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Novel Treatment Targets Based on Insights in the Etiology of Depression: Role of IL-6 Trans-Signaling and Stress-Induced Elevation of Glutamate and ATP

Retired pharmacologist, Gänsbühlgartenweg 7, CH4132 Muttenz, Switzerland
Pharmaceuticals 2019, 12(3), 113; https://doi.org/10.3390/ph12030113
Received: 25 June 2019 / Revised: 10 July 2019 / Accepted: 26 July 2019 / Published: 29 July 2019
(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)
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Abstract

Inflammation and psychological stress are risk factors for major depression and suicide. Both increase central glutamate levels and activate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Both factors also affect the function of the chloride transporters, Na-K-Cl-cotransporter-1 (NKCC1) and K-Cl-cotransporter-2 (KCC2), and provoke interleukin-6 (IL-6) trans-signaling. This leads to measurable increases in circulating corticosteroids, catecholamines, anxiety, somatic and psychological symptoms, and a decline in cognitive functions. Recognition of the sequence of pathological events allows the prediction of novel targets for therapeutic intervention. Amongst others, these include blockade of the big-K potassium channel, blockade of the P2X4 channel, TYK2-kinase inhibition, noradrenaline α2B-receptor antagonism, nicotinic α7-receptor stimulation, and the Sgp130Fc antibody. A better understanding of downstream processes evoked by inflammation and stress also allows suggestions for tentatively better biomarkers (e.g., SERPINA3N, MARCKS, or 13C-tryptophan metabolism). View Full-Text
Keywords: major depressive disorder; suicide; inflammasome; ketamine; vagus nerve major depressive disorder; suicide; inflammasome; ketamine; vagus nerve
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Kalkman, H.O. Novel Treatment Targets Based on Insights in the Etiology of Depression: Role of IL-6 Trans-Signaling and Stress-Induced Elevation of Glutamate and ATP. Pharmaceuticals 2019, 12, 113.

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