一种p75神经营养素受体稀释神经生长因子通过靶向小胶质细胞保护视网膜神经节细胞免于神经退化

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Laura Latini, Daniel Souza Monteiro De Araujo, Rosario Amato, Alessio Canovai, Lucia Buccarello, Francesco De Logu, Elena Novelli, Anastasiia Vlasiuk, Francesca Malerba, Ivan Arisi, Rita Florio, Hiroki Asari, Simona Capsoni, Enrica Strettoi, Gino Villetti, Bruno Pietro Imbimbo, Massimo Dal Monte, Romina Nassini, Pierangelo Geppetti, Silvia Marinelli, Antonino Cattaneo
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引用次数: 0

摘要

背景和目的视网膜神经节细胞(RGC)通过轴突形成视神经(ON),是视网膜信息处理的输出阶段。视神经轴突受损会导致轴突变性和 RGC 死亡,从而导致视力受损。神经生长因子(NGF)信号对 RGC 的运行和视觉功能至关重要。实验方法新生大鼠和成年大鼠,无论是否发生视网膜损伤,均接受含有 hNGFp 或 hNGFwt 的玻璃体内注射或滴眼液治疗。在损伤后第1天、第4天或第7天给予不同剂量的药物,最长持续10天,然后进行免疫荧光、电生理学、细胞形态学、细胞因子阵列和行为研究。结果hNGFp通过作用于小胶质细胞对RGC神经起到了有效的保护作用,在挽救RGC变性和减少炎症分子方面优于hNGFwt。与使用 hNGFwt 治疗相比,在 ON 病变后延迟使用 hNGFp 可获得更好的疗效。此外,基于 hNGFp 的滴眼液比 hNGFwt 的致藻性更低。结论与启示我们的数据表明,小胶质细胞是一个新的细胞靶点,NGF诱导的TrkA信号可通过它对RGC发挥神经保护作用,这强调了hNGFp是一种治疗视网膜变性的有效药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A p75 neurotrophin receptor-sparing nerve growth factor protects retinal ganglion cells from neurodegeneration by targeting microglia

A p75 neurotrophin receptor-sparing nerve growth factor protects retinal ganglion cells from neurodegeneration by targeting microglia

Background and Purpose

Retinal ganglion cells (RGCs) are the output stage of retinal information processing, via their axons forming the optic nerve (ON). ON damage leads to axonal degeneration and death of RGCs, and results in vision impairment. Nerve growth factor (NGF) signalling is crucial for RGC operations and visual functions. Here, we investigate a new neuroprotective mechanism of a novel therapeutic candidate, a p75-less, TrkA-biased NGF agonist (hNGFp) in rat RGC degeneration, in comparison with wild type human NGF (hNGFwt).

Experimental Approach

Both neonate and adult rats, whether subjected or not to ON lesion, were treated with intravitreal injections or eye drops containing either hNGFp or hNGFwt. Different doses of the drugs were administered at days 1, 4 or 7 after injury for a maximum of 10 days, when immunofluorescence, electrophysiology, cellular morphology, cytokine array and behaviour studies were carried out. Pharmacokinetic evaluation was performed on rabbits treated with hNGFp ocular drops.

Results

hNGFp exerted a potent RGC neuroprotection by acting on microglia cells, and outperformed hNGFwt in rescuing RGC degeneration and reducing inflammatory molecules. Delayed use of hNGFp after ON lesion resulted in better outcomes compared with treatment with hNGFwt. Moreover, hNGFp-based ocular drops were less algogenic than hNGFwt. Pharmacokinetic measurements revealed that biologically relevant quantities of hNGFp were found in the rabbit retina.

Conclusions and Implications

Our data point to microglia as a new cell target through which NGF-induced TrkA signalling exerts neuroprotection of the RGC, emphasizing hNGFp as a powerful treatment to tackle retinal degeneration.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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