The role of 11β-hydroxysteroid dehydrogenases in the brain
Section snippets
11β-Hydroxysteroid dehydrogenases
11β-Hydroxysteroid dehydrogenases (11β-HSDs) are enzymes that metabolise glucocorticoids and hence regulate the intracellular levels of steroids available to activate corticosteroid receptors. There are two isozymes, 11β-HSD type 1 and type 2, which in most tissues and conditions drive the enzyme reaction in opposite directions (Fig. 1). 11β-HSD2 inactivates glucocorticoids (corticosterone in the rat or mouse, cortisol in humans) to produce 11-dehydrocorticosterone (11-DHC), or cortisone,
11β-HSD1 and HPA axis regulation
Glucocorticoid secretion is regulated by the neuroendocrine axis, the HPA axis, which is activated in stress and terminated by glucocorticoids themselves in a negative feedback loop. Significantly, areas of 11β-HSD1 expression include central sites of negative feedback of glucocorticoids, including the paraventricular nucleus of the hypothalamus, the hippocampus and the cerebral cortex. Furthermore, the extensive expression of 11β-HSD1 in the liver may potentially provide a significant source
Stress
When the HPA axis is activated by restraint stress, the peak corticosterone response is exaggerated in 11β-HSD1-null mice but peak ACTH levels are unaltered. These data suggest that the corticosterone hypersecretion is mainly due to the hypersensitive adrenal. However, the turn-off phase of the ACTH response, which correlates with glucocorticoid negative-feedback efficiency, is delayed. Administration of cortisol, the human glucocorticoid, 2 h prior to restraint stress, causes a greater
Strain variability in HPA axis regulation
It is well documented that different strains of rats and mice exhibit different degrees of HPA axis activity, both basally and in response to stress. Notably, the BalbC mouse strain has large adrenals and an exaggerated stress responsivity compared to the C57BL/6 mouse and this results in altered behaviour of increased aggressiveness and anxiety (Zaharia et al., 1996). In fact the C57BL/6 strain shows a particularly tight control of glucocorticoid secretion in most circumstances. It therefore
11-HSD1 and brain aging
Glucocorticoids are considered a major risk factor in aging processes, potentiating age-related cognitive impairments (Sapolsky et al., 1986). Although the hippocampus requires glucocorticoids for neuronal function and survival, it is also particularly vulnerable to the adverse effects of chronic glucocorticoid excess, which produces atrophy of dendrites, neuronal and cognitive dysfunction and even, in some strains of rats, neuronal loss. In primary cultures of hippocampal cells from E18 rat
The role of 11β-HSD2
The most important role of 11β-HSD2 in the periphery is to protect the intrinsically non-selective mineralocorticoid receptors (MR) of the kidney from being activated by corticosterone instead of their primary in vivo ligand, aldosterone (Edwards et al., 1988). Without this pre-receptor metabolism MR are activated by corticosterone producing the syndrome of apparent mineralocorticoid excess (SAME). This is seen in patients with reduced activity of 11β-HSD2 due to mutations in the 11β-HSD2 gene (
11β-HSD2 in the brain
In the brain of the adult rat 11β-HSD2 is expressed in a few, discrete nuclei mostly implicated in mediating central control of salt/water balance and blood pressure (e.g. SCO, subcommissural organ; NTS, nucleus tractus solitarius; central nucleus of the amygdala; lateral hypothalamus) (Robson et al., 1998, Roland et al., 1995). In the adult mouse brain there is an even more limited 11β-HSD2 expression confined to the NTS (Robson, Holmes, unpublished observation), consistent with the different
Glucocorticoid effects on cerebellar postnatal development
Several previous studies in the rat have shown that postnatal treatment with glucocorticoids (cortisol, dexamethasone, corticosterone) results in a delayed and malformed development of the cerebellum. The cerebellum is still proliferating postnatally and a considerable amount of cell migration, differentiation as well as cerebellar secondary folding takes place between postnatal day (P) 1 and P28. Neonatal adrenalectomy prolongs mitosis and delays disappearance of the external granule layer
Prenatal glucocorticoid programming and the role of 11β-HSD2
The early life effects of glucocorticoids in the rodent have been studied in some detail in the rat, though effects in the mouse are less well documented. Other species have also been studied such as the guinea-pig and sheep and correlations have been made with human data (Matthews, 2002, Weinstock, 2001, Welberg and Seckl, 2001). In the rat, exogenous administration of corticosterone or the synthetic glucocorticoid, dexamethasone, during pregnancy can have life-long effects on the offspring,
Summary
11β-HSD knockout mice have been invaluable in dissecting the roles of both isozymes in many systems, but particularly in the brain. The lack of tissue-specific glucocorticoid regeneration in the 11β-HSD1−/− mice, attenuates glucocorticoid effects within the brain producing a deficit in the tight regulation of the HPA axis and a consequent rise in plasma corticosterone concentrations. However, the loss of the enzyme in central regions results in apparent low intracellular corticosterone levels,
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2019, General and Comparative EndocrinologyCitation Excerpt :Systemic DHC levels may increase in response to stress for two reasons: 1) increased conversion of corticosterone to the inactive DHC, thus protecting tissues from harmful effects of corticosterone or 2) provide a reservoir for specific tissues to intracellularly regenerate DHC to corticosterone. Evidence for the latter includes high levels of 11β-HSD1 in the rat brain (Diaz et al., 1998; Holmes and Seckl, 2006; Wyrwoll et al., 2011) and prolonged stress-induced increases in blood corticosterone in 11β-HSD1-deficient mice (Harris et al., 2001). Together, the data suggest that 11β-HSD1 plays a pivotal role in hypothalamic-pituitary-adrenal axis regulation by utilizing systemic DHC to intracellularly regenerate corticosterone, to provide increased negative feedback on the hypothalamic-pituitary-adrenal axis and prevent a heightened and prolonged stress response.
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