Department of Biology, University of Bologna, Bologna, Italy.
Curr Mol Pharmacol. 2009 Jan;2(1):95-109. doi: 10.2174/1874467210902010095.
Valproic acid (VPA, 2-propylpentanoic acid) has been widely used as an antiepileptic drug and for the therapy of bipolar disorders for several years. Its mechanism of action was initially found to be primarily related to neurotransmission and modulation of intracellular pathways. More recently, it emerged as an anti-neoplastic agent as well, by acting on cell growth, differentiation and apoptosis. Here, it mainly exerts its effect by regulating gene expression at the molecular level, through epigenetic mechanisms. In particular, it has been demonstrated the effect of VPA in chromatin remodeling, as VPA directly inhibits histone deacetylases (HDACs) activity. Interestingly, it has been observed that these biochemical and molecular pathways are involved not only in beneficial effect of VPA against epilepsy and malignancies, but they are also responsible for more general neuroprotective mechanisms. In particular, it has been demonstrated that VPA is neuroprotective in several models of neurodegenerative diseases. Moreover, due to the involvement of the VPA-affected mechanisms in complex behaviors, VPA is increasingly used as a psychotherapeutic agent. This review summarizes the more recent data on VPA neuroprotective mechanisms at the biochemical, molecular and epigenetic levels, focusing on both in vitro and in vivo models of neurodegenerative diseases. In particular, attention is paid to mechanisms by which VPA affects neuronal survival/apoptosis and proliferation/differentiation balance, as well as synaptic plasticity, by acting both directly on neurons and indirectly through glial cells. Perspective applications of the VPA neuroprotective potential in human neurodegenerative diseases are discussed, when relevant.
丙戊酸（VPA，2-丙基戊酸）已被广泛用作抗癫痫药物和双相情感障碍的治疗药物多年。其作用机制最初主要与神经递质传递和细胞内途径的调节有关。最近，它也被发现是一种抗肿瘤药物，通过作用于细胞生长、分化和凋亡。在这里，它主要通过在分子水平上调节基因表达来发挥作用，通过表观遗传机制。特别是，已经证明 VPA 在染色质重塑中的作用，因为 VPA 直接抑制组蛋白去乙酰化酶（HDACs）的活性。有趣的是，人们观察到这些生化和分子途径不仅参与了 VPA 对癫痫和恶性肿瘤的有益作用，而且还负责更普遍的神经保护机制。特别是，已经证明 VPA 在几种神经退行性疾病模型中具有神经保护作用。此外，由于 VPA 影响的机制涉及复杂的行为，VPA 越来越多地被用作精神治疗剂。本综述总结了 VPA 在神经保护方面的生化、分子和表观遗传水平上的最新数据，重点介绍了神经退行性疾病的体外和体内模型。特别关注 VPA 通过直接作用于神经元和间接作用于神经胶质细胞来影响神经元存活/凋亡和增殖/分化平衡以及突触可塑性的机制。当涉及到人类神经退行性疾病时，讨论了 VPA 神经保护潜力的潜在应用。
