Williams Pete A, Harder Jeffrey M, John Simon W M
The Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME.
Department of Ophthalmology, Tufts University of Medicine, Boston, MA.
J Glaucoma. 2017 Dec;26(12):1161-1168. doi: 10.1097/IJG.0000000000000767.
Mitochondrial dysfunction may be an important, if not essential, component of human glaucoma. Using transcriptomics followed by molecular and neurobiological techniques, we have recently demonstrated that mitochondrial dysfunction within retinal ganglion cells is an early feature in the DBA/2J mouse model of inherited glaucoma. Guided by these findings, we discovered that the retinal level of nicotinamide adenine dinucleotide (NAD, a key molecule for mitochondrial health) declines in an age-dependent manner. We hypothesized that this decline in NAD renders retinal ganglion cells susceptible to damage during periods of elevated intraocular pressure. To replete NAD levels in this glaucoma, we administered nicotinamide (the amide of vitamin B3). At the lowest dose tested, nicotinamide robustly protected from glaucoma (~70% of eyes had no detectable glaucomatous neurodegeneration). At this dose, nicotinamide had no influence on intraocular pressure and so its effect was neuroprotective. At the highest dose tested, 93% of eyes had no detectable glaucoma. This represents a ~10-fold decrease in the risk of developing glaucoma. At this dose, intraocular pressure still became elevated but there was a reduction in the degree of elevation showing an additional benefit. Thus, nicotinamide is unexpectedly potent at preventing this glaucoma and is an attractive option for glaucoma therapeutics. Our findings demonstrate the promise for both preventing and treating glaucoma by interventions that bolster metabolism during increasing age and during periods of elevated intraocular pressure. Nicotinamide prevents age-related declines in NAD (a decline that occurs in different genetic contexts and species). NAD precursors are reported to protect from a variety of neurodegenerative conditions. Thus, nicotinamide may provide a much needed neuroprotective treatment against human glaucoma. This manuscript summarizes human data implicating mitochondria in glaucoma, and argues for studies to further assess the safety and efficacy of nicotinamide in human glaucoma care.
线粒体功能障碍即便不是人类青光眼的必要组成部分，也可能是其重要组成部分。通过转录组学及随后的分子和神经生物学技术，我们最近证明，视网膜神经节细胞内的线粒体功能障碍是遗传性青光眼DBA/2J小鼠模型的一个早期特征。基于这些发现，我们发现烟酰胺腺嘌呤二核苷酸（NAD，线粒体健康的关键分子）的视网膜水平会随着年龄增长而下降。我们推测，NAD的这种下降使视网膜神经节细胞在眼压升高期间易受损伤。为了补充这种青光眼中的NAD水平，我们给予了烟酰胺（维生素B3的酰胺）。在测试的最低剂量下，烟酰胺对青光眼有强大的保护作用（约70%的眼睛未检测到青光眼性神经变性）。在此剂量下，烟酰胺对眼压没有影响，因此其作用是神经保护作用。在测试的最高剂量下，93%的眼睛未检测到青光眼。这意味着患青光眼的风险降低了约10倍。在此剂量下，眼压仍会升高，但升高程度有所降低，显示出额外的益处。因此，烟酰胺在预防这种青光眼方面具有意想不到的强大作用，是青光眼治疗的一个有吸引力的选择。我们的研究结果表明，通过在年龄增长和眼压升高期间增强代谢的干预措施来预防和治疗青光眼是有前景的。烟酰胺可预防与年龄相关的NAD下降（这种下降发生在不同的遗传背景和物种中）。据报道，NAD前体可预防多种神经退行性疾病。因此，烟酰胺可能为人类青光眼提供急需的神经保护治疗。本手稿总结了涉及线粒体与青光眼关系的人类数据，并主张开展研究以进一步评估烟酰胺在人类青光眼治疗中的安全性和有效性。
