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一种脑源性神经营养因子模拟物足以恢复遗传性失明模型中的视锥光感受器视觉功能。

A Brain-Derived Neurotrophic Factor Mimetic Is Sufficient to Restore Cone Photoreceptor Visual Function in an Inherited Blindness Model.

机构信息

UCD School of Biomolecular & Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

Food for Health Ireland, Science Centre South, University College Dublin, Belfield, Dublin 4, Ireland.

出版信息

Sci Rep. 2017 Sep 12;7(1):11320. doi: 10.1038/s41598-017-11513-5.

DOI:10.1038/s41598-017-11513-5
PMID:28900183
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5595969/
Abstract

Controversially, histone deacetylase inhibitors (HDACi) are in clinical trial for the treatment of inherited retinal degeneration. Utilizing the zebrafish dye model, we determined if treatment with HDACi can rescue cone photoreceptor-mediated visual function. dye exhibit defective visual behaviour and retinal morphology including ciliary marginal zone (CMZ) cell death and decreased photoreceptor outer segment (OS) length, as well as gross morphological defects including hypopigmentation and pericardial oedema. HDACi treatment of dye results in significantly improved optokinetic (OKR) (43 fold, p < 0.001) and visualmotor (VMR) (3 fold, p < 0.05) responses. HDACi treatment rescued gross morphological defects and reduced CMZ cell death by 80%. Proteomic analysis of dye eye extracts suggested BDNF-TrkB and Akt signaling as mediators of HDACi rescue in our dataset. Co-treatment with the TrkB antagonist ANA-12 blocked HDACi rescue of visual function and associated Akt phosphorylation. Notably, sole treatment with a BDNF mimetic, 7,8-dihydroxyflavone hydrate, significantly rescued dye visual function (~58 fold increase in OKR, p < 0.001, ~3 fold increase in VMR, p < 0.05). In summary, HDACi and a BDNF mimetic are sufficient to rescue retinal cell death and visual function in a vertebrate model of inherited blindness.

摘要

有争议的是，组蛋白去乙酰化酶抑制剂（HDACi）正在临床试验中用于治疗遗传性视网膜变性。利用斑马鱼染料模型，我们确定 HDACi 的治疗是否可以挽救锥体细胞介导的视觉功能。染料表现出视觉行为和视网膜形态缺陷，包括纤毛边缘区（CMZ）细胞死亡和光感受器外节（OS）长度减少，以及包括色素减退和心包水肿在内的大体形态缺陷。HDACi 处理染料导致明显改善的视觉运动反应（OKR）（43 倍，p < 0.001）和视觉运动反应（VMR）（3 倍，p < 0.05）。HDACi 处理挽救了大体形态缺陷，并将 CMZ 细胞死亡减少了 80%。染料眼提取物的蛋白质组学分析表明 BDNF-TrkB 和 Akt 信号作为我们数据集 HDACi 挽救的介质。用 TrkB 拮抗剂 ANA-12 共同处理阻断了 HDACi 对视觉功能的挽救以及相关的 Akt 磷酸化。值得注意的是，仅用 BDNF 模拟物 7,8-二羟基黄酮水合物处理，就显著挽救了染料的视觉功能（OKR 增加约 58 倍，p < 0.001，VMR 增加约 3 倍，p < 0.05）。总之，HDACi 和 BDNF 模拟物足以挽救遗传性失明的脊椎动物模型中的视网膜细胞死亡和视觉功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/8ed665f6a21e/41598_2017_11513_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/8ca59339cd4f/41598_2017_11513_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/3cde8eda556f/41598_2017_11513_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/92cb94398910/41598_2017_11513_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/230114e9d930/41598_2017_11513_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/06424d9a1466/41598_2017_11513_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/8ed665f6a21e/41598_2017_11513_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/8ca59339cd4f/41598_2017_11513_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/3cde8eda556f/41598_2017_11513_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/92cb94398910/41598_2017_11513_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/230114e9d930/41598_2017_11513_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/06424d9a1466/41598_2017_11513_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a3/5595969/8ed665f6a21e/41598_2017_11513_Fig6_HTML.jpg

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