Do you know of anyone doing clinical research into cognitive impairment from bipolar illness ? Because they are doing it wrong.

And they don’t realize it.

Do you know of anyone doing clinical research into cognitive impairment from bipolar illness or from migraine or from iron deficiency or from thiamine deficiency or any other brain illnesses potentially caused by secondary problems far away from the brain?

These are hard problems for which we have no good consistent knowledgeable treatments. [There are treatments for iron deficiency and thiamine deficiency but these conditions are hard to diagnose and easy to miss. They affect the brain because they affect all cells.]

To better understand bipolar illness, migraine, schizophrenia and dementia or any illness resulting in potentially reversible altered mental status, we need all the clues we can gather, including the evaluating and monitoring of vital signs, especially and including respiratory rate and tidal volume at rest, during periods of health and during periods of illness. Breathing and mind are surely intimately related. No one since* Dr Emile Kraepelin has carefully looked at physical signs in bipolar attacks. * Manic Depressive Insanity Ch. 3 Bodily Signs 1926.

Dr Kraepelin found the vital signs in bipolar patients with mood and mental impairment to be abnormal in different ways during depressive attacks and during manic ones. Heart rate, blood pressure, body temperature, higher mental functions, appetite, sleep and respiratory rate were all abnormal.

Dr Kraepelin concluded that bipolar attacks must be due to a metabolic problem, an internal physiological problem. But he did not have the tools to investigate further.

Today, investigators are looking into the possibility that endogenous ouabain is involved in both depressive and manic attacks of bipolar illness. Role of endogenous ouabain in the etiology of bipolar disorder Rif S. El-MallakhYonglin Gao & Pan You , Sci Rep. 2019; 9: 15627. Intracerebroventricular injection of ouabain causes mania-like behavior in mice through D2 receptor activation Raul Gainetdinov et al., Am J Physiol Heart Circ Physiol. 2014 Sep 1; 307(5): H635–H639. Why isn’t endogenous ouabain more widely accepted? Mordecai P. Blaustein, Int J Mol Sci. 2018 Jul; 19(7): 1948. Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases Marco SimoniniPaola CasanovaLorena CitterioElisabetta MessaggioChiara Lanzani, and  Paolo Manunta*

Ouabain affects the sodium/potassium pump and can provoke intracellular edema of the brain.   Stroke    A Journal of Cerebral Circulation    1979    Ischemic Cerebral Edema. A Review     M.D. O’BRIEN, M.D., M.R.C.P

Imbalance of endogenous ouabain most likely can cause the same, I would think.

Brain Swelling Due to Intracellular Edema

This has been called “metabolic” or “cytotoxic” edema. It is caused by anything which damages cell metabolism, in particular the sodium pump mechanism, producing a change in the osmotic balance across the cell membrane and intracellular edema. This type of edema corresponds to the dry edematous brain, because the edema is contained in the cells and the cut surface of the brain is, therefore, not unduly wet. It can be produced experimentally with a wide range of poisons such as cyanide and hexachlorophene, by specific sodium pump inhibitors such as ouabain and by direct damage to the cell with trauma, including cold.                   Stroke    A Journal of Cerebral Circulation    1979    Ischemic Cerebral Edema. A Review     M.D. O’BRIEN, M.D., M.R.C.P

Incidentally, although cytotoxic edema (oncotic cell swelling) is referred to as “edema” for purely historical reasons, it results in intracellular, rather than extracellular, fluid accumulation, it does not include a swelling component, and it is best regarded as a premorbid precursor to extracellular ionic edema. Molecular pathophysiology of cerebral edema Jesse A Stokum,1 Volodymyr Gerzanich,1 and  J Marc Simard J Cereb Blood Flow Metab. 2016 Mar; 36(3): 513–538.

Intracellular changes to brain cells are difficult to measure, as you can imagine. So we are left with observations of behaviour changes and clues from looking at the patterns of vital signs.

Interestingly, injection of ouabain-one of the the cardiac steroid poisons- causes the behavioural symptoms of mania and depression in animals, most likely, in my opinion, from cytotoxic edema or intracellular fluid accumulation due to disruption of the sodium pump or perhaps a regulated dose-related rise in intracranial pressure. Sci Rep. 2019; 9: 15627. Intracerebroventricular injection of ouabain causes mania-like behavior in mice through D2 receptor activation Raul Gainetdinov et al.

Ouabain also causes depressive behaviours. “The present study aimed to assess manic- and depressive-like behaviors, potential alteration in the hypothalamic-pituitary-adrenal (HPA) system and oxidative stress parameters after a single OUA ICV administration in adult male Wistar rats. Moreover, we evaluated Li effects in this experimental setting. Data show that OUA ICV administration could constitute a suitable model for BD since the injection of the drug triggered manic- and depressive-like behaviors in the same animal. Additionally, the OUA model mimics significant physiological and neurochemical alterations detected in BD patients, including an increase in oxidative stress and change in HPA axis. Our findings suggest that decreased Na+/K+-ATPase activity detected in bipolar patients may be linked to increased secretion of glucocorticoid hormones and oxidative damage, leading to the marked behavioral swings. The Li administration mitigated these pathological changes in the rats. The proposed OUA model is regarded as suitable to simulate BD by complying with all validities required to a proper animal model of the psychiatric disorder”. Int J Biomed Sci. 2014 Jun; 10(2): 85–102. Validation of the animal model of bipolar disorder induced by Ouabain: face, construct and predictive perspectives João Quevedo et al

Ouabain disrupts the operation of the sodium pump. [Ouabain is a cardiac glycoside that inhibits ATP-dependent sodium-potassium exchange across cell membranes. Ouabain – Proteopedia, life in 3D ] Lithium [Li] seems to restore the sodium pump. Discovery of the sodium pump is fairly recent, 1957, and it has been the subject of research ever since.

