Corticosteroids, 11β‐Hydroxysteroid Dehydrogenase Isozymes and the Rabbit Choroid Plexus

Abstract

The epithelial cells of the choroid plexus (CP) are responsible for cerebrospinal fluid (CSF) secretion into the ventricles of the brain. The balance between CSF production and drainage, in part, facilitates a normal intracranial pressure. The secretion of Na(+) and anions by the CP creates an osmotic gradient driving water into the ventricles. This is opposite to classical Na(+) transporting tissues, such as the kidney, where Na(+) and water reabsorption is mediated by 11beta-hydroxysteroid dehydrogenase type 2 that protects the mineralocorticoid receptor by abrogating active cortisol to inactive cortisone. In the human ocular ciliary epithelium, Na(+) and water secretion is dependent on a novel mediator of ciliary epithelial Na(+) transport, 11beta-HSD type 1 (11beta-HSD1), that generates intraocular cortisol. In a mechanism analogous to that of the embryologically related ocular ciliary epithelium, we propose that autocrine regulation of intracranial cortisol is dependent on 11beta-HSD1 expression in the CP epithelial cells. By conducting immunolocalisation studies on brains from New Zealand White Albino rabbits, we defined the expression of 11beta-HSD1 in the secretory CP epithelial cells. Enzyme assays performed on intact rabbit CP whole tissue explants confirmed predominant 11beta-HSD1 activity, generating cortisol that was inhibited by glycyrrhetinic acid (an 11beta-HSD inhibitor). Using the real time-polymerase chain reaction, rabbit CP tissue was found to express levels of 11beta-HSD1, glucocorticoid receptor alpha and serum and glucocorticoid-regulated kinase 1 mRNA comparable to that expressed in rabbit ocular ciliary body, thereby highlighting the similarity between these two tissues. Furthermore, an enzyme-linked immunosorbent assay of rabbit CSF revealed a median cortisol concentration of 1.7 nmol/l (range 1.4-4.3 nmol/l, n = 9). Our data have identified a functional 11beta-HSD1 within the CP, mediating intracranial cortisol bioavailability. Expression of 11beta-HSD1 may be fundamental in the regulation of CSF secretion and the local generation of cortisol may represent a pathophysiological mechanism underlying cortisol-dependent neuroendocrine diseases.

Cerebrospinal Fluid Corticosteroid Levels and Cortisol Metabolism in Patients with Idiopathic Intracranial Hypertension: A Link between 11β-HSD1 and Intracranial Pressure Regulation?

“…We previously suggested that 11␤-HSD1 may influence ICP through the regulation of CSF homeostasis in a fashion analogous to that reported by our group in the ciliary body (22,23). In keeping with this, we have demonstrated 11␤-HSD1 immunoreactivity in the CSF secreting CP epithelial cells.…”

“…Here, cortisol generation by 11␤-HSD1 stimulates serum and glucocorticoid-regulated kinase (sgk) 1 to increase epithelium Na ϩ transport and aqueous humor production (22). Inhibition of 11␤-HSD1 lowers intraocular pressure (23). We suggest that, akin to the ocular ciliary body, in the CP CSF secretion may be regulated by 11␤-HSD1 (Fig.…”

Cushing’s Disease and Idiopathic Intracranial Hypertension: Case Report and Review of Underlying Pathophysiological Mechanisms

“…Although the mechanism by which steroids modulate CSF absorption is unknown, a putative mechanism exists for their effects on CSF production. The enzyme 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1) is highly expressed in choroid plexus (CP) epithelium, and despite being a bidirectional enzyme, its main activity is the reduction of inactive cortisone to cortisol (14). In addition, mineralocorticoid receptors are highly abundant in CP epithelium and are activated by cortisol and aldosterone with a similar affinity (15).…”

Idiopathic Intracranial Hypertension After Surgical Treatment of Cushing Disease: Case Report and Review of Management Strategies

“…Two main targets of these theories are mineralocorticoid receptors and the enzyme 1β-hydroxysteroid dehydrogenase (11β-HSD). 24,25 Mineralocorticoid receptors have been identified in the choroid plexus (CP) epithelium and they function in a way similar to their role in the kidney, through activation of Na/K ATPase, altering the composition of CSF, while high GC levels are known to activate mineralocorticoid receptors. The enzyme 1β-hydroxysteroid dehydrogenase (11β-HSD) is also expressed in CP epithelium and its normal function is to activate cortisol from cortisone (11β-HSD1) or vice versa (11β-HSD2).…”