanced axon regeneration response was correlated with a significant increase in activation of glial fibrillary acidic protein+retinal glia. Using a dissociated retinal ganglion cell culture model we showed that reducing the number of activated retinal glia with a glial specific toxin, α-Aminoadipic acid, significantly reduced the growth potential of retinal ganglion cells from glaucomatous rat eyes, suggesting that activated retinal glia mediate, at least in part, the growth promoting effect. This was shown to be mediated by both membrane-bound and soluble glial-derived factors. Neurotrophin and ciliary neurotrophic/leukemia inhibitory factor blockers did not affect the regenerative potential, excluding these growth factors as principal mediators of the enhanced growth response occurring in glaucomatous retinal cultures. These observations are the first to reveal that retinal ganglion cells from glaucomatous rat eyes have an enhanced regenerative capacity. Furthermore, our results suggest that activated retinal glia mediate at least part of this response. Further work to understand and enhance the regeneration-promoting effect of activated retinal glia is required to determine if this approach could be useful as part of a therapeutic strategy to encourage optic nerve regeneration in glaucoma.
青光眼是一种主要的致盲原因，是一种神经退行性疾病，其特征是视神经中的视网膜神经节细胞轴突和视网膜中的细胞体进行性丧失。已经观察到青光眼患者的视网膜神经胶质发生了反应性变化，但这种神经胶质变化在疾病发病机制中的作用尚不清楚。在本研究中，我们发现青光眼实验动物模型中的视网膜神经节细胞具有增加的轴突再生潜力。在体内，当与眼压诱导的实验性青光眼相结合时，视神经挤压后成年大鼠视网膜神经节细胞轴突的再生明显增加。这种增强的轴突再生反应与胶质纤维酸性蛋白+视网膜神经胶质的显著激活相关。使用分离的视网膜神经节细胞培养模型，我们表明，用神经胶质特异性毒素α-氨基己二酸减少激活的视网膜神经胶质的数量，显著降低了来自青光眼大鼠眼睛的视网膜神经节细胞的生长潜力，表明激活的视网膜神经胶质至少部分介导了促进生长的作用。这是通过膜结合和可溶性神经胶质衍生因子介导的。神经营养因子和睫状神经营养因子/白血病抑制因子阻断剂不影响再生潜能，排除了这些生长因子作为发生在青光眼视网膜培养物中的增强生长反应的主要介质。这些观察结果是首次揭示来自青光眼大鼠眼睛的视网膜神经节细胞具有增强的再生能力。此外，我们的结果表明，激活的视网膜神经胶质至少介导了部分反应。需要进一步研究以了解和增强激活的视网膜神经胶质的再生促进作用，以确定这种方法是否可以作为促进青光眼视神经再生的治疗策略的一部分有用。
