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Publications

Journal Article Epublish

PubMed: 40305337 DOI: 10.3390/biom15040588

Valproate Damaging Effect on Erythrocyte Metabolism as a Decisive Factor in the Development of Encephalopathy.

Biomolecules 15(4)

Authors: Lyudmila Tikhonova, Eugene Maevsky, Carmina Montoliu, Elena Kosenko

Affiliations

  • 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.
  • Pathology Department, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

MeSH

Erythrocytes, Brain, Brain Diseases, Therapeutics