Discovery of Personalized Treatment for Immuno-Metabolic Depression — Focus on 11beta Hydroxysteroid Dehydrogenase Type 2 (11betaHSD2) and Toll-like Receptor 4 (TLR4) Inhibition with Enoxolone
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MDPI
Abstract
Treatment options for major depression are limited: only about one-third of patients achieve
remission with first line treatments with no established predictive markers. Parameters
associated with treatment refractory depression, including metabolic markers (increased
BMI, increased triglyceride levels), inflammation markers (C-reactive protein, CRP), autonomic
disturbances (reduced blood pressure, reduced heart rate variability), and brain
morphology changes (increased volume of the choroid plexus and brain ventricle volumes),
may serve such purpose. These features can be linked mechanistically to an increase in
aldosterone plasma concentration due to a reduced mineralocorticoid receptor (MR) sensitivity.
The primary CNS target of aldosterone is the nucleus of the solitary tract (NTS),
which is also the entry point of the vagus nerve. This nucleus integrates signals from
endocrine, inflammatory, chemoreceptive, and physiological parameters, including blood
pressure. In search of a mechanism to overcome this pathology, we identified a molecule
which is derived from the licorice plant glycyrrhiza glabra, namely glycyrrhizin and its
biologically active metabolite enoxolone. These molecules potentially reverse the abovedescribed
pathology. They inhibit the enzyme 11beta hydroxysteroid-dehydrogenase type
2 (11betaHSD2) and the toll-like receptor 4 (TLR4). 11betaHSD2 regulates the activity of the
mineralocorticoid receptor (MR) by degrading cortisol/corticosterone, which allows aldosterone
to bind to the MR. TLR4 is the ligand for lipopolysaccharide (LPS, endotoxin) and
trigger of innate immunity. Consequently, patients with increased inflammation markers,
increased aldosterone, or low blood pressure may preferentially benefit from the treatment
with glycyrrhizin/enoxolone. Importantly, these patients can be identified BEFORE
treatment is initiated. Clinically, patients sharing these biological indicators are primarily
young females or patients with a history of childhood trauma. A combination of enoxolone
with standard antidepressants may therefore avoid a trial-and-error approach and allow to
achieve recovery faster.
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