Interactions Between Na⁺/K⁺-ATPase Inhibition and Protein Kinase C Signaling in Bipolar Disorder: Insights from Translational Data.
4 affiliations
- 1Laboratório de Psiquiatria Translacional, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil.
- 2Programa de Pós-Graduação em Saúde Coletiva, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil.
- 3Center for Interventional Psychiatry, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX, USA.
- 4Laboratório de Psiquiatria Translacional, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil. [email protected].
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.
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BibTeX
@article{aguiargeraldo2026interactions,
title = {{Interactions Between Na⁺/K⁺-ATPase Inhibition and Protein Kinase C Signaling in Bipolar Disorder: Insights from Translational Data.}},
author = {Jorge M Aguiar-Geraldo and Jefté Peper-Nascimento and Taise Possamai-Della and Thiani Daminelli and Tatiéli Scheffer-Luiz and Vitória Bisognin-Ceretta and Luciane B Ceretta and João Quevedo and Samira S Valvassori},
journal = {Neurochemical research},
year = {2026},
month = oct,
doi = {10.1007/s11064-026-04924-2},
url = {https://europepmc.org/article/MED/42911450},
note = {CC BY},
}
RIS
TY - JOUR
TI - Interactions Between Na⁺/K⁺-ATPase Inhibition and Protein Kinase C Signaling in Bipolar Disorder: Insights from Translational Data.
AU - Jorge M Aguiar-Geraldo
AU - Jefté Peper-Nascimento
AU - Taise Possamai-Della
AU - Thiani Daminelli
AU - Tatiéli Scheffer-Luiz
AU - Vitória Bisognin-Ceretta
AU - Luciane B Ceretta
AU - João Quevedo
AU - Samira S Valvassori
PY - 2026
DA - 2026/10/22
JO - Neurochemical research
DO - 10.1007/s11064-026-04924-2
UR - https://europepmc.org/article/MED/42911450
AB - 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.
SN - 0364-3190
SN - 1573-6903
ER -