Fig. 9

The neuroprotective function of FG4592 is attenuated by UPR inhibiting. A Representative TTC images corresponding to coronal brain sections from mice treated with vehicle (n = 12), FG4592 (5 mg/kg, n = 11), FG4592 + 4-PBA (inhibitor of ER stress, 42 mg/kg, n = 12) and 4-PBA (42 mg/kg, n = 10) on one day after tMCAO. 4-PBA was injected 1 hour before surgery. All experimental groups underwent 1 hour of tMCAO and 24 hours of reperfusion. Layer thickness = 1 mm, scar bar = 1 cm. B and C The infarct volumes (one-way ANOVA followed by Dunnett’s post-hoc test) and mNSS score (non-parametric Kruskal-Wallis test followed by Dunn’s post-hoc) were assessed 24 hours after reperfusion. Data are presented as mean ± SEM, vehicle vs FG4592: ***p < 0.001, *p < 0.01. FG4592 vs FG4592+4-PBA or 4-PBA: ###p < 0.001, ##p < 0.01, #p < 0.01. D-F Representative immunoblots and bar graphs of sATF6, sXBP1, p-eif2α, Beclin-1, LC3-II and p62 in peri-infarct tissue of mouse brains after 24 hours of tMCAO. The data are expressed as mean ± SEM. Sham vs vehicle or FG4592: ***p < 0.001, **p < 0.01, *p < 0.05. vehicle vs FG4592: ###p < 0.001, ##p < 0.01, #p < 0.05, FG4592 vs FG4592+4-PBA or 4-PBA: †††p < 0.001, †p < 0.05 (one-way ANOVA followed by the Dunnett’s post-hoc test. n = 6). G The schematic diagram for the activation role of FG4592 in UPR. The activation of UPR by FG4592 may involve two pathways. Namely, FG4592 can activate the UPR via inhabiting its novel target OGFOD1 or possibly inhibiting the classical target PHD2. The activation of UPR subsequently promotes autophagy and alleviates I/R injury