Role of endogenous ouabain in the etiology of bipolar disorder

Abstract

Background Bipolar disorder is a severe psychiatric illness with poor prognosis and problematic and suboptimal treatments. Understanding the pathoetiologic mechanisms may improve treatment and outcomes. Discussion Dysregulation of cationic homeostasis is the most reproducible aspect of bipolar pathophysiology. Correction of ionic balance is the universal mechanism of action of all mood stabilizing medications. Recent discoveries of the role of endogenous sodium pump modulators (which include ‘endogenous ouabain’) in regulation of sodium and potassium distribution, inflammation, and activation of key cellular second messenger systems that are important in cell survival, and the demonstration that these stress-responsive chemicals may be dysregulated in bipolar patients, suggest that these compounds may be candidates for the coupling of environmental stressors and illness onset. Specifically, individuals with bipolar disorder appear to be unable to upregulate endogenous ouabain under conditions that require it, and therefore may experience a relative deficiency of this important regulatory hormone. In the absence of elevated endogenous ouabain, neurons are unable to maintain their normal resting potential, become relatively depolarized, and are then susceptible to inappropriate activation. Furthermore, sodium pump activity appears to be necessary to prevent inflammatory signals within the central nervous system. Nearly all available data currently support this model, but additional studies are required to solidify the role of this system. Conclusion Endogenous ouabain dysregulation appears to be a reasonable candidate for understanding the pathophysiology of bipolar disorder.

Endogenous Cardiac Steroids in Bipolar Disorder: State of the Art

“…Cardenolides, such as ouabain and digoxin, and bufadienolides, such as bufalin, are steroids originally identified in plants (Digitalis, Strophantus) and toads (Bufo), which have been used for hundreds of years in Western and Eastern medicine to treat heart failure, arrhythmias, and other maladies. In the past 25 years, the cardenolides ouabain and digoxin, and the bufadienolides 19-norbufalin, marinobufagenin, and cinobufagenin were identified as normal constituents of mammalian tissues, including the brain [21][22][23][24]. These compounds, collectively termed endogenous cardiac steroids (ECS), are synthesized in the adrenal and hypothalamus of mammals [25][26][27], and they are considered a new class of hormones implicated in many physiological and pathophysiological mechanisms, including cell growth and cancer, vascular tone homeostasis, blood pressure, hypertension, natriuresis, heart contractility, and inflammation [22,24,28].…”

“…Despite the limited available data on the metabolism of ECS in general, and EO in particular, these compounds are referred to by some as "a hormone family" [21,27,[47][48][49][50][51][52]. However, at the same time, as is evident from the lack of reference in textbooks and reviews, these steroids are ignored almost completely by mainstream biochemists, physiologists, and endocrinologists.…”

“…More importantly, euthymic patients with bipolar illness do not increase circulating EO in the setting of exercise to exhaustion, as occurs with matched non-bipolar controls [81] or the general population [45]. It has been proposed that sleep deprivation, which is associated with increased production of EO and corticosterone in mice [82], might be a trigger for a manic switch in bipolar subjects [21,83]. As little as 24 h of sleep deprivation in humans is enough to increase serum cortisol [84][85][86] and manic-like symptoms [87].…”

“…It is proposed that physiological elevations in EO levels that may normally occur with inflammation, severe illness [103], or sleep deprivation [82], do not occur in subjects with BD, and they experience a relative EO deficiency. Considering that physiologic levels of EO activate Na + , K + -ATPase activity, the relative deficiency results in sodium pump hypofunction in relation to the need, and consequent depolarization of neural tissues [18,21].…”

NMDA receptor inhibition prevents intracellular sodium elevations in human olfactory neuroepithelial precursors derived from bipolar patients

“…Furthermore, ion regulatory abnormalities are among the most reproducible findings in studies of BD 7 . Most important is the elevation of intracellular sodium ([Na] i ) and dysfunction of ion transport systems 7 , 8 . Several ion regulatory systems have been shown to be uniquely disrupted in bipolar patients versus controls 7 – 10 .…”