Neuroprotection and reduced proliferation of microglia in ribavirin-treated bornavirus-infected rats

Abstract

In a rat model of Borna disease, intracerebral ribavirin caused clinical improvement without changes in virus titer or nucleic acid. Levels of microglia and infiltrating CD4 and CD8 cells were decreased, despite increases in mRNAs encoding interleukin-1beta (IL-1beta), IL-10, and gamma interferon in the brain. Intracerebral ribavirin may reduce morbidity through effects on microglia cell proliferation.

FIG. 1.

Clinical effects of ribavirin treatment of BDV-infected rats. (A) Body weights, plotted against experimental days, of infected rats receiving ribavirin at 1.25 or 2.5 mg/kg/day or a vehicle control (0-mg/kg/day dose). Body weight was significantly increased in the 2.5-mg/kg/day ribavirin treatment group in comparison with the 0-mg/kg/day dose group. Individual means comparisons revealed a significant increase on the seventh (last) day of treatment (∗, P < 0.05). The values shown are means ± the standard error of the mean. (B) Clinical scores of infected rats receiving ribavirin at 1.25 or 2.5 mg/kg/day or a vehicle control (0-mg/kg/day dose). Clinical scores were improved in the ribavirin-treated groups, with a maximal effect between the 2.5- and 0-mg/kg/day dose groups (∗∗, P < 0.01).

FIG. 2.

Reduction in the numbers of CD4, CD8, and microglia cells in PFCs of BDV-infected rats treated with ribavirin. Twenty-micrometer coronal sections through the PFCs of vehicle control (A, C, and E)- or ribavirin (B, D, and F)-treated rats were immunostained with the mouse W3/25 (A and B), OX-8 (C and D), and OX-42 (E and F) monoclonal antibodies; a biotinylated secondary antibody; and 3,3′-diaminobenzidine. A and B, reduced numbers of perivascular CD4 cells with ribavirin treatment; C and D, reduced numbers of perivascular and parenchymal CD8 cells with ribavirin treatment; E and F, reduced numbers of microglia cells with ribavirin treatment. Magnification, ×100.

FIG. 3.

Cytokine expression in the PFCs of rats infected with BDV and treated with ribavirin at 1.25 or 2.5 mg/kg/day or a vehicle control (0-mg/kg/day dose). Cytokine factor mRNAs were detected by multiprobe RNase protection assay and quantitated by phosphorimaging. Significant increases in IL-1β, IL-10, and IFN-γ levels were observed in the 2.5-mg/kg/day ribavirin treatment group, compared to the 0-mg/kg/day dose group. The values shown are mean optical densities in arbitrary units ± the standard error of the mean. Groups were analyzed by ANOVA, followed by pairwise t-test comparisons. ∗, P < 0.05; ∗∗∗, P < 0.0001 (relative to the 0-mg/kg/day dose group).