IRCCS Santa Lucia Foundation, Preclinical Neuroscience, Via del Fosso di Fiorano 65, 00143 Rome, Italy.
Institute for Systems Analysis and Computer Science "A. Ruberti" (IASI), National Research Council (CNR), Via dei Taurini 19, 00185 Rome, Italy.
Int J Mol Sci. 2022 Jun 6;23(11):6347. doi: 10.3390/ijms23116347.
Multiple sclerosis is an autoimmune disease with a strong neuroinflammatory component that contributes to severe demyelination, neurodegeneration and lesions formation in white and grey matter of the spinal cord and brain. Increasing attention is being paid to the signaling of the biogenic amine histamine in the context of several pathological conditions. In multiple sclerosis, histamine regulates the differentiation of oligodendrocyte precursors, reduces demyelination, and improves the remyelination process. However, the concomitant activation of histamine H1-H4 receptors can sustain either damaging or favorable effects, depending on the specifically activated receptor subtype/s, the timing of receptor engagement, and the central versus peripheral target district. Conventional drug development has failed so far to identify curative drugs for multiple sclerosis, thus causing a severe delay in therapeutic options available to patients. In this perspective, drug repurposing offers an exciting and complementary alternative for rapidly approving some medicines already approved for other indications. In the present work, we have adopted a new network-medicine-based algorithm for drug repurposing called SAveRUNNER, for quantifying the interplay between multiple sclerosis-associated genes and drug targets in the human interactome. We have identified new histamine drug-disease associations and predicted off-label novel use of the histaminergic drugs amodiaquine, rupatadine, and diphenhydramine among others, for multiple sclerosis. Our work suggests that selected histamine-related molecules might get to the root causes of multiple sclerosis and emerge as new potential therapeutic strategies for the disease.
多发性硬化症是一种自身免疫性疾病，具有强烈的神经炎症成分，导致脊髓和大脑的白质和灰质严重脱髓鞘、神经退行性变和损伤形成。人们越来越关注生物胺组胺在几种病理情况下的信号传导。在多发性硬化症中，组胺调节少突胶质前体细胞的分化，减少脱髓鞘，并改善髓鞘再生过程。然而，组胺 H1-H4 受体的同时激活可以维持损害或有利的作用，这取决于具体激活的受体亚型/、受体结合的时间以及中央与外周靶区。迄今为止，传统的药物开发未能确定多发性硬化症的治愈药物，从而导致患者可获得的治疗选择严重延迟。在这种情况下，药物再利用为快速批准一些已经批准用于其他适应症的药物提供了令人兴奋和互补的替代方案。在本工作中，我们采用了一种新的基于网络医学的药物再利用算法称为 SAveRUNNER，用于量化多发性硬化症相关基因和药物靶点在人类相互作用组中的相互作用。我们已经确定了新的组胺药物-疾病关联，并预测了其他组胺能药物如阿莫地喹、鲁帕他定和苯海拉明等的非标签新用途，用于多发性硬化症。我们的工作表明，选定的与组胺相关的分子可能会深入了解多发性硬化症的根本原因，并成为该疾病新的潜在治疗策略。
