Neurology Clinic, University of Perugia - S. Maria della Misericordia Hospital, Perugia, Italy.
Pediatric Clinic, University of Perugia - S. Maria della Misericordia Hospital, Perugia, Italy.
Curr Neuropharmacol. 2019;17(10):926-946. doi: 10.2174/1570159X17666181227165722.
After more than a century from its discovery, valproic acid (VPA) still represents one of the most efficient antiepileptic drugs (AEDs). Pre and post-synaptic effects of VPA depend on a very broad spectrum of actions, including the regulation of ionic currents and the facilitation of GABAergic over glutamatergic transmission. As a result, VPA indirectly modulates neurotransmitter release and strengthens the threshold for seizure activity. However, even though participating to the anticonvulsant action, such mechanisms seem to have minor impact on epileptogenesis. Nonetheless, VPA has been reported to exert anti-epileptogenic effects. Epigenetic mechanisms, including histone deacetylases (HDACs), BDNF and GDNF modulation are pivotal to orientate neurons toward a neuroprotective status and promote dendritic spines organization. From such broad spectrum of actions comes constantly enlarging indications for VPA. It represents a drug of choice in child and adult with epilepsy, with either general or focal seizures, and is a consistent and safe IV option in generalized convulsive status epilepticus. Moreover, since VPA modulates DNA transcription through HDACs, recent evidences point to its use as an anti-nociceptive in migraine prophylaxis, and, even more interestingly, as a positive modulator of chemotherapy in cancer treatment. Furthermore, VPA-induced neuroprotection is under investigation for benefit in stroke and traumatic brain injury. Hence, VPA has still got its place in epilepsy, and yet deserves attention for its use far beyond neurological diseases. In this review, we aim to highlight, with a translational intent, the molecular basis and the clinical indications of VPA.
从发现至今已有一个多世纪，丙戊酸（VPA）仍然是最有效的抗癫痫药物（AEDs）之一。VPA 的前突触和后突触效应取决于非常广泛的作用，包括调节离子电流和促进 GABA 能传递超过谷氨酸能传递。因此，VPA 间接调节神经递质释放并增强癫痫发作活动的阈值。然而，尽管参与抗惊厥作用，但这些机制似乎对癫痫发生的影响较小。尽管如此，已有报道称 VPA 具有抗癫痫发生作用。表观遗传机制，包括组蛋白去乙酰化酶（HDACs）、BDNF 和 GDNF 调节，对于将神经元定向到神经保护状态并促进树突棘组织具有重要作用。VPA 的广泛作用不断扩大其适应症。它是儿童和成人癫痫患者的首选药物，无论是全身性还是局灶性癫痫发作，并且是全身性惊厥性癫痫持续状态的一致和安全的 IV 选择。此外，由于 VPA 通过 HDACs 调节 DNA 转录，最近的证据表明其可用作偏头痛预防中的抗伤害感受药物，更有趣的是，作为癌症治疗中化疗的正调节剂。此外，VPA 诱导的神经保护作用正在研究中，以在中风和创伤性脑损伤中获益。因此，VPA 在癫痫中仍然有其地位，但由于其在神经疾病之外的用途值得关注。在这篇综述中，我们旨在以转化为目的强调 VPA 的分子基础和临床适应症。
