11beta-Hydroxysteroid dehydrogenase in the brain: a novel regulator of glucocorticoid action?

Corticosteroids (glucocorticoids and mineralocorticoids) have multiple actions in the brain which are mediated via specific intracellular receptors. Recently, a novel and important control of glucocorticoid action has been identified in peripheral tissues; prereceptor metabolism by 11beta-hydroxysteroid dehydrogenase (11beta-HSD). This enzyme catalyses the conversion of the active glucocorticoids corticosterone and cortisol to inert 11 keto-products (11-dehydrocorticosterone, cortisone), thus regulating access of glucocorticoids to receptors. Two distinct isozymes occur. 11beta-HSD-1 is a widespread, NADP(H)-dependent enzyme, which shows bidirectional activity in tissue homogenates and microsomal preparations, but may predominantly function as an 11beta-reductase (regenerating active glucocorticoids) in intact cells. 11beta-HSD-2 is a much higher affinity, NAD-dependent, exclusive 11beta-dehydrogenase (glucocorticoid inactivating enzyme), which, when colocalized with otherwise nonselective mineralocorticoid receptors (MR), ensures selective access for aldosterone in vivo. Accumulating evidence indicates widespread expression of 11beta-HSD-1 in the brain. The highest levels are found in cerebellum, hippocampus, cortex, and pituitary, but detectable activity is also present in the hypothalamus (including the paraventricular nucleus) and other regions of neuroendocrine interest. 11beta-HSD-1 protein has been detected on Western blots of brain and immunostaining is widespread, localized predominantly in neurons and their processes. The mRNA encoding 11beta-HSD-1 is also widely expressed in the brain, its distribution broadly paralleling enzyme bioactivity and immunostaining. 11beta-HSD-1 expression is regulated during late prenatal and postnatal ontogeny and by glucocorticoids and stress, prompting suggestions that this isoform may play a role in protecting the brain from the deleterious consequences of glucocorticoid excess. However, in primary cultures of hippocampal neurons, 11beta-HSD-1 functions as a predominant 11beta-reductase, reactivating inert corticoids and thus potentiating neurotoxicity. The functions of 11beta-HSD-1 in the CNS are not defined, but may relate to mood, neuronal survival, and glucocorticoid feedback. The identification of aldosterone-selective actions in the brain (upon blood pressure and salt appetite) predict the presence of 11beta-HSD-2. This isozyme has very limited expression in the adult brain, probably confined to the subregions of the brain stem and the subcommissural organ, where some aldosterone-selective actions may be mediated. However, the midgestation fetal brain highly expresses 11beta-HSD-2, which might modulate glucocorticoid effects on CNS development. Studies with licorice-derived enzyme inhibitors indicate functional effects for 11beta-HSD in the adult brain, notably in the periventricular hypothalamus and limbic system. Thus, 11beta-HSD represents a novel and potentially important level of control of glucocorticoid action in the CNS. Enzyme modulation by pharmacological or other agents may provide a useful means to target increased or attenuated glucocorticoid action to specific sites in the brain.