Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9-20133 Milano, Italy.
Expert Opin Investig Drugs. 2013 Feb;22(2):217-33. doi: 10.1517/13543784.2013.749237. Epub 2012 Dec 19.
Mood and anxiety disorders are among the major causes of disability worldwide. Despite clear need for better therapies, efforts to develop novel drugs have been relatively unsuccessful. One major reason is lack of translation into neuropsychopharmacology of the impressive recent array of knowledge accrued by clinical and preclinical researches on the brain. Here focus is on epigenetics mechanisms, including microRNAs, which seem particularly promising for the identification of new targets for alternative pharmacological approaches.
First, the current knowledge about epigenetic mechanisms, including DNA methylation, posttranslational modification of histone proteins, focusing on histone methylation and acetylation, and posttranscriptional modulation of gene expression by microRNAs is described. Then evidence showing involvement of epigenetics and microRNAs in the pathophysiology of mood and anxiety disorders as well as evidence showing that some of the currently employed antidepressants and mood stabilizers also affect epigenetic and microRNA mechanisms are reviewed. Finally current evidence and novel approaches in favor of drugs regulating epigenetic and microRNA mechanisms as potential therapeutics for these disorders are discussed.
Although still in its infancy, research investigating the effects of pharmacological modulation of epigenetic and microRNA mechanisms in neuropsychiatric disorders continues to provide encouraging findings, suggesting new avenues for treatment of mood and anxiety disorders.
情绪和焦虑障碍是全球范围内导致残疾的主要原因之一。尽管迫切需要更好的治疗方法,但开发新型药物的努力相对来说并不成功。一个主要原因是,临床和临床前研究在大脑方面取得的大量令人印象深刻的新知识,未能很好地转化为神经精神药理学。这里关注的是表观遗传学机制,包括 microRNAs,它们似乎特别有希望为替代药物治疗方法确定新的靶点。
首先,描述了包括 DNA 甲基化、组蛋白蛋白的翻译后修饰(重点是组蛋白甲基化和乙酰化)以及 microRNAs 对基因表达的转录后调节在内的表观遗传学机制的当前知识。然后,综述了表观遗传学和 microRNAs 参与情绪和焦虑障碍的病理生理学的证据,以及一些目前使用的抗抑郁药和心境稳定剂也影响表观遗传学和 microRNA 机制的证据。最后,讨论了目前有利于调节表观遗传学和 microRNA 机制的药物的证据和新方法,这些药物可能是这些疾病的潜在治疗方法。
尽管仍处于起步阶段,但研究药物调节神经精神疾病中的表观遗传学和 microRNA 机制的效果仍在继续提供令人鼓舞的发现,为治疗情绪和焦虑障碍提供了新的途径。