Rosenberg G
D-Pharm Ltd., Kiryat Weizman Science Park, Bldg. 7, P.O. Box 2313, Rehovot, 76123, Israel.
Cell Mol Life Sci. 2007 Aug;64(16):2090-103. doi: 10.1007/s00018-007-7079-x.
After more than 40 years of clinical use, the mechanisms of action of valproate in epilepsy, bipolar disorder and migraine are still not fully understood. However, recent findings reviewed here shed new light on the cellular effects of valproate. Beyond the enhancement of gamma-aminobutyric acid-mediated neurotransmission, valproate has been found to affect signalling systems like the Wnt/beta-catenin and ERK pathways and to interfere with inositol and arachidonate metabolism. Nevertheless, the clinical relevance of these effects is not always clear. Valproate treatment also produces marked alterations in the expression of multiple genes, many of which are involved in transcription regulation, cell survival, ion homeostasis, cytoskeletal modifications and signal transduction. These alterations may well be relevant to the therapeutic effects of valproate, and result from its enhancement of activator protein-1 DNA binding and direct inhibition of histone deacetylases, and possibly additional, yet unknown, mechanism(s). Most likely, both immediate biochemical and longer-term genomic influences underlie the effects of valproate in all three indications.
在临床应用40多年后，丙戊酸盐在癫痫、双相情感障碍和偏头痛中的作用机制仍未完全明确。然而，本文所综述的近期研究结果为丙戊酸盐的细胞效应带来了新的认识。除增强γ-氨基丁酸介导的神经传递外，还发现丙戊酸盐会影响诸如Wnt/β-连环蛋白和ERK通路等信号系统，并干扰肌醇和花生四烯酸代谢。然而，这些效应的临床相关性并不总是清晰的。丙戊酸盐治疗还会使多个基因的表达发生显著改变，其中许多基因参与转录调控、细胞存活、离子稳态、细胞骨架修饰和信号转导。这些改变很可能与丙戊酸盐的治疗效果相关，是由于其增强了活化蛋白-1与DNA的结合并直接抑制组蛋白脱乙酰酶，以及可能存在的其他未知机制所致。很可能，即时的生化影响和长期的基因组影响共同构成了丙戊酸盐在这三种适应症中的作用基础。
