Interactions Between Na⁺/K⁺-ATPase Inhibition and Protein Kinase C Signaling in Bipolar Disorder: Insights from Translational Data

Abstract Protein Kinase C (PKC) dysregulation can affect Na⁺/K⁺-ATPase function, while alterations in Na⁺/K⁺-ATPase activity can conversely influence the PKC pathway. Therefore, this study investigated the interactions between Na⁺/K⁺-ATPase inhibition and PKC signaling, as well as the associated oxidative stress, using a translational approach that combines preclinical (in vitro and in vivo) models and clinical data from patients with bipolar disorder. In the in vitro model, cells were exposed to ouabain (OUA), a Na + /K + ATPase inhibitor, and then treated with a PKC inhibitor (PKCi - tamoxifen). In the in vivo model, animals received intracerebroventricular OUA and were treated with PKCi. The animals underwent behavioral tests to evaluate manic- and depressive-like behaviors. The clinical study included a case-control protocol with 36 BD patients and 46 healthy controls. In both preclinical and clinical settings, the markers (4-hydroxynonenal [4-HNE], 8-isoprostane [8-ISO], thiobarbituric acid reactive substances [TBARS], carbonyl, and 3-nitrotyrosine [3-nitro]), as well as Na+/K+ ATPase and PKC activities, were assessed. In the in vivo and in vitro protocols, OUA increased PKC activity and reduced Na + /K + ATPase activity. However, when combined with PKCi, OUA failed to inhibit Na + /K + ATPase activity. Additionally, OUA was able to induce manic- and depressive-like behaviors and oxidative stress, which was also reversed by PKCi. Moreover, the clinical protocol identified increased PKC activity and reduced Na+/K+ ATPase activity, consistent with the preclinical protocols. Taken together, the data indicates that the interconnection between Na⁺/K⁺-ATPase and PKC signaling pathways represents an important component of BD pathophysiology.