The effect of exendin-4 (Ex-4) and Ex-4-loaded poly(D,L-lactide-co-glycolide) microspheres (PEx-4) on carotid artery occlusion (CAO)-induced oxidative stress and endoplasmic reticulum stress in control and diabetes mellitus (DM) rats. (A) The apparatus used for real-time and continuous measurement of cerebral O2− responses in the rat. The exposed rat brain was positioned under the detector for direct measurement of O2−. The resulting in vivo real-time original data and statistical data are shown for the eight groups (n=6 each). When compared with control rats (102±10 counts/10 seconds), the O2− level was significantly increased in DM (358±49 counts/10 seconds, P=0.019), CAO (1259±168 counts/10 s, P<0.001), and DM+CAO (1986±259 counts/10 seconds, P<0.001) rats. The O2− level from the brain surface in DM+CAO rats was higher (P=0.0041) than that of CAO rats. PEx-4 decreased the O2− level more effectively than Ex-4 in CAO and DM+CAO rats. (B) NADPH oxidase gp91 and CCAAT/-enhancer-binding protein homologous protein (CHOP) expression in the control and DM rat cerebral cortex after CAO injury were evaluated by immunohistochemistry and immunofluorescence (n=6 each). Brown gp91 staining (B1–B6) and green fluorescence of the CHOP (B6–B12) were observed in the brain sections from the DM, CAO, and DM+CAO groups. There were low expression levels of gp91 and CHOP in control rat brains. Expression levels of gp91 and CHOP expression were significantly increased in comparison with control rats. PEx-4 treatment depressed gp91 and CHOP expression more effectively than Ex-4 treatment in CAO and DM+CAO rats. (C) Western blotting for gp91 and CHOP protein expression in the eight groups (n=4 each). DM, CAO, and DM+CAO significantly enhanced gp91 and CHOP expression. PEx-4 treatment inhibited gp91 and CHOP expression more effectively than Ex-4 treatment in CAO and DM+CAO rats. Group differences were compared by one-way analysis of variance, followed by Tukey's multiple comparison tests. P<0.05 indicates a significant difference. *Different from control (Con); #different from DM; +different from CAO; adifferent from DM+CAO; bdifferent from the Ex-4-treated group.