Systems pharmacology demonstrates broad-spectrum efficacy in animal models of retinopathies

IF 3 3区医学 Q1 OPHTHALMOLOGY

Acta Ophthalmologica Pub Date : 2025-01-19 DOI:10.1111/aos.16935

Henri Leinonen, Katri Vainionpää, Ahmed Montaser, Umair Seemab, Jianye Zhang, Laurence Occelli, Alexander Kolesnikov, Vladimir Kefalov, Philip Kiser, Marcin Tabaka, Simon Petersen-Jones, Krzysztof Palczewski

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引用次数: 0

Abstract

Aims/Purpose: Excessive levels of the intracellular second messengers Ca²⁺ and cAMP have been linked with photoreceptor cell death during retinal degeneration (RD). We investigated if a combination (TMB) of common clinical drugs; tamsulosin and metoprolol (alpha- and beta-adrenergic antagonists, Gq- and Gs-coupled, respectively), and bromocriptine (a D2-like dopamine-receptor agonist, Gi-coupled), that inhibit intracellular Ca²⁺ and cAMP signaling could be repurposed to mitigate RD.

Methods: Drug efficacy was tested in four distinct RD models: rd10, P23H, and Rpe65^−/− mice; and PDE6A^−/− dogs. The duration of the drug trials ranged from 1-wk to 7-months. Drug serum levels were measured by liquid chromatography-mass spectrometry (LC-MS). We used primarily photopic and scotopic electroretinography (ERG) and optical coherence tomography (OCT) to assess drug efficacy. Molecular biology methods such as immunohistochemistry, immunoblotting, and RNA-sequencing (bulk and single cell) were used to document therapeutic mechanisms, as well as to confirm therapeutic effects.

Results: Dietary TMB improved cone function and slowed cone degeneration in P23H mice. In rd10 mice, both rod and cone function were significantly improved by TMB; and cone degeneration was significantly slowed. In dark-reared rd10 mice, the drug efficacy was associated with decreased lipid peroxidation preceding the onset of cone degeneration. Dietary TMB improved retinal function and optomotor responses in Rpe65^−/− mice but did not halt rod or cone degeneration. Seven-month-long subcutaneous sustained infusion of TMB into PDE6A^−/− dogs led to higher cone counts at the end of the trial. TMB mitigated forskolin-induced cAMP activity in an ex vivo retina preparation.

Conclusions: Our results suggest that simultaneous inhibition of Gs- and Gq-coupled receptors and activation of Gi-coupled receptors by a combination of existing drugs is a viable therapeutic strategy for RD.

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系统药理学证明了视网膜病变动物模型的广谱疗效

目的/目的：细胞内第二信使Ca2+和cAMP水平过高与视网膜变性（RD）期间的光感受器细胞死亡有关。我们调查了临床常用药物的联合用药（TMB）；坦索罗辛和美托洛尔（α -和β -肾上腺素能拮抗剂，分别为Gq和gs偶联），溴啡亭（d2样多巴胺受体激动剂，gi偶联），抑制细胞内Ca2+和cAMP信号，可以重新用于减轻RD。方法：在四种不同的RD模型中测试药物疗效：rd10， P23H和Rpe65 - / -小鼠；PDE6A−/−狗。药物试验的持续时间从1周到7个月不等。采用液相色谱-质谱法（LC-MS）测定血清药物水平。我们主要使用光位和暗位视网膜电图（ERG）和光学相干断层扫描（OCT）来评估药物疗效。分子生物学方法，如免疫组织化学、免疫印迹和rna测序（散装和单细胞）被用来记录治疗机制，并确认治疗效果。结果：TMB可改善P23H小鼠的锥体功能，减缓锥体变性。在rd10小鼠中，TMB显著改善了视杆和视锥功能；锥体变性明显减慢。在黑暗饲养的rd10小鼠中，药物功效与锥体变性发生前脂质过氧化降低有关。饮食中的TMB改善了Rpe65 - / -小鼠的视网膜功能和视运动反应，但没有阻止杆状或锥体变性。PDE6A - / -犬皮下持续输注TMB 7个月后，试验结束时锥体计数较高。TMB在离体视网膜制剂中减轻了福斯克林诱导的cAMP活性。结论：我们的研究结果表明，联合现有药物同时抑制g -和gq偶联受体和激活gi偶联受体是一种可行的治疗RD的策略。

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来源期刊

Acta Ophthalmologica 医学-眼科学

CiteScore

7.60

自引率

5.90%

发文量

433

审稿时长

6 months

期刊介绍： Acta Ophthalmologica is published on behalf of the Acta Ophthalmologica Scandinavica Foundation and is the official scientific publication of the following societies: The Danish Ophthalmological Society, The Finnish Ophthalmological Society, The Icelandic Ophthalmological Society, The Norwegian Ophthalmological Society and The Swedish Ophthalmological Society, and also the European Association for Vision and Eye Research (EVER). Acta Ophthalmologica publishes clinical and experimental original articles, reviews, editorials, educational photo essays (Diagnosis and Therapy in Ophthalmology), case reports and case series, letters to the editor and doctoral theses.