11β-Hydroxysteroid dehydrogenase and the brain: Not (yet) lost in translation.
11β-hydroxysteroid dehydrogenase
ageing
cognition
glucocorticoid
mineralocorticoid
Journal
Journal of internal medicine
ISSN: 1365-2796
Titre abrégé: J Intern Med
Pays: England
ID NLM: 8904841
Informations de publication
Date de publication:
08 Nov 2023
08 Nov 2023
Historique:
medline:
9
11
2023
pubmed:
9
11
2023
entrez:
9
11
2023
Statut:
aheadofprint
Résumé
11-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.
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
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