Glucocorticoid and type 1 interferon interactions at the blood-brain barrier: relevance for drug therapies for multiple sclerosis.
The pharmacological effect of glucocorticoids and type 1 interferons (IFNs), simultaneously used as therapeuticals for multiple sclerosis (MS), on the (inflamed) blood-brain barrier (BBB) was investigated in vitro. Although both drugs additively decreased BBB permeability, they did not prevent the increase in BBB permeability induced by lipopolysaccharide (LPS), which served as a pro-inflammatory stimulus. The beneficial clinical effect of glucocorticoid and IFN therapy for MS seems there- fore not to be mediated through a direct action at the level of the BBB. Most strikingly, however, pretreatment with type 1 IFNs (alpha and beta) potentiated the effect of glucocorticoids by two orders of magnitude. This lead us to hypothesize that type 1 IFNs may restore the dysfunctional T-helper 1 (Th1)/Th2 balance associated with MS, by a mechanism that involves an increased sensitivity for glucocorticoids.
Gaillard
P J
PJ
Department of Pharmacology, Leiden/Amsterdam Center for Drug Research (LACDR), Leiden University, Sylvius Laboratory, P.O. Box 9503, 2300 RA Leiden, The Netherlands.
van Der Meide
P H
PH
de Boer
A G
AG
Breimer
D D
DD
D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D002417:Cattle; D003345:Corticosterone / Q000494:pharmacology* / Q000627:therapeutic use; D004347:Drug Interactions / Q000502:physiology; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000494:pharmacology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar
D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D005938:Glucocorticoids; D007370:Interferon Type I; D008070:Lipopolysaccharides; D003345:Corticosterone