Forloni Gianluigi
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Italy.
Biomed Pharmacother. 2025 Jul;188:118159. doi: 10.1016/j.biopha.2025.118159. Epub 2025 May 13.
The identification of active interventions in neurodegenerative disorders is a major challenge in neurology; the use of repurposed drugs may represent a valuable strategy. Tetracyclines, a second generation of antibiotic molecules, offer various potential applications. Following an anecdotal observation of the potential anti-amyloidogenic activity of iododoxorubicin, the search for chemical analogs with a better safety profile led to tetracyclines. Their heterocyclic structures with a planar conformation interfere with b-sheet amyloid formation. Thus, doxycycline, a derivative with favorable blood-brain barrier penetration, emerged as a strong candidate to combat peripheral and central amyloidosis. In particular, we tested the anti-prion activity of doxycycline in vitro and in vivo experiments, confirming its capacity to disrupt or inhibit the formation of prion protein aggregates associated with pathological events. Treatment with doxycycline in human subjects with prion - related encephalopathies yielded contradictory results, suggesting that a preventive approach is a more favorable condition to verify efficacy; a clinical trial involving subjects at genetic risk of developing fatal familial insomnia, exposed to doxycycline for ten years, is currently ongoing. The anti-amyloidogenic capacity of doxycycline, combined with its safety profile in long-term treatment, has suggested its use in peripheral amyloidosis, which was tested with positive results. A specific interaction with β-amyloid or α-synuclein oligomers, as well as tau aggregation has also been demonstrated. More recently, the action of doxycycline has been extended to its anti-inflammatory and antioxidant capacities. In particular, the anti-inflammatory activity of doxycycline may explain the drug 's efficacy in numerous experimental models where protein misfolding has been associated with neuroinflammation, including Huntington's and Parkinson' s diseases. Thus, the pleiotropic action of doxycycline appears to be an interesting tool for addressing progressive neuronal dysfunction in multifactorial neurodegenerative diseases. The application of precision medicine principles to doxycycline treatment represents the best strategy to determine its efficacy. These aspects are illustrated here concerning another pleiotropic tetracycline, minocycline.
确定神经退行性疾病的有效干预措施是神经病学领域的一项重大挑战；使用重新利用的药物可能是一种有价值的策略。四环素是第二代抗生素分子，具有多种潜在应用。在对碘柔比星的潜在抗淀粉样蛋白生成活性进行轶事观察后，对具有更好安全性的化学类似物的研究导致了四环素的发现。它们具有平面构象的杂环结构会干扰β-折叠淀粉样蛋白的形成。因此，强力霉素作为一种具有良好血脑屏障穿透性的衍生物，成为对抗外周和中枢淀粉样变性的有力候选药物。特别是，我们在体外和体内实验中测试了强力霉素的抗朊病毒活性，证实了其破坏或抑制与病理事件相关的朊病毒蛋白聚集体形成的能力。在患有朊病毒相关脑病的人类受试者中使用强力霉素治疗产生了矛盾的结果，这表明预防方法是验证疗效的更有利条件；一项涉及有发展为致命性家族性失眠症遗传风险的受试者、服用强力霉素十年的临床试验目前正在进行。强力霉素的抗淀粉样蛋白生成能力及其在长期治疗中的安全性表明可将其用于外周淀粉样变性，测试结果为阳性。还证明了其与β-淀粉样蛋白或α-突触核蛋白寡聚体以及tau聚集的特异性相互作用。最近，强力霉素的作用已扩展到其抗炎和抗氧化能力。特别是，强力霉素的抗炎活性可能解释了该药物在许多实验模型中的疗效，在这些模型中蛋白质错误折叠与神经炎症有关，包括亨廷顿舞蹈症和帕金森病。因此，强力霉素的多效性作用似乎是解决多因素神经退行性疾病中进行性神经元功能障碍的一个有趣工具。将精准医学原则应用于强力霉素治疗是确定其疗效的最佳策略。本文就另一种多效性四环素——米诺环素阐述了这些方面。
