Glucocorticoid hedgehog agonists in neurogenesis

Abstract

The process of neurogenesis in mammals, which is prolific and widespread at birth, gradually slows with aging and in humans becomes restricted to areas including the cerebellum and hippocampus. It has been reported that exposure to glucocorticoids can impair neurogenesis in both adults and children. Glucocorticoids are known to bind with high affinity to intracellular receptors. Glucocorticoid blood levels are normally regulated by environmental stresses, but because of their clinical utility, exogenous glucocorticoids are frequently administered in drug formulations. Consequently, concerns have arisen about the consequences of glucocorticoid use on neurogenesis and health, especially in the pediatric population. In this article, we will review recent findings that a select number of related glucocorticoids, halcinonide, fluticasone propionate, clobetasol propionate, and fluocinonide, also bind the hedgehog pathway receptor Smoothened. We will discuss their pharmacology and also a most surprising result; that this select group of compounds, which includes FDA approved drugs, unlike typical glucocorticoids such as dexamethasone, stimulate stem cell growth, and thus enhance neurogenesis.

Figure 1

Primary neuronal granule cell precursor (GCP) proliferation in the cerebellum is Hedgehog signaling dependent.

Figure 2

Select glucocorticoids affect cell growth through both the glucocorticoid receptor and the Smo receptor.

Figure 3

Working model of glucocorticoid Smo agonist activity.