11β‐Hydroxysteroid dehydrogenase and the brain: Not (yet) lost in translation

Abstract

Abstract11‐beta‐hydroxysteroid dehydrogenases (11β‐HSDs) catalyse the conversion of active 11‐hydroxy glucocorticoids (cortisol, corticosterone) and their inert 11‐keto forms (cortisone, 11‐dehydrocorticosterone). They were first reported in the body and brain 70 years ago, but only recently have they become of interest. 11β‐HSD2 is a dehydrogenase, potently inactivating glucocorticoids. In the kidney, 11β‐HSD2 generates the aldosterone‐specificity of intrinsically non‐selective mineralocorticoid receptors. 11β‐HSD2 also protects the developing foetal brain and body from premature glucocorticoid exposure, which otherwise engenders the programming of neuropsychiatric and cardio‐metabolic disease risks. In the adult CNS, 11β‐HSD2 is confined to a part of the brain stem where it generates aldosterone‐specific central control of salt appetite and perhaps blood pressure. 11β‐HSD1 is a reductase, amplifying active glucocorticoid levels within brain cells, notably in the cortex, hippocampus and amygdala, paralleling its metabolic functions in peripheral tissues. 11β‐HSD1 is elevated in the ageing rodent and, less certainly, human forebrain. Transgenic models show this rise contributes to age‐related cognitive decline, at least in mice. 11β‐HSD1 inhibition robustly improves memory in healthy and pathological ageing rodent models and is showing initial promising results in phase II studies of healthy elderly people. Larger trials are needed to confirm and clarify the magnitude of effect and define target populations. The next decade will be crucial in determining how this tale ends – in new treatments or disappointment.

Treatment with Glycyrrhiza glabra Extract Induces Anxiolytic Effects Associated with Reduced Salt Preference and Changes in Barrier Protein Gene Expression

“…Only a few areas in the brain are sensitive to aldosterone, in particular the nucleus of the solitary tract (NTS), which co-expresses MR and 11β-HSD2 [ 45 , 46 ]. This enzyme provides specificity to aldosterone by quickly degrading cortisol/corticosterone, which competes with aldosterone [ 20 , 47 ]. The NTS structure is crucial for autonomic and affect regulation [ 48 , 49 ], including salt appetite [ 7 , 8 , 50 , 51 , 52 ].…”

“…One of the possibilities to influence aldosterone signaling is to inhibit the enzyme 11β -hydroxysteroid-dehydrogenase type 2 (11β-HSD2), a key enzyme necessary for the specificity of MR to aldosterone [ 20 ]. One of the 11β-HSD2 inhibitors is glycyrrhizin, an active component of licorice ( Glycyrrhiza glabra ).…”

Progress and recognition of idiopathic intracranial hypertension: A narrative review

“…These inactive metabolites are then regenerated into cortisol through 11β‐HSD1 in tissues such as the liver and fat. 149 In individuals with obesity, 11β‐HSD1 activity is increased in subcutaneous adipose tissue, and this activity correlates positively with BMI, as indicated by increased messenger RNA levels of 11β‐HSD1 ( p < 0.05). 150 11β‐HSD1 expression is observed not only in the kidneys, liver, and adipose tissue but also in the CP, which could involve it in CSF regulation.…”

“…11β‐HSD, which comes in two variants, 11β‐HSD1 and 11β‐HSD2, plays a crucial role in controlling glucocorticoid levels in the body. 149 Cortisol is broken down into inert metabolites by 11β‐HSD2 in the kidneys. These inactive metabolites are then regenerated into cortisol through 11β‐HSD1 in tissues such as the liver and fat.…”