Tikhonova Lyudmila, Maevsky Eugene, Montoliu Carmina, Kosenko Elena
Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia.
Hospital Clinico Research Foundation, INCLIVA Health Research Institute, 46010 Valencia, Spain.
Biomolecules. 2025 Apr 15;15(4):588. doi: 10.3390/biom15040588.
Valproic acid (VPA) is a mainstay of treatment for epilepsy. Although VPA is generally considered well tolerated, it has serious adverse effects related to the pathological impact on cerebral perfusion and oxidative metabolism, leading to progressive encephalopathy. Erythrocytes directly deliver oxygen to the tissues. To understand how the brain pathology may be related to limited oxygenation, it is important to determine whether VPA-related changes occur in the intracellular erythrocyte metabolism responsible for the oxygen transport function.
To determine whether different therapeutic VPA doses affect major metabolic pathways in rat erythrocytes, the activity of rate-limiting enzymes and levels of metabolites of glycolysis, the Rapoport-Luebering shunt, the pentose phosphate pathway and the antioxidant systems were measured.
Our data showed that VPA-induced G6PD inhibition leads to profound oxidative stress, increased MetHb formation and decreased 2,3-DPG and ATP levels in erythrocytes that underlie the loss of their oxygen transport function, thus being a cause of a brain energy crisis that precedes encephalopathy.
The measurement of parameters in metabolic pathways modulating the redox-signaling and oxygen-carrying capacity of erythrocytes is needed for further elucidation of complex mechanisms underlying VPA-induced brain hypoperfusion and encephalopathy.
丙戊酸（VPA）是癫痫治疗的主要药物。尽管VPA通常被认为耐受性良好，但它具有与对脑灌注和氧化代谢的病理影响相关的严重不良反应，可导致进行性脑病。红细胞直接向组织输送氧气。为了解脑部病理与氧合受限之间的关系，确定负责氧运输功能的红细胞内代谢是否发生与VPA相关的变化非常重要。
为了确定不同治疗剂量的VPA是否会影响大鼠红细胞的主要代谢途径，我们测量了限速酶的活性以及糖酵解、Rapoport-Luebering旁路、磷酸戊糖途径和抗氧化系统的代谢物水平。
我们的数据表明，VPA诱导的葡萄糖-6-磷酸脱氢酶（G6PD）抑制导致红细胞中严重的氧化应激、高铁血红蛋白（MetHb）形成增加以及2,3-二磷酸甘油酸（2,3-DPG）和三磷酸腺苷（ATP）水平降低，这些是其氧运输功能丧失的基础，因此是脑病之前脑能量危机的一个原因。
需要测量调节红细胞氧化还原信号和携氧能力的代谢途径中的参数，以进一步阐明VPA诱导的脑灌注不足和脑病的复杂机制。
