title: Reduced cortisol levels in cerebrospinal fluid and differential distribution of 11beta-hydroxysteroid dehydrogenases in multiple sclerosis: implications for lesion pathogenesis.
abstract: Relapses during multiple sclerosis (MS) are treated by administration of exogenous corticosteroids. However, little is known about the bioavailability of endogenous steroids in the central nervous system (CNS) of MS patients. We thus determined cortisol and dehydroepiandrosterone (DHEA) levels in serum and cerebrospinal fluid (CSF) samples from 34 MS patients, 28 patients with non-inflammatory neurological diseases (NIND) and 16 patients with other inflammatory neurological diseases (OIND). This revealed that MS patients - in sharp contrast to patients with OIND - show normal cortisol concentrations in serum and lowered cortisol levels in the CSF during acute relapses. This local cortisol deficit may relate to poor local activation of cortisone via 11beta-hydroxysteroid dehydrogenase type 1 (11bHSD1) or to inactivation via 11bHSD2. Accordingly, 11bHSD2 was found to be expressed within active plaques, whereas 11bHSD1 was predominantly detected in surrounding "foamy" macrophages. Our study thus provides new insights into the impaired endogenous CNS cortisol regulation in MS patients and its possible relation to MS lesion pathogenesis. Moreover, an observed upregulation of 11bHSD1 in myelin-loaded macrophages in vitro suggests an intriguing hypothesis for the self-limiting nature of MS lesion development. Finally, our findings provide an attractive explanation for the effectivity of high- vs. low-dose exogenous corticosteroids in the therapy of acute relapses.
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Heidbrink
authors.forename: Sebastian F M
authors.initials: SF
authors.lastname: Häusler
authors.forename: Mathias
authors.initials: M
authors.lastname: Buttmann
authors.forename: Monika
authors.initials: M
authors.lastname: Ossadnik
authors.forename: Herwig M
authors.initials: HM
authors.lastname: Strik
authors.forename: Andreas
authors.initials: A
authors.lastname: Keller
authors.forename: Dorothea
authors.initials: D
authors.lastname: Buck
authors.forename: Evert
authors.initials: E
authors.lastname: Verbraak
authors.forename: Marjan
authors.initials: M
authors.lastname: van Meurs
authors.forename: Mathias
authors.initials: M
authors.lastname: Krockenberger
authors.forename: Matthias
authors.initials: M
authors.lastname: Mehling
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Jörg
authors.initials: J
authors.lastname: Wischhusen
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis / Q000134:cerebrospinal fluid; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis / Q000134:cerebrospinal fluid; D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000134:cerebrospinal fluid*; D000328:Adult; D001921:Brain / Q000201:enzymology; D002452:Cell Count; D003687:Dehydroepiandrosterone / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D005487:Foam Cells / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000134:cerebrospinal fluid*; D007150:Immunohistochemistry; D008264:Macrophages / Q000201:enzymology; D008297:Male; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid* / Q000201:enzymology / Q000473:pathology*; D009185:Myelin Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D009185:Myelin Proteins; D003687:Dehydroepiandrosterone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone