The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms

Abstract

Major depressive disorder (MDD) is a heterogeneous psychiatric disease characterized by persistent low mood, diminished interests, and impaired cognitive and social functions. The multifactorial etiology of MDD is still largely unknown because of the complex genetic and environmental interactions involved. Therefore, no established mechanism can explain all the aspects of the disease. In this light, an extensive research about the pathophysiology of MDD has been carried out. Several pathogenic hypotheses, such as monoamines deficiency and neurobiological alterations in the stress-responsive system, including the hypothalamic-pituitary-adrenal (HPA) axis and the immune system, have been proposed for MDD. Over time, remarkable studies, mainly on preclinical rodent models, linked the serum-and glucocorticoid-regulated kinase 1 (SGK1) to the main features of MDD. SGK1 is a serine/threonine kinase belonging to the AGK Kinase family. SGK1 is ubiquitously expressed, which plays a pivotal role in the hormonal regulation of several ion channels, carriers, pumps, and transcription factors or regulators. SGK1 expression is modulated by cell stress and hormones, including gluco-and mineralocorticoids. Compelling evidence suggests that increased SGK1 expression or function is related to the pathogenic stress hypothesis of major depression. Therefore, the first part of the present review highlights the putative role of SGK1 as a critical mediator in the dysregulation of the HPA axis, observed under chronic stress conditions, and its controversial role in the neuroinflammation as well. The second part depicts the negative regulation exerted by SGK1 in the expression of both the brain-derived neurotrophic factor (BDNF) and the vascular endothelial growth factor (VEGF), resulting in an anti-neurogenic activity. Finally, the review focuses on the antidepressant-like effects of anti-oxidative nutraceuticals in several preclinical model of depression, resulting from the restoration of the physiological expression and/or activity of SGK1, which leads to an increase in neurogenesis. In summary, the purpose of this review is a systematic analysis of literature depicting SGK1 as molecular junction of the complex mechanisms underlying the MDD in an effort to suggest the kinase as a potential biomarker and strategic target in modern molecular antidepressant therapy.

Stress-Related Dysfunction of Adult Hippocampal Neurogenesis—An Attempt for Understanding Resilience?

“…Noteworthy, analysis of newborn’s cord blood DNA showed significant associations between this score and maternal depression and anxiety [ 287 ]. Likewise, in another study, the serum- and GC-inducible kinase 1 (SGK1), a GC target gene with relevant implications for MDD pathogenesis [ 288 ], was identified as a crucial molecular mediator of GC-dependent neurogenesis impairment in in vitro cultured human NPCs [ 245 ]. Importantly, SGK1 mRNA levels were increased in the peripheral blood of drug-free depressed patients and in the hippocampus of rats that underwent either prenatal stress or UCMS [ 245 ].…”

Merging the Multi-Target Effects of Kleeb Bua Daeng, a Thai Traditional Herbal Formula in Unpredictable Chronic Mild Stress-Induced Depression

“…GR is kept in an inactive state in the cytoplasm, only translocating from the cytoplasm to the nucleus to execute its functions when it binds to glucocorticoid. Impaired signaling via corticosteroid-activated GR leads to impaired negative feedback regulation and partial glucocorticoid resistance appears to be one of the most robust biological abnormalities observed in mood disorders [ 42 ]. FKBP5, an Hsp90 co-chaperone is a negative modulator of GR activity that promotes GR stability and reduces GR sensitivity to glucocorticoid.…”

“…Although SGK1 was initially described for its role in regulating sodium transport in renal collecting duct cells [ 15 ], recent studies have provided evidence for a role of SGK1 in stress and glucocorticoid actions on the brain. Compelling data suggests that SGK1 is involved in the GC-induced reduction in the proliferation and differentiation of human hippocampal progenitor cells and that increased SGK1 expression or function is related to the pathogenic stress hypothesis of major depression [ 42 ]. SGK1 mRNA expression has been found to be significantly increased (positive correlation with FKBP mRNA expression) in the peripheral blood of drug-free depressive patients, as well as in the hippocampus of rats subjected to chronic stress [ 15 ].…”

Potential Adverse Effects of Dexamethasone Therapy on COVID-19 Patients: Review and Recommendations

“…The raised level of cortisol in the blood will exacerbate depression by impairing brain functions, such as neuronal survival, neuronal excitability, neurogenesis and memory acquisition [144]. Notably, Skupio et al have found that the co-chaperone FK506 binding protein 51 and serum-and glucocorticoid-inducible-kinase-1 proteins increased in the prefrontal cortex, hippocampus and striatum of mice treated with dexamethasone [137], which could regulate GR sensitivity [145], mediate glucocorticoid effects on neuronal function and contribute to major depressive disorder [146].…”