Abstract
Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Although in past decades the “monoamine hypothesis” has dominated our understanding of both the pathophysiology of depressive disorders and the action of pharmacological treatments, recent studies focus on the involvement of additional neurotransmitters/neuromodulators systems and cellular processes in BD. Here, evidence for the participation of Na+, K+-ATPase and its endogenous regulators, the endogenous cardiac steroids (ECS), in the etiology of BD is reviewed. Proof for the involvement of brain Na+, K+-ATPase and ECS in behavior is summarized and it is hypothesized that ECS-Na+, K+-ATPase-induced activation of intracellular signaling participates in the mechanisms underlying BD. We propose that the activation of ERK, AKT, and NFκB, resulting from ECS-Na+, K+-ATPase interaction, modifies neuronal activity and neurotransmission which, in turn, participate in the regulation of behavior and BD. These observations suggest Na+, K+-ATPase-mediated signaling is a potential target for drug development for the treatment of BD.
Highlights
Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania
Strong evidence showed that mitochondrial function [19,20] and oxidative stress [21] and inflammation [22,23] participate in the etiology of BD: Reduced antioxidant capacity was described in bipolar patients, manifested by decreased levels of glutathione in post-mortem prefrontal cortex samples [24]
A complete description of Na+, K+-ATPase and endogenous cardiac steroids (ECS) is beyond the scope of this article, a cursory review of these entities will be presented before focusing on their possible involvement in BD
Summary
Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. In addition to the permanent changes, several studies found a correlation between manic or depressive mood states and the levels of oxidative damage biomarkers in bipolar individuals [26]. The pioneering observation that the addition of low concentrations of ouabain to cultured neonatal cardiac myocytes or A7r5 smooth muscle cells rapidly activates Src [73] set the ground for intense and versatile research into the signaling processes of CS-Na+, K+-ATPase interactions.
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