Na+, K+-ATPase α Isoforms and Endogenous Cardiac Steroids in Prefrontal Cortex of Bipolar Patients and Controls

Shiv Vardan Singh,David Lichtstein,Wen Wei,Noa Horesh,Asher Ilani,Haim Rosen,Olga V Fedorova

doi:10.3390/ijms21165912

Shiv Vardan Singh, David Lichtstein + Show 5 more

Open Access

https://doi.org/10.3390/ijms21165912

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Abstract

Bipolar disorder is a chronic multifactorial psychiatric illness that affects the mood, cognition, and functioning of about 1–2% of the world’s population. Its biological basis is unknown, and its treatment is unsatisfactory. The α1, α2, and α3 isoforms of the Na+, K+-ATPase, an essential membrane transporter, are vital for neuronal and glial function. The enzyme and its regulators, endogenous cardiac steroids like ouabain and marinobufagenin, are implicated in neuropsychiatric disorders, bipolar disorder in particular. Here, we address the hypothesis that the α isoforms of the Na+, K+-ATPase and its regulators are altered in the prefrontal cortex of bipolar disease patients. The α isoforms were determined by Western blot and ouabain and marinobufagenin by specific and sensitive immunoassays. We found that the α2 and α3 isoforms were significantly higher and marinobufagenin levels were significantly lower in the prefrontal cortex of the bipolar disease patients compared with those in the control. A positive correlation was found between the levels of the three α isoforms in all samples and between the α1 isoform and ouabain levels in the controls. These results are in accordance with the notion that the Na+, K+-ATPase-endogenous cardiac steroids system is involved in bipolar disease and suggest that it may be used as a target for drug development.

Highlights

Bipolar disorder (BD) is a chronic multifactorial psychiatric illness that affects the mood, cognition, and functioning of about 1–2% of the global population [1]
In view of these observations, we hypothesized that the levels of the α isoforms of the Na+, K+-ATPase and of Endogenous cardiac steroids (ECSs) in the brain may be altered in BD
The study was performed on two cohorts of postmortem brain samples of BD and controls obtained from the Human Brain Collection Core (HBCC) of the National Institute of Mental Health

Summary

Introduction

Bipolar disorder (BD) is a chronic multifactorial psychiatric illness that affects the mood, cognition, and functioning of about 1–2% of the global population [1]. Numerous studies implicated neuronal activity in the PFC in both the manic and depressive phases of BD [32]: Reduced glial cell number [33] and decreased cortical thickness [34] were found in the PFC of BD; increased gyrification, a marker of early developmental pathology, was found to be increased in BD patients [35]; and discrete miRNA alterations [36] and a reduced density of GABA-synthesizing enzyme, glutamic acid decarboxylase [37], were observed in the PFC of BD patients In view of these observations, we hypothesized that the levels of the α isoforms of the Na+, K+-ATPase and of ECS in the brain may be altered in BD. We compared the levels of the three α isoforms of the Na+, K+-ATPase and of endogenous OUA and MBG in the PFC of bipolar patients with their levels in age- and sex-matched controls and evaluated the potential correlations among the different isoforms and the two steroids

Results

Determination of Endogenous OUA and MBG in Brain Samples

Statistical Analysis