title: Glucocorticoid resistance following herpes simplex-1 infection: role of hippocampal glucocorticoid receptors.
abstract: Herpes simplex-1 (HSV-1) is a sporadic cause of viral encephalitis. We have previously demonstrated that corneal HSV inoculation markedly activates the hypothalamo-pituitary-adrenal (HPA) axis. This activation depends on host derived brain interleukine-1 and was resistant to pretreatment with dexamethasone (dex), possibly because immune factors such as pro-inflammatory cytokines can modify the binding capacity of glucocorticoids in the hippocampus. In the present study, we examined whether resistance of the HPA axis activation following intracerebral HSV-1 infection to dex-induced suppression is associated with modifications in hippocampal or pituitary glucocorticoids (GC) receptors or GC receptors in cultured astrocytes. Male rats were injected intracerebroventricularly with purified HSV-1 or vehicle. 48 h later, dex or vehicle was injected intraperitoneally. Rats were sacrificed 3.5 h later. ACTH and corticosterone (CS) were measured in the serum. Specific binding of 3H-dex was measured in the cytosolic fraction of the hippocampus and the pituitary. Dex failed to reduce ACTH and CS responses to HSV-1 infection. In contrast, dex significantly reduced ACTH and CS responses to acoustic neural stimuli. Infection with HSV-1 markedly reduced the hippocampal maximal specific binding of dex with no effect on the dissociation constant (Kd) values. HSV-1 had no effect on the binding of dex in the pituitary. Infection of cultured astrocytes with HSV-1 also reduced the maximal specific binding of dex, but increased the Kd value. The results suggest that HSV-1 induced GC resistance may be mediated by downregulation of GC receptors in hippocampal tissue. These results may clarify a mechanism responsible for GC resistance following immune challenges.
authors.affiliation: Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Dafna
authors.initials: D
authors.lastname: Bener
authors.forename: Avital
authors.initials: A
authors.lastname: Wohlman
authors.forename: Anna
authors.initials: A
authors.lastname: Itzik
authors.forename: Raz
authors.initials: R
authors.lastname: Yirmiya
authors.forename: Tamir
authors.initials: T
authors.lastname: Ben-Hur
authors.forename: Joseph
authors.initials: J
authors.lastname: Weidenfeld
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D005938:Glucocorticoids / Q000494:pharmacology*; D006561:Herpes Simplex / Q000150:complications*; D018259:Herpesvirus 1, Human; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology; D008297:Male; D011485:Protein Binding; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone