Takahashi Nobuyuki, Matsunaga Naoko, Natsume Takahiro, Kitazawa Chinatsu, Itani Yoshitaka, Hama Aldric, Hayashi Ikuo, Shimazawa Masamitsu, Hara Hideaki, Takamatsu Hiroyuki
Pharmacology, Hamamatsu Pharma Research, Inc., 1-3-7, Shinmiyakoda, Kita-ku, Hamamatsu, Shizuoka, 431-2103, Japan.
Hamamatsu Pharma Research USA, Inc., 4660 La Jolla Village Drive, San Diego, CA, 92122 USA.
Heliyon. 2021 Apr 6;7(4):e06701. doi: 10.1016/j.heliyon.2021.e06701. eCollection 2021 Apr.
Early detection of optic neuropathy is crucial for initiating treatment that could delay or prevent visual field loss. Preclinical studies have advanced a number of potential neuroprotective strategies to prevent retinal ganglion cell (RGC) degeneration, but none have successfully completed clinical trials. One issue related to the lack of preclinical to clinical translation is the lack of preclinical morphometric assessments that could be used to track neuroprotection, as well as neurodegeneration, over time within the same animal. Thus, to assess whether clinically used morphometric assessments can identify neuroprotection of RGC, the current study compared optic nerve fractional anisotropy (FA) obtained with diffusion tensor imaging (DTI) and retinal nerve fiber layer (RNFL) thickness measured with spectral domain optical coherence tomography (SD-OCT) to observe not only the early progression of RGC axonal degeneration but to also discern which imaging modality identifies signs of neuroprotection during treatment with the alpha-adrenoceptor agonist brimonidine. Elevated and sustained intraocular pressure (IOP) was observed following laser photocoagulation of the trabecular meshwork in one eye of nonhuman primates (NHP). Either brimonidine (0.1%) or control treatment was instilled twice daily for two months. In control-treated eyes, increased IOP, increased vertical cup-to-disc (C/D), reduced rim-to-disc (R/D) ratio, decreased RNFL thickness and decreased FA were observed. While IOP remained elevated during the course of the study, brimonidine tended to delay the progression of RNFL thinning. However, in the same animal, optic nerve FA did not appear to decline. Brimonidine treatment did not affect other measures of RGC axonal degeneration. The current findings demonstrate that early progression of optic neuropathy can be tracked over time in a nonhuman primate model of ocular hypertension using either DTI or SD-OCT. Furthermore, the delayed changes to RNFL thickness and FA appear to be a neuroprotective effect of brimonidine independent of its effect on IOP.
早期发现视神经病变对于启动能够延缓或预防视野丧失的治疗至关重要。临床前研究已经提出了许多潜在的神经保护策略来预防视网膜神经节细胞（RGC）变性，但尚无一项成功完成临床试验。与临床前到临床转化缺乏相关的一个问题是缺乏可用于在同一动物体内随时间跟踪神经保护以及神经变性的临床前形态学评估。因此，为了评估临床使用的形态学评估是否能够识别RGC的神经保护作用，本研究比较了通过扩散张量成像（DTI）获得的视神经分数各向异性（FA）和通过光谱域光学相干断层扫描（SD-OCT）测量的视网膜神经纤维层（RNFL）厚度，以不仅观察RGC轴突变性的早期进展，而且辨别哪种成像方式能够识别在用α-肾上腺素能受体激动剂溴莫尼定治疗期间的神经保护迹象。在非人类灵长类动物（NHP）的一只眼睛中，对小梁网进行激光光凝后观察到眼内压（IOP）升高并持续存在。每天两次滴注溴莫尼定（0.1%）或对照治疗，持续两个月。在接受对照治疗的眼睛中，观察到IOP升高、垂直杯盘比（C/D）增加、盘缘与盘径比（R/D）降低、RNFL厚度降低和FA降低。虽然在研究过程中IOP仍然升高，但溴莫尼定倾向于延缓RNFL变薄的进展。然而，在同一动物中，视神经FA似乎并未下降。溴莫尼定治疗并未影响RGC轴突变性的其他指标。目前的研究结果表明，使用DTI或SD-OCT可以在高眼压的非人类灵长类动物模型中随时间跟踪视神经病变的早期进展。此外，RNFL厚度和FA的延迟变化似乎是溴莫尼定的神经保护作用，与其对IOP的作用无关。
