Delayed but not early glucocorticoid treatment protects the host during experimental herpes simplex virus encephalitis in mice

Background. Glucocorticoids (GCs) have not been established as an evidence-based therapy for herpes simplex virus (HSV) encephalitis. We sought to evaluate the effects of early versus delayed GC administration in a model of HSV-1 encephalitis. Methods. Mice were inoculated intranasally with a clinical HSV-1 strain and had access to corticosterone (Cort; 0.2 mg/mL) in drinking water or received dexamethasone (DEX; 10 mg/kg) intraperitoneally. Cort was started immediately or 72 h after infection, whereas DEX was administrated 3 days after infection. Results. Expression of the thymidine kinase transcript indicated widespread viral replication in the brain stem and many regions of the mediovestibular system. This neurovirulence provoked neuronal death and transcriptional activation of several immune genes. Notably, Toll-like receptors 2, 3, and 9 transcripts were strongly up-regulated. Mean life expectancy was higher in the group of mice that received delayed Cort (56%) than in the mice that received no Cort (44%) or early Cort treatments (13%) (P < .05, early vs. delayed or no Cort treatments). Delayed DEX treatment suppressed not only the expression of inflammatory genes as expected but also that of viral genes. Conclusions. Administration of GCs at a critical time during viral infection is associated with neuroprotection and survival in experimental HSV-1 encephalitis.