title: A novel permissive role for glucocorticoids in induction of febrile and behavioral signs of experimental herpes simplex virus encephalitis.
abstract: Herpes simplex virus type 1 (HSV-1) encephalitis may present with fever and behavioral changes, to the extent of a psychotic state and psychomotor agitation. We developed a clinically relevant experimental model of HSV-1 encephalitis and investigated host brain responses associated with its clinical signs and whether these responses depend on the presence of circulating glucocorticoids. Intracerebral inoculation of HSV-1 in rats induced fever, motor hyperactivity and aggressive behavior. In adrenalectomized rats HSV-1 failed to induce these signs, although mortality rate was identical to sham-operated rats. Hypophysectomy or blocking glucocorticoid receptors also prevented HSV-1-induced fever. Dexamethasone replacement therapy to adrenalectomized rats restored the HSV-1-induced fever and behavioral abnormalities. HSV-1 inoculation produced hyperproduction of prostaglandin E(2) by brain slices. This effect was abolished in adrenalectomized rats and was restored by dexamethasone treatment. In intact rats HSV-1 induced brain interleukin-1beta (IL-1beta) gene expression. Adrenalectomy alone caused brain IL-1beta expression, which did not increase after HSV-1 infection. Similarly, HSV-1 induced IL-1beta expression in astrocyte cultures. Removal of cortisol from the culture medium caused basal IL-1beta mRNA expression which was not increased by infection. In conclusion, fever, motor hyperactivity and aggressive behavior during experimental HSV-1 encephalitis are dependent on brain responses, including prostaglandin E(2) and IL-1beta synthesis. Circulating glucocorticoids play an essential permissive role in the induction of these host brain responses.
authors.affiliation: Department of Neurology, Hadassah Hebrew University Hospital, Jerusalem, Israel. tamir@hadassah.org.il
authors.forename: T
authors.initials: T
authors.lastname: Ben-Hur
authors.forename: R
authors.initials: R
authors.lastname: Cialic
authors.forename: A
authors.initials: A
authors.lastname: Itzik
authors.forename: O
authors.initials: O
authors.lastname: Barak
authors.forename: R
authors.initials: R
authors.lastname: Yirmiya
authors.forename: J
authors.initials: J
authors.lastname: Weidenfeld
mesh_terms: D000315:Adrenalectomy; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D015232:Dinoprostone / Q000502:physiology; D020803:Encephalitis, Herpes Simplex / Q000150:complications* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology*; D005334:Fever / Q000209:etiology*; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology*; D018259:Herpesvirus 1, Human; D007016:Hypophysectomy; D007375:Interleukin-1 / Q000235:genetics; D008297:Male; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors
chemical_list: D005938:Glucocorticoids; D007375:Interleukin-1; D011965:Receptors, Glucocorticoid; D015232:Dinoprostone