At Physiologically Relevant Concentrations, Valproic Acid and Lithium Carbonate Reduce Oxidative Stress in Human Astrocytoma Cells

Abstract

Background: The pathophysiology of bipolar disorder is largely unknown; however, recent studies have suggested that metabolic dysfunction, particularly at the mitochondrial level, may represent a previously unexplored pathway. Lithium carbonate, valproic acid, and a combination of these represent the mainstay of treatment for bipolar disorder; however, the mechanisms underpinning the drugs’ clinical efficacy are not well characterised. At present, such mechanistic studies use concentrations which widely differ from the known bioavailability, thus, there is a need to establish the effect of lithium carbonate, valproic acid, and combination therapy at physiologically relevant doses. Methods: Human astrocytoma 1321N1 cells were treated for 4, 24, and 48 hours. The MTT method was used to detect cytotoxicity upon drug treatment. Reactive oxygen species (ROS) production was quantified by dichlorofluorescin diacetate fluorescence. Results: Upon H2O2-induced cellular stress, cell viability was significantly reduced; however, lithium exhibited a protective effect. In the absence of the stressor, the drugs had no negative effect on 1321N1 cellular viability. All the drug treatments exhibited protection against H2O2-induced ROS accumulation with lithium, bringing it closer to the control baseline. Conclusion: The findings contribute to the understanding of the drugs’ biological effects, particularly as oxidative stress reducers. Furthermore, it highlights the need for research using comparable physiologically relevant models. This may advance the discovery of diagnostic biomarkers and new research approaches to the diagnosis of bipolar disorder.