Department of Food and Drug, University of Parma, Parma, Italy.
Division of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, Federico II University of Naples, Naples, Italy.
J Pineal Res. 2024 Nov;76(8):e70008. doi: 10.1111/jpi.70008.
The identification of protective agents for the treatment of neurodegenerative diseases is the mainstay therapeutic goal to modify the disease course and arrest the irreversible disability progression. Pharmacological therapies synergistically targeting multiple pathogenic pathways, including oxidative stress, mitochondrial dysfunction, and inflammation, are prime candidates for neuroprotection. Combination or synergistic therapy with melatonin, whose decline correlates with altered sleep/wake cycle and impaired glymphatic "waste clearance" system in neurodegenerative diseases, has a great therapeutic potential to treat inflammatory neurodegenerative states. Despite the protective outcomes observed in preclinical studies, mild or poor outcomes were observed in clinical settings, suggesting that melatonin combinations promoting synergistic actions at appropriate doses might be more suitable to treat multifactorial neurodegenerative disorders. In this review, we first summarize the key melatonin actions and pathways contributing to cell protection and its therapeutic implication in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We remark the major controversies in the field, mostly generated by the lack of a common consensus for the optimal dosing, molecular targets, and toxicity. Then, we review the literature investigating the efficacy of melatonin combinations with approved or investigational neuroprotective agents and of melatonin-containing hybrid molecules, both in vitro and in animal models of AD, PD, and MS, as well as the efficacy of add-on melatonin in clinical settings. We highlight the rationale for such melatonin combinations with a focus on the comparison with single-agent treatment and on the assays in which an additive or a synergistic effect has been achieved. We conclude that a better characterization of the mechanisms underlying such melatonin synergistic actions under neuroinflammation at appropriate doses needs to be tackled to advance successful clinical translation of neuroprotective melatonin combination therapies or melatonin-based hybrid molecules.
鉴定神经退行性疾病的保护剂是改变疾病进程和阻止不可逆转的残疾进展的主要治疗目标。协同靶向多种致病途径的药物治疗，包括氧化应激、线粒体功能障碍和炎症，是神经保护的主要候选药物。褪黑素联合或协同治疗，褪黑素的下降与神经退行性疾病中改变的睡眠/觉醒周期和受损的神经胶质“废物清除”系统有关，具有治疗炎症性神经退行性状态的巨大治疗潜力。尽管在临床前研究中观察到了保护作用，但在临床环境中观察到了轻微或较差的结果，这表明促进适当剂量协同作用的褪黑素联合治疗可能更适合治疗多因素神经退行性疾病。在这篇综述中，我们首先总结了褪黑素在细胞保护中的关键作用和途径及其在阿尔茨海默病（AD）、帕金森病（PD）和多发性硬化症（MS）中的治疗意义。我们注意到该领域的主要争议，这些争议主要是由缺乏最佳剂量、分子靶点和毒性的共识引起的。然后，我们综述了褪黑素与已批准或正在研究的神经保护剂联合使用的研究，以及褪黑素与含有批准或正在研究的神经保护剂的化合物的研究，包括在 AD、PD 和 MS 的体外和动物模型中的研究，以及在临床环境中添加褪黑素的研究。我们强调了这种褪黑素联合治疗的基本原理，重点是比较单一药物治疗和达到相加或协同作用的检测。我们得出的结论是，需要更好地研究神经炎症下适当剂量的褪黑素协同作用的机制，以推进神经保护褪黑素联合治疗或基于褪黑素的混合分子的成功临床转化。
