锂的药理学和毒理学的新进展：神经生物学导向的概述。
New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview.
机构信息
Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain (A.B.); Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain (A.B., G.F., E.V.); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain (A.B., G.F., E.V.); Hospital Clinic, Institute of Neuroscience, University of Barcelona, Barcelona, Spain (G.F., E.V.); IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Victoria, Australia (M.B., A.F.C.); Department of Psychiatry, University of Ottawa, Ontario, Canada (M.S.); The Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa Hospital, Ontario, Canada (M.S.); Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany (M.S.); Section of Psychiatry, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Naples, Italy (M.F.); Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UT Health), Houston, Texas (J.Q.); Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.); Copenhagen Affective Disorders Research Centre (CADIC), Psychiatric Center Copenhagen, Rigshospitalet, Denmark (L.V.K.); and Department of Clinical Medicine, University of Copenhagen, Denmark (L.V.K.).
Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain (A.B.); Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain (A.B., G.F., E.V.); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain (A.B., G.F., E.V.); Hospital Clinic, Institute of Neuroscience, University of Barcelona, Barcelona, Spain (G.F., E.V.); IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Victoria, Australia (M.B., A.F.C.); Department of Psychiatry, University of Ottawa, Ontario, Canada (M.S.); The Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa Hospital, Ontario, Canada (M.S.); Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany (M.S.); Section of Psychiatry, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Naples, Italy (M.F.); Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UT Health), Houston, Texas (J.Q.); Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.); Copenhagen Affective Disorders Research Centre (CADIC), Psychiatric Center Copenhagen, Rigshospitalet, Denmark (L.V.K.); and Department of Clinical Medicine, University of Copenhagen, Denmark (L.V.K.)
出版信息
Pharmacol Rev. 2024 May 2;76(3):323-357. doi: 10.1124/pharmrev.120.000007.
Over the last six decades, lithium has been considered the gold standard treatment for the long-term management of bipolar disorder due to its efficacy in preventing both manic and depressive episodes as well as suicidal behaviors. Nevertheless, despite numerous observed effects on various cellular pathways and biologic systems, the precise mechanism through which lithium stabilizes mood remains elusive. Furthermore, there is recent support for the therapeutic potential of lithium in other brain diseases. This review offers a comprehensive examination of contemporary understanding and predominant theories concerning the diverse mechanisms underlying lithium's effects. These findings are based on investigations utilizing cellular and animal models of neurodegenerative and psychiatric disorders. Recent studies have provided additional support for the significance of glycogen synthase kinase-3 (GSK3) inhibition as a crucial mechanism. Furthermore, research has shed more light on the interconnections between GSK3-mediated neuroprotective, antioxidant, and neuroplasticity processes. Moreover, recent advancements in animal and human models have provided valuable insights into how lithium-induced modifications at the homeostatic synaptic plasticity level may play a pivotal role in its clinical effectiveness. We focused on findings from translational studies suggesting that lithium may interface with microRNA expression. Finally, we are exploring the repurposing potential of lithium beyond bipolar disorder. These recent findings on the therapeutic mechanisms of lithium have provided important clues toward developing predictive models of response to lithium treatment and identifying new biologic targets. SIGNIFICANCE STATEMENT: Lithium is the drug of choice for the treatment of bipolar disorder, but its mechanism of action in stabilizing mood remains elusive. This review presents the latest evidence on lithium's various mechanisms of action. Recent evidence has strengthened glycogen synthase kinase-3 (GSK3) inhibition, changes at the level of homeostatic synaptic plasticity, and regulation of microRNA expression as key mechanisms, providing an intriguing perspective that may help bridge the mechanistic gap between molecular functions and its clinical efficacy as a mood stabilizer.
在过去的六十年中，由于锂在预防躁狂和抑郁发作以及自杀行为方面的疗效，它一直被认为是双相情感障碍长期管理的金标准治疗方法。然而，尽管锂对各种细胞途径和生物系统有许多观察到的影响，但锂稳定情绪的确切机制仍然难以捉摸。此外，最近有研究支持锂在其他脑部疾病中的治疗潜力。
这篇综述全面考察了当代对锂作用的不同机制的理解和主要理论。这些发现基于利用神经退行性和精神疾病的细胞和动物模型进行的研究。最近的研究为糖原合酶激酶-3（GSK3）抑制作为一个关键机制提供了额外的支持。此外，研究还揭示了 GSK3 介导的神经保护、抗氧化和神经可塑性过程之间的相互联系。
此外，最近在动物和人类模型中的进展提供了宝贵的见解，了解锂诱导的在稳态突触可塑性水平的改变如何在其临床疗效中发挥关键作用。我们专注于提示锂可能与 microRNA 表达相互作用的转化研究结果。最后，我们正在探索锂在双相情感障碍以外的重新定位潜力。
这些关于锂治疗机制的最新发现为开发预测对锂治疗反应的模型和确定新的生物学靶点提供了重要线索。
意义
锂是治疗双相情感障碍的首选药物，但它稳定情绪的作用机制仍难以捉摸。
这篇综述介绍了锂的各种作用机制的最新证据。
最近的证据加强了糖原合酶激酶-3（GSK3）抑制、稳态突触可塑性水平的变化以及 microRNA 表达的调节作为关键机制，为可能有助于弥合分子功能与其作为情绪稳定剂的临床疗效之间的机制差距提供了一个有趣的视角。
Zotero 插件