PARP inhibition preserves cone photoreceptors in rd2 retina.

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Pakize Nur Akkaya, María Miranda, Inmaculada Almansa, Cigdem Elmas, Dragana Trifunovic, Zohreh Hosseinzadeh, Ayse Sahaboglu
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Abstract

The rd2 mouse model, characterized by a mutation in the Prph2 gene, exhibits abnormal development of photoreceptor outer segments, resulting in progressive retinal degeneration. While the correlation between poly-ADP-ribose polymerase (PARP) activity and the degeneration of rod photoreceptors is established in the rd2 model, the specific mechanism driving cone degeneration in this model remains unclear. Furthermore, it is yet to be determined whether inhibiting PARP activity can effectively impede the degeneration of cone photoreceptors in this context. We demonstrated that PARP inhibitors Olaparib, BMN-673, and 3-aminobenzamide (3AB), effectively reduced photoreceptor cell loss in the rd2 retina. Notably, rd2 retinas exhibited decreased cone density, but treatment with PARP inhibitors significantly protected cone photoreceptors. The PARP inhibitors, particularly BMN-673, demonstrated a significant protective effect as evidenced by increased rhodopsin expression within the outer segment and a concurrent decrease in Müller cell activity indicated by GFAP expression. The treatment also resulted in significant changes for markers of oxidative stress, such as glutathione (GSH), and oxidized glutathione (GSSG). Notably, the administration of PARP inhibitors also reduced CD9 expression (extracellular vesicle marker), which were significantly increased within the outer nuclear layer (ONL) in the rd2 retinas. Among PARP inhibitors, BMN-673 demonstrated the highest efficacy in preserving photoreceptors, particularly benefiting cone cells.

以 Prph2 基因突变为特征的 rd2 小鼠模型表现出感光器外节发育异常,导致视网膜进行性退化。在 rd2 模型中,多聚 ADP 核糖聚合酶(PARP)活性与杆状光感受器退化之间的相关性已经确定,但该模型中锥体退化的具体驱动机制仍不清楚。此外,在这种情况下,抑制 PARP 活性是否能有效阻止锥体光感受器的退化也有待确定。我们证实,PARP抑制剂奥拉帕利(Olaparib)、BMN-673和3-氨基苯甲酰胺(3AB)能有效减少rd2视网膜中感光细胞的丢失。值得注意的是,rd2视网膜的视锥密度降低,但PARP抑制剂能显著保护视锥光感受器。PARP抑制剂,尤其是BMN-673,表现出明显的保护作用,外节段内的视紫红质表达增加,同时Müller细胞活性降低,GFAP表达显示了这一点。治疗还导致谷胱甘肽(GSH)和氧化谷胱甘肽(GSSG)等氧化应激标志物发生明显变化。值得注意的是,PARP 抑制剂还能降低 CD9(细胞外囊泡标记物)的表达,而 CD9 在 rd2 视网膜核外层(ONL)中的表达明显增加。在 PARP 抑制剂中,BMN-673 在保护感光细胞方面的疗效最高,尤其有利于视锥细胞。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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