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. 2025 May 21;122(21):e2417224122. doi: 10.1073/pnas.2417224122

Fig. 4.

Fig. 4.

15-PGDH inhibition protects mice from TBI-induced cognitive impairment, oxidative stress, neurodegeneration, and BBB damage. (A) Schematic diagram of experimental procedure for evaluating the protective efficacy of (+)-SW033921-mediated 15-PGDH inhibition in TBI. 8-wk-old mice were administered multimodal TBI on day 0, and 24 h later started on a 21 d regimen of twice daily (+)-SW03391 (5 mg/kg × 2 = 10 mg/kg/day). MWM testing was conducted between days 14 and 18, and brain tissue was harvested for analysis on day 21. (B) Post–TBI administration of (+)-SW033291, initiated 24 h after injury and continued for 2 wk, inhibited brain 15-PGDH activity (****P < 0.0001, unpaired t test). (C) Vehicle-treated TBI-injured mice show significantly worse memory than sham-injury mice, as evidenced by significantly greater latency time to cross the platform area in the MWM probe test of memory. Treatment of TBI mice with (+)-SW033921 completely prevented post–TBI memory impairment (Interaction P < 0.01, ****P < 0.0001, two-way ANOVA and Tukey’s post hoc analysis). (D) Vehicle-treated TBI-injured mice showed significantly worse memory than sham-injury mice, as shown by a significantly lower number of platform area crossings on the MWM probe test of memory. Treatment of TBI mice with (+)-SW033921 prevented post–TBI memory impairment. (Interaction P < 0.05, **P < 0.01, two-way ANOVA and Tukey’s post hoc analysis). (E) TBI induces axonal degeneration, which was reversed by 15-PGDH pharmacologic inhibition with (+)-SW03329. Axonal degeneration was visualized and quantified by silver staining analysis, using percent positive area. (**P < 0.01, one-way ANOVA and Tukey’s post hoc analysis, (Scale bar, 5 µm). (Each dot represents average value from one mouse as determined from 6 images/mouse). (F) TEM analysis and its quantification show that TBI-induced structural BBB damage, as evidenced by swelling of astrocyte endfeet, was blocked by 15-PGDH pharmacologic inhibition with (+)-SW033291 (****P < 0.0001, one-way ANOVA and Tukey’s post hoc analysis). (G) 3-NT staining and its quantification show that TBI-induced oxidative stress, as evidenced by increased 3-NT, was blocked by 15-PGDH pharmacologic inhibition with (+)-SW033291 (***P < 0.001, ****P < 0.0001, one-way ANOVA and Tukey’s post hoc analysis; 2 to 3 brain sections/mouse). (H) Schematic diagram of experimental procedure for evaluating the protective efficacy of genetic 15-PGDH inhibition in TBI. Control 8-wk-old Hpgd+/+ (WT) and Hpgd−/− (KO) mice were subjected to multimodal TBI. Brain tissue was harvested for analysis 3 wk after TBI. (I) TBI induces axonal degeneration, which was reversed by biallelic Hpgd gene deletion (Hpgd−/−). Axonal degeneration was visualized and quantified by silver staining analysis, using percent positive area. (**P < 0.01, ***P < 0.001, one-way ANOVA and Tukey’s post hoc analysis, (Scale bar, 5 µm). (Each dot represents average value from one mouse as determined from 6 images/mouse). (J) Electron microscopy analysis and its quantification show that TBI-induced structural BBB damage, as evidenced by swelling of astrocyte endfeet, was blocked by biallelic Hpgd gene deletion (Hpgd−/−) (****P < 0.0001, one-way ANOVA and Tukey’s post hoc analysis). (K) 3-NT staining and its quantification show that TBI-induced oxidative stress, as evidenced by increased 3-NT, was blocked by biallelic Hpgd gene deletion (Hpgd−/−) (****P < 0.0001, one-way ANOVA and Tukey’s post hoc analysis; 2 to 3 brain sections/mouse). In all graphs (A–K), data points indicate values of individual mice.