Fig. 6

Inhibition of SARM1 by FK866 or SIC4 alleviates neuropathology and brain inflammation in neurotropic viruses-infected mice. Eight-week-old mouse pups were intracranially infected with 2 × 10⁶ PFU of JEV or HSV-1, or 2 × 10⁶ TCID₅₀ of RABV in 0.5 µl, or mock-infected, and subsequently treated twice a day with FK866 (20 mg/kg, i.p.), SIC4 (20 mg/kg, i.p.), or vehicle (PEG-300/PBS/DMSO). (A-C) Survival curves of JEV (A), HSV-1 (B), RABV (C)- and mock-infected mice treated with FK866, SIC4, or control vehicle (n = 6 for each mock-infected; n = 18 for each neurotropic virus infection group). (D) Pathological scores of the cerebral cortex sections. (E) Quantitative analysis of the number of NeuN⁺ cells of JEV (5 dpi), HSV-1 (5 dpi), RABV (8 dpi) or mock-infected mice treated with FK866, SIC4 or vehicle. (F) Quantitative analysis of density of Nissl bodies in the mouse cerebral cortex. Mice were infected and treated as above described. (G) Double immunostaining P2RY12 (red) and GFAP (green) in coronal cerebral cortex slices of JEV (5 dpi), HSV-1 (5 dpi), RABV (8 dpi) or mock-infected mice treated with FK866, SIC4 or vehicle (n = 5 per group). (H and I) Area fraction occupied by P2RY12⁺ (H) and GFAP⁺ (I) cells and the average density in the same area; data shown as fold change (FC) relative to mock-infected mice, with one dot being one mouse. (J) Flow cytometric analysis of cerebral cortex infiltration of CD45⁺ cells 5 days after JEV or mock infection of mouse brain tissues. (K) Bar graphs show the number of leukocytes expressing CD45 in the cerebral cortex of JEV (5 dpi), HSV-1 (5 dpi), RABV (8 dpi) or mock-infected mice treated with FK866, SIC4 or vehicle (n = 4 per group). All data are presented as mean ± SEM, and statistical significance was determined using one-way ANOVA test. Kaplan-Meier survival curves of animals infected with these viruses using a log-rank test are shown. ns, not significant. *P < 0.05, **P < 0.01, ***P < 0.001