MPTP 帕金森病小鼠模型中视网膜功能和结构的特征。
Characterization of retinal function and structure in the MPTP murine model of Parkinson's disease.
机构信息
Ocular Biomarkers Laboratory, Department of Optometry and Vision Sciences, University of Melbourne, Parkville, VIC, 3010, Australia.
Caring Futures Institute, College of Nursing and Health Sciences, Flinders University, Bedford Park, SA, 5042, Australia.
出版信息
Sci Rep. 2022 May 9;12(1):7610. doi: 10.1038/s41598-022-11495-z.
In addition to well characterized motor symptoms, visual disturbances are increasingly recognized as an early manifestation in Parkinson's disease (PD). A better understanding of the mechanisms underlying these changes would facilitate the development of vision tests which can be used as preclinical biomarkers to support the development of novel therapeutics for PD. This study aims to characterize the retinal phenotype of a mouse model of dopaminergic dysfunction and to examine whether these changes are reversible with levodopa treatment. We use a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD to characterize the neurotoxic effects of MPTP on in vivo retinal function (electroretinography, ERG), retinal structure (optical coherence tomography, OCT) and retinal dopaminergic cell number (tyrosine hydroxylase immunohistochemistry, IHC) at two time points (21 and 45 days) post MPTP model induction. We also investigate the effect of levodopa (L-DOPA) as a proof-of-principle chronic intervention against MPTP-induced changes in the retina. We show that MPTP decreases dopaminergic amacrine cell number (9%, p < 0.05) and that a component of the ERG that involves these cells, in particular oscillatory potential (OP) peak timing, was significantly delayed at Day 45 (7-13%, p < 0.01). This functional deficit was paralleled by outer plexiform layer (OPL) thinning (p < 0.05). L-DOPA treatment ameliorated oscillatory potential deficits (7-13%, p < 0.001) in MPTP animals. Our data suggest that the MPTP toxin slows the timing of inner retinal feedback circuits related to retinal dopaminergic pathways which mirrors findings from humans with PD. It also indicates that the MPTP model causes structural thinning of the outer retinal layer on OCT imaging that is not ameliorated with L-DOPA treatment. Together, these non-invasive measures serve as effective biomarkers for PD diagnosis as well as for quantifying the effect of therapy.
除了特征明显的运动症状外，视觉障碍也越来越被认为是帕金森病（PD）的早期表现。更好地了解这些变化的机制将有助于开发可以作为临床前生物标志物的视力测试，以支持开发治疗 PD 的新疗法。本研究旨在描述多巴胺能功能障碍的小鼠模型的视网膜表型，并研究这些变化是否可以通过左旋多巴治疗逆转。我们使用 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）PD 小鼠模型来描述 MPTP 对体内视网膜功能（视网膜电图，ERG）、视网膜结构（光学相干断层扫描，OCT）和视网膜多巴胺能细胞数量（酪氨酸羟化酶免疫组织化学，IHC）的神经毒性作用在 MPTP 模型诱导后两个时间点（21 和 45 天）。我们还研究了左旋多巴（L-DOPA）作为对抗 MPTP 诱导的视网膜变化的慢性干预的初步原理的效果。我们表明，MPTP 减少多巴胺能无长突细胞数量（9%，p<0.05），并且涉及这些细胞的 ERG 的一个成分，特别是振荡电位（OP）峰值时间，在第 45 天（7-13%，p<0.01）显著延迟。这种功能缺陷与外丛状层（OPL）变薄（p<0.05）平行。L-DOPA 治疗改善了 MPTP 动物的振荡电位缺陷（7-13%，p<0.001）。我们的数据表明，MPTP 毒素会减慢与视网膜多巴胺能途径相关的内视网膜反馈回路的定时，这与 PD 患者的发现相吻合。它还表明，MPTP 模型在外视网膜 OCT 成像上引起的结构变薄，而 L-DOPA 治疗并不能改善。这些非侵入性措施共同作为 PD 诊断的有效生物标志物，以及用于量化治疗效果的生物标志物。
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