In the present article evidence showing Na+, K+-ATPase involvement in signaling pathways, enzyme changes in diverse neurological diseases as well as during aging, have been summarized. Issues refer mainly to Na+, K+-ATPase studies in ischemia, brain injury, depression and mood disorders, mania, stress, Alzheimer´s disease, learning and memory, and neuronal hyperexcitability and epilepsy.

Hypercapnia also disrupts the function of the sodium pump. Int J Mol Sci. 2020 Feb; 21(4): 1467. Hypercapnia Impairs Na,K-ATPase Function by Inducing Endoplasmic Reticulum Retention of the β-Subunit of the Enzyme in Alveolar Epithelial Cells  István Vadász et al [The sodium-potassium pump is found in the plasma membrane of almost every human cell and is common to all cellular life. It helps maintain cell potential and regulates cellular volume. 2.16: Sodium-Potassium Pump – Biology LibreTexts ]

Although CO2 is a normal metabolite, it is toxic at elevated levels. just like endogenous ouabain. High C02 can increase intracranial pressure and also cause cerebral oedema or swelling.

The animal models point to bipolar attacks induced by endogenous ouabain. Paula is missing salt/sugar receptors [taste buds, papillae fungiform] on the front of her tongue. She has a normal sense of taste despite this because of cells in the palate and the rest of the mouth. Salt [and sugar] taste signals from her anterior tongue should be transduced via epithelial sodium channels (ENaCs) residing in the apical cellular pole of taste cells. But they are not, she seems to be missing these ENaCs due to the permanent atrophy of these cells…which usually regenerate every 10 days or so. What does this have to do with endogenous ouabain and the sodium pump? I don’t know…but I am sure there is a connection that should be explored.

……...disruptions in ENaC function are associated with diseases that are characterized by sodium and water imbalances. These diseases manifest in tissues where ENaC is expressed including the kidney, colon and lung [160,192,202,226]. Biochim Biophys Acta. 2010 Dec; 1802(12): 1166–1177. Regulation of the epithelial sodium channel (ENaC) by membrane trafficking Michael B. Butterworth

Paula’s at rest vital signs and Kraepelin’s study of vital signs in thousands of patients point to “control of breathing” problems and possible hypercapnia.

Both endogenous ouabain and endogenous carbon dioxide will cause altered mental status and deterioration of cognition, altered function of the sodium pump and some amount of cellular swelling in the brain.

Perhaps the link between the two are disruptions in ENac function.

Epithelial Na+ channels (ENaC) are of importance in Na+-absorptive epithelium, such as in the airway, the alveolus, the kidney, and the distal colon, and control the overall rate of transapical Na+ transport. ENaC proteins are mainly located in the apical membrane of polarized epithelial cells and have four homologous subunits (i.e., the α, β, γ and δ subunits) 12. The α or δ ENaC subunit, which is essential for acting as a sodium channel, forms the channel pore, whereas the β and γ ENaC subunits are critical for amplifying the efficiency of Na+ influx. In mouse, the gene scnn1d, which encodes δ ENaC, is assumed to be a pseudogene 2.

In the lungs, alveolar lining fluid is critical for efficient gas exchange, and ENaC complexes play a crucial role in alveolar fluid clearance to maintain homeostasis of the luminal liquid. Pulmonary diseases, including acute lung injury, cystic fibrosis, chronic obstructive pulmonary disease, and asthma result from or are associated with the dysfunction or dysregulation of ENaC, and the regeneration of epithelial cells and the restoration of ion transport are two key steps in recovery from those diseases. In this article, we review the progress of research on ENaC-mediated lung injury repair, in particular the role of ENaC proteins in re-epithelialization by endogenous and allogeneic stem/progenitor cells.Int J Biol Sci. 2016; 12(9): 1150–1154. Epithelial Sodium Channels in Pulmonary Epithelial Progenitor and Stem Cells Yang Liu,1 Bi-Jie Jiang,2 Run-Zhen Zhao,3,4 and  Hong-Long Ji3,4,✉

Disruption of Epithelial Na+ channels (ENaC) in the brain, in the digestive system [ie.papillae fungiform of the tongue and airway] and the respiratory epithelia and in the lung during episodes of Hypercapnia might be the Stressor in bipolar subjects. and perhaps Lithium and/or Paxil or a combination of the two restores the function of the sodium pump and restores carbon dioxide levels in the brain and blood to previous levels seen before bipolar attacks.

Proposed model of role of endogenous ouabain in pathophysiology of bipolar disorder

Fig. 1

figure 1

El-Mallakh, R.S., Gao, Y. & You, P. Role of endogenous ouabain in the etiology of bipolar disorderInt J Bipolar Disord 9, 6 (2021).

I think that we can all agree that the neurochemistry of bipolar illness is complex and that a careful paediatric and adult medical history and a careful physical examination of these patients can add vital clues that are needed to understand and to treat these conditions more effectively.

Physical signs are part of the key to more precise biological knowledge.

Just look at Paula.

Are control of breathing issues common in bipolar patients?

Are permanently atrophied papillae fungiform part of the bipolar phenotype?

These are the kind of questions we should be asking. But first, we need to look for hidden clues even the patients do not know.

to be continued…..

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