Goralczyk R, Buser S, Bausch J, Bee W, Zühlke U, Barker F M
Department of Exploratory Research, F. Hoffmann-La Roche AG, Basel, Switzerland.
Invest Ophthalmol Vis Sci. 1997 Mar;38(3):741-52.
To reproduce and investigate in a primate animal model the phenomenon of the red carotenoid canthaxanthin (beta, beta-carotene-4'4'-dione) to induce crystal-like retinal deposits as they have been observed in the ocular fundus of humans after high canthaxanthin intake (i.e., more than 30 mg/day).
Groups of four cynomolgus monkeys (Macaca fascicularis) per gender and dose were administered 5.4, 16.2, or 48.6 mg canthaxanthin/kg body weight daily by oral gavage for 2.5 years. Eight control animals received placebo. In vivo ophthalmoscopy was performed at intervals of 3 months along with electroretinography after 12 and 24 months and retinal biomicroscopy just before the monkeys were killed. Retinal wholemounts or frozen sections were investigated postmortem by polarization, bright field, and differential interference contrast microscopy. Retinal and preterminal plasma canthaxanthin concentrations were determined by high-performance liquid chromatography (HPLC).
By ophthalmoscopy and retinal biomicroscopy in vivo, no crystals or other light-reflecting particles were observed in the central paramacular retina. However, postmortem polarization microscopy of all 24 canthaxanthin-treated animals showed a circular zone in the peripheral retina containing birefringent, polymorphous red, orange, or white inclusions. The density of these inclusions was diminished within 1 to 8 mm posterior to the ora serrata. These inclusions were located mainly in the inner retinal layers, that is the nerve fiber layer and ganglion cell layer, inner plexiform layer, and inner nuclear layer. Twelve of the 24 canthaxanthin-treated animals showed yellow, golden birefringent inclusions in the macula. Retinas of placebo-treated monkeys were free of birefringent, crystal-like inclusions. The HPLC confirmed the presence of all-trans canthaxanthin, and 4-OH-echinenone and isozeaxanthin as well, in the retinas of all canthaxanthin-treated animals. Neither electroretinography nor histopathology indicated any adverse effects of the canthaxanthin-induced retinal inclusions seen in this study.
A high intake of canthaxanthin for 2.5 years led to the deposition of crystal-like birefringent inclusions in the inner layers of the peripheral retina and, to some extent, the central retina of cynomolgus monkeys. The presence of these deposits did not interfere with morphology nor with retinal function.
在灵长类动物模型中重现并研究红色类胡萝卜素角黄素（β,β - 胡萝卜素 - 4'4'- 二酮）诱导晶状体样视网膜沉积物的现象，这种现象已在人类高剂量摄入角黄素（即每天超过30毫克）后的眼底观察到。
按性别和剂量分组，每组4只食蟹猴（猕猴），通过口服灌胃每天给予5.4、16.2或48.6毫克/千克体重的角黄素，持续2.5年。8只对照动物接受安慰剂。每隔3个月进行一次活体眼底镜检查，在12个月和24个月后进行视网膜电图检查，并在处死猴子前进行视网膜生物显微镜检查。死后通过偏光、明场和微分干涉对比显微镜对视网膜整装片或冰冻切片进行研究。通过高效液相色谱法（HPLC）测定视网膜和终末前血浆中的角黄素浓度。
通过活体眼底镜检查和视网膜生物显微镜检查，在黄斑旁中央视网膜未观察到晶体或其他反光颗粒。然而，对所有24只接受角黄素治疗的动物进行死后偏光显微镜检查发现，周边视网膜有一个圆形区域，含有双折射、多形的红色、橙色或白色内含物。这些内含物的密度在锯齿缘后方1至8毫米范围内降低。这些内含物主要位于视网膜内层，即神经纤维层和神经节细胞层、内网状层和内核层。24只接受角黄素治疗的动物中有12只在黄斑区出现黄色、金色双折射内含物。接受安慰剂治疗的猴子视网膜没有双折射、晶体样内含物。HPLC证实所有接受角黄素治疗的动物视网膜中均存在全反式角黄素、4 - 羟基海胆烯酮和异玉米黄质。本研究中观察到的角黄素诱导的视网膜内含物，无论是视网膜电图还是组织病理学检查均未显示任何不良反应。
高剂量摄入角黄素2.5年导致食蟹猴周边视网膜内层以及在一定程度上中央视网膜出现晶体样双折射内含物沉积。这些沉积物的存在并未干扰形态学或视网膜功能。
