The effect of herpes simplex virus-1 on nitric oxide synthase in the rat brain: the role of glucocorticoids.
OBJECTIVE
Herpes simplex virus-1 (HSV-1) is a common cause of viral encephalitis manifested by activation of the adrenocortical axis, fever and behavioral changes. We investigated the early effects of HSV-1 on constitutive (c) and inducible (i) nitric oxide synthase (NOS) activity in rat brain and in mixed glial cell culture. The effect of glucocorticoids (GCs) on NOS responses to HSV-1 was also determined.


METHODS
NOS activity was evaluated by the conversion of ³H-arginine to ³H-citrulline. Nitrites were measured in supernatants of activated glial cells.


RESULTS
Under basal conditions, the highest cNOS activity was found in the cerebellum, while activity was much lower in the pons and negligible in the hypothalamus and hippocampus. Forty-eight hours after intracerebral injection of HSV-1, serum corticosterone was increased and NOS activity in the cerebellum and pons was inhibited. Adrenalectomy had no effect on the basal NOS activity but completely abrogated the inhibitory effect of HSV-1. Administration of the iNOS inhibitor aminoguanidine did not significantly change NOS activity, suggesting that the activity found in the cerebellum and pons can be attributed to the cNOS isoform. In mixed glial cell culture infected with HSV-1 and then activated with lipopolysaccharide, NOS activity and nitrite production were inhibited by 77 and 53%, respectively.


CONCLUSIONS
These results suggest that brain NOS activity is inhibited in the early stages of HSV-1 infection and requires the presence of circulating GCs. HSV-1-induced brain NOS inhibition may play a role in neuronal viral invasion and in the activation of the adrenocortical axis.
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel.
Joseph
J
Hasson
Joseph
J
Weidenfeld
Rachel
R
Mizrachi-Kol
Tamir
T
Ben-Hur
Haim
H
Ovadia
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000821:virology; D003345:Corticosterone / Q000097:blood; D020803:Encephalitis, Herpes Simplex / Q000378:metabolism*; D005938:Glucocorticoids / Q000097:blood*; D018259:Herpesvirus 1, Human; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D051381:Rats
D005938:Glucocorticoids; D007527:Isoenzymes; D019001:Nitric Oxide Synthase; D003345:Corticosterone