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
{"title":"系统药理学证明了视网膜病变动物模型的广谱疗效","authors":"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","doi":"10.1111/aos.16935","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <p><b>Aims/Purpose:</b> Excessive levels of the intracellular second messengers Ca<sup>2+</sup> 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 Ca<sup>2+</sup> and cAMP signaling could be repurposed to mitigate RD.</p>\n \n <p><b>Methods:</b> Drug efficacy was tested in four distinct RD models: rd10, P23H, and <i>Rpe65</i><sup>−<i>/</i>−</sup> mice; and <i>PDE6A</i><sup>−<i>/</i>−</sup> 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.</p>\n \n <p><b>Results:</b> 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 <i>Rpe65</i><sup>−<i>/</i>−</sup> mice but did not halt rod or cone degeneration. Seven-month-long subcutaneous sustained infusion of TMB into <i>PDE6A</i><sup>−<i>/</i>−</sup> dogs led to higher cone counts at the end of the trial. TMB mitigated forskolin-induced cAMP activity in an <i>ex vivo</i> retina preparation.</p>\n \n <p><b>Conclusions:</b> 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.</p>\n </section>\n </div>","PeriodicalId":6915,"journal":{"name":"Acta Ophthalmologica","volume":"103 S284","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/10.1111/aos.16935","citationCount":"0","resultStr":"{\"title\":\"Systems pharmacology demonstrates broad-spectrum efficacy in animal models of retinopathies\",\"authors\":\"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\",\"doi\":\"10.1111/aos.16935\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <p><b>Aims/Purpose:</b> Excessive levels of the intracellular second messengers Ca<sup>2+</sup> 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 Ca<sup>2+</sup> and cAMP signaling could be repurposed to mitigate RD.</p>\\n \\n <p><b>Methods:</b> Drug efficacy was tested in four distinct RD models: rd10, P23H, and <i>Rpe65</i><sup>−<i>/</i>−</sup> mice; and <i>PDE6A</i><sup>−<i>/</i>−</sup> 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.</p>\\n \\n <p><b>Results:</b> 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 <i>Rpe65</i><sup>−<i>/</i>−</sup> mice but did not halt rod or cone degeneration. Seven-month-long subcutaneous sustained infusion of TMB into <i>PDE6A</i><sup>−<i>/</i>−</sup> dogs led to higher cone counts at the end of the trial. TMB mitigated forskolin-induced cAMP activity in an <i>ex vivo</i> retina preparation.</p>\\n \\n <p><b>Conclusions:</b> 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.</p>\\n </section>\\n </div>\",\"PeriodicalId\":6915,\"journal\":{\"name\":\"Acta Ophthalmologica\",\"volume\":\"103 S284\",\"pages\":\"\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2025-01-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/10.1111/aos.16935\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta Ophthalmologica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/aos.16935\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Ophthalmologica","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/aos.16935","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
Systems pharmacology demonstrates broad-spectrum efficacy in animal models of retinopathies
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.
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.
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