Kampasis Dionysis, Uliassi Elisa, Bolognesi Maria Laura
Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna 40126 Bologna, Italy.
Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna 40126 Bologna, Italy.
Adv Drug Deliv Rev. 2025 Aug;223:115621. doi: 10.1016/j.addr.2025.115621. Epub 2025 May 28.
Circadian rhythm disruption (CRD) is a common feature of several brain disorders. The restoration of circadian clock function and the development of circadian-based therapies may have significant therapeutic implications for brain diseases that extend beyond sleep disorders. However, several challenges persist due to the complexity of circadian interactions with multiple cellular pathways underlying CRD in brain diseases, together with the CNS compartmentalization, including the presence of the blood-brain barrier (BBB). Against these drawbacks, polypharmacology is a promising strategy to potentially provide greater efficacy by targeting multiple components of the CRD network through drug combinations or multi-target-directed ligands. Polypharmacology also offers innovative approaches to brain drug delivery by enhancing BBB penetration of CNS-directed drugs using combinations, co-drugs, and targeted prodrugs. Herein, we review polypharmacological strategies to improve BBB permeability of CNS agents and suggest the exploitation of polypharmacology as a promising new avenue for circadian clock modulation in the treatment of brain disorders.
昼夜节律紊乱（CRD）是几种脑部疾病的常见特征。恢复昼夜节律功能以及开发基于昼夜节律的疗法可能对脑部疾病具有重大治疗意义，其影响范围超出睡眠障碍。然而，由于昼夜节律与脑部疾病中CRD潜在的多种细胞途径相互作用的复杂性，以及中枢神经系统的分区化，包括血脑屏障（BBB）的存在，仍存在一些挑战。针对这些缺点，多药理学是一种有前景的策略，通过药物组合或多靶点导向配体靶向CRD网络的多个成分，有可能提供更高的疗效。多药理学还通过使用组合药物、共药物和靶向前药增强中枢神经系统导向药物的血脑屏障穿透性，为脑部药物递送提供了创新方法。在此，我们综述了提高中枢神经系统药物血脑屏障通透性的多药理学策略，并建议将多药理学作为治疗脑部疾病中昼夜节律调节的一种有前景的新途径加以利用。
