Fig. 3: Small-molecule targeting of Rev-erbα alleviates acute and chronic seizures.

a Effects of SR8278 pretreatment (25 mg/kg, i.p.) on seizure stages of wild-type (WT) mice induced by kainic acid (KA, 20 mg/kg, i.p.) at ZT6. P < 0.0001 (two-sided Kruskal–Wallis test). b Effects of SR8278 pretreatment on seizure parameters (severity, onset, and duration) of KA-induced acute seizure mice. Two-sided t test p values: p < 0.0001 (seizure severity); p < 0.0001 (onset); p < 0.0001 (seizure duration). c Representative EEG tracings in mice (pretreated with SR8278 or vehicle) before (3 h) and after (3 h) KA injection (20 mg/kg, i.p.). d FJB staining of hippocampus at 24 h after KA (20 mg/kg, i.p.) administration to WT mice pretreated with SR8278 (25 mg/kg, i.p.) or vehicle. Similar results were obtained in three independent experiments. e TUNEL staining of hippocampus at 24 h after KA (20 mg/kg, i.p.) administration to WT mice pretreated with SR8278 (25 mg/kg, i.p.) or vehicle. Similar results were obtained in three independent experiments. f Hippocampus NeuN and GFAP staining in mice (pretreated with SR8278 or vehicle) at 24 h after treatment with KA (20 mg/kg, i.p.). Similar results were obtained in three independent experiments. g Effects of SR8278 pretreatment (25 mg/kg, i.p.) on seizure stages of Rev-erbα^−/− and WT mice induced by KA (20 mg/kg, i.p.) at ZT6. Two-sided Kruskal–Wallis test p values: p < 0.0001 (ZT6); p = 0.1027 (ZT18). h Effects of SR8278 pretreatment (25 mg/kg, i.p.) on seizure severity of Rev-erbα^−/− and WT mice induced by KA (20 mg/kg, i.p.) at ZT6. P < 0.0001 (WT, seizure severity); p = 0.0893 (KO, seizure severity); p < 0.0001 (WT, onset); p = 0.0635 (KO, onset); p < 0.0001 (WT, seizure duration); p = 0.0643 (KO, seizure duration; two-way ANOVA followed by Bonferroni post hoc test). Scale bar = 50 μm. In a, b, g and h, data are presented as mean ± SEM. n = 6 mice per group. * represents a p value of <0.05. FJB Fluoro-Jade-B, n.s. no significant